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Li X, Zhou F, Niu K, Wang Y, Shi Y, Li Y, Gao X, Zhao W, Chen T, Zhang Y. Emerging discoveries on the role of TRIM14: from diseases to immune regulation. Cell Death Discov 2024; 10:513. [PMID: 39719450 DOI: 10.1038/s41420-024-02276-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/04/2024] [Accepted: 12/16/2024] [Indexed: 12/26/2024] Open
Abstract
TRIM14 is an important member of the TRIM family and is widely expressed in a variety of tissues. Like other members of the TRIM family, TRIM14 is also involved in ubiquitination modifications. TRIM14 was initially reported as an interferon-stimulated gene (ISG). In recent years, many studies have focused on the regulatory role of TRIM14 in signaling pathways such as the PI3K/Akt, NF-κB, and cGAS/STING pathways and revealed its mechanism of action in a variety of pathophysiological processes, and the regulation of TRIM14 has attracted the interest of many researchers as a new direction for the treatment of various diseases. However, there are no reviews on the role of TRIM14 in diseases. In this paper, we will describe the structure of TRIM14, review its role in cancer, cardiovascular disease, cervical spondylosis, inflammation and antiviral immunity, and provide an outlook on future research directions.
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Affiliation(s)
- Xinhao Li
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Feilong Zhou
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Kaiyi Niu
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yizhu Wang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yanlong Shi
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yunxin Li
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xin Gao
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Weijie Zhao
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Tianyi Chen
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yewei Zhang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
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Zhang C, Chen T, Li Z, Lu Q, Luo X, Cai S, Zhou J, Ren J, Cui J. DSCI: a database of synthetic biology components for innate immunity and cell engineering decision-making processes. ADVANCED BIOTECHNOLOGY 2024; 2:29. [PMID: 39883249 PMCID: PMC11740867 DOI: 10.1007/s44307-024-00036-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/12/2024] [Accepted: 08/22/2024] [Indexed: 01/31/2025]
Abstract
Although significant progress of clinical strategy has been made in gene editing and cell engineering in immunotherapy, it is now apparent that design and modification in terms of complex signaling pathways and motifs on medical synthetic biology are still full of challenges. Innate immunity, the first line of host defense against pathogens, is critical for anti-pathogens immune response as well as regulating durable and protective T cell-mediated anti-tumor responses. Here, we introduce DSCI (Database of Synthetic Biology Components for Innate Immunity, https://dsci.renlab.cn/ ), a web-accessible and integrative database that provides better insights and strategies for innate immune signaling circuit design in biosynthesis. Users can interactively navigate comprehensive and carefully curated components resources that presented as visualized signaling motifs that participate in innate immunity. The current release of DSCI incorporates 1240 independent components and more than 4000 specific entries contextually annotated from public literature with experimental verification. The data integrated into DSCI includes the components of pathways, relationships between regulators, signal motifs based on regulatory cascades, and loop graphs, all of which have been comprehensively annotated to help guide modifications to gene circuits. With the support of DSCI, users can easily obtain guidance of gene circuits construction to make decision of cell engineering based on innate immunity. DSCI not only provides comprehensive and specialized resource on the biological components of innate immune synthesis, but also serves as a useful tool to offer modification or generation strategies for medical synthetic biology.
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Affiliation(s)
- Chenqiu Zhang
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
| | - Tianjian Chen
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
| | - Zhiyu Li
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
| | - Qing Lu
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
| | - Xiaotong Luo
- State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China
| | - Sihui Cai
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
| | - Jie Zhou
- State Key Laboratory of Membrane Biology & Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, 100101, China
- Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, 100101, China
| | - Jian Ren
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China.
- State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
| | - Jun Cui
- MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China.
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3
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Oh S, Mandell MA. Regulation of Mitochondria-Derived Immune Activation by 'Antiviral' TRIM Proteins. Viruses 2024; 16:1161. [PMID: 39066323 PMCID: PMC11281404 DOI: 10.3390/v16071161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Mitochondria are key orchestrators of antiviral responses that serve as platforms for the assembly and activation of innate immune-signaling complexes. In response to viral infection, mitochondria can be triggered to release immune-stimulatory molecules that can boost interferon production. These same molecules can be released by damaged mitochondria to induce pathogenic, antiviral-like immune responses in the absence of infection. This review explores how members of the tripartite motif-containing (TRIM) protein family, which are recognized for their roles in antiviral defense, regulate mitochondria-based innate immune activation. In antiviral defense, TRIMs are essential components of immune signal transduction pathways and function as directly acting viral restriction factors. TRIMs carry out conceptually similar activities when controlling immune activation related to mitochondria. First, they modulate immune-signaling pathways that can be activated by mitochondrial molecules. Second, they co-ordinate the direct removal of mitochondria and associated immune-activating factors through mitophagy. These insights broaden the scope of TRIM actions in innate immunity and may implicate TRIMs in diseases associated with mitochondria-derived inflammation.
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Affiliation(s)
- Seeun Oh
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA;
| | - Michael A. Mandell
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA;
- Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
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Schäfer A, Gralinski LE, Leist SR, Hampton BK, Mooney MA, Jensen KL, Graham RL, Agnihothram S, Jeng S, Chamberlin S, Bell TA, Scobey DT, Linnertz CL, VanBlargan LA, Thackray LB, Hock P, Miller DR, Shaw GD, Diamond MS, de Villena FPM, McWeeney SK, Heise MT, Menachery VD, Ferris MT, Baric RS. Genetic loci regulate Sarbecovirus pathogenesis: A comparison across mice and humans. Virus Res 2024; 344:199357. [PMID: 38508400 PMCID: PMC10981091 DOI: 10.1016/j.virusres.2024.199357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/15/2024] [Accepted: 03/16/2024] [Indexed: 03/22/2024]
Abstract
Coronavirus (CoV) cause considerable morbidity and mortality in humans and other mammals, as evidenced by the emergence of Severe Acute Respiratory CoV (SARS-CoV) in 2003, Middle East Respiratory CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. Although poorly characterized, natural genetic variation in human and other mammals modulate virus pathogenesis, as reflected by the spectrum of clinical outcomes ranging from asymptomatic infections to lethal disease. Using multiple human epidemic and zoonotic Sarbecoviruses, coupled with murine Collaborative Cross genetic reference populations, we identify several dozen quantitative trait loci that regulate SARS-like group-2B CoV pathogenesis and replication. Under a Chr4 QTL, we deleted a candidate interferon stimulated gene, Trim14 which resulted in enhanced SARS-CoV titers and clinical disease, suggesting an antiviral role during infection. Importantly, about 60 % of the murine QTL encode susceptibility genes identified as priority candidates from human genome-wide association studies (GWAS) studies after SARS-CoV-2 infection, suggesting that similar selective forces have targeted analogous genes and pathways to regulate Sarbecovirus disease across diverse mammalian hosts. These studies provide an experimental platform in rodents to investigate the molecular-genetic mechanisms by which potential cross mammalian susceptibility loci and genes regulate type-specific and cross-SARS-like group 2B CoV replication, immunity, and pathogenesis in rodent models. Our study also provides a paradigm for identifying susceptibility loci for other highly heterogeneous and virulent viruses that sporadically emerge from zoonotic reservoirs to plague human and animal populations.
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Affiliation(s)
- Alexandra Schäfer
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Lisa E Gralinski
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Sarah R Leist
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Brea K Hampton
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Michael A Mooney
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, OR, USA; Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA
| | - Kara L Jensen
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Rachel L Graham
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sudhakar Agnihothram
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sophia Jeng
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - Steven Chamberlin
- Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, OR, USA; Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA
| | - Timothy A Bell
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - D Trevor Scobey
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Colton L Linnertz
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Laura A VanBlargan
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Larissa B Thackray
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Pablo Hock
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Darla R Miller
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ginger D Shaw
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Michael S Diamond
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology & Immunology2, Washington University School of Medicine, St. Louis, MO, USA; Department of Molecular Microbiology3, Washington University School of Medicine, St. Louis, MO, USA
| | - Fernando Pardo Manuel de Villena
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Shannon K McWeeney
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA; Division of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, OR, USA; Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA; Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR, USA
| | - Mark T Heise
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina, Chapel Hill NC, USA
| | - Vineet D Menachery
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston TX, USA; Department of Pathology and Center for Biodefense & Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, USA
| | - Martin T Ferris
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Ralph S Baric
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina, Chapel Hill NC, USA.
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5
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Bynigeri RR, Malireddi RKS, Mall R, Connelly JP, Pruett-Miller SM, Kanneganti TD. The protein phosphatase PP6 promotes RIPK1-dependent PANoptosis. BMC Biol 2024; 22:122. [PMID: 38807188 PMCID: PMC11134900 DOI: 10.1186/s12915-024-01901-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 04/23/2024] [Indexed: 05/30/2024] Open
Abstract
BACKGROUND The innate immune system serves as the first line of host defense. Transforming growth factor-β-activated kinase 1 (TAK1) is a key regulator of innate immunity, cell survival, and cellular homeostasis. Because of its importance in immunity, several pathogens have evolved to carry TAK1 inhibitors. In response, hosts have evolved to sense TAK1 inhibition and induce robust lytic cell death, PANoptosis, mediated by the RIPK1-PANoptosome. PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. While PANoptosis can be beneficial to clear pathogens, excess activation is linked to pathology. Therefore, understanding the molecular mechanisms regulating TAK1 inhibitor (TAK1i)-induced PANoptosis is central to our understanding of RIPK1 in health and disease. RESULTS In this study, by analyzing results from a cell death-based CRISPR screen, we identified protein phosphatase 6 (PP6) holoenzyme components as regulators of TAK1i-induced PANoptosis. Loss of the PP6 enzymatic component, PPP6C, significantly reduced TAK1i-induced PANoptosis. Additionally, the PP6 regulatory subunits PPP6R1, PPP6R2, and PPP6R3 had redundant roles in regulating TAK1i-induced PANoptosis, and their combined depletion was required to block TAK1i-induced cell death. Mechanistically, PPP6C and its regulatory subunits promoted the pro-death S166 auto-phosphorylation of RIPK1 and led to a reduction in the pro-survival S321 phosphorylation. CONCLUSIONS Overall, our findings demonstrate a key requirement for the phosphatase PP6 complex in the activation of TAK1i-induced, RIPK1-dependent PANoptosis, suggesting this complex could be therapeutically targeted in inflammatory conditions.
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Affiliation(s)
- Ratnakar R Bynigeri
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - R K Subbarao Malireddi
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Raghvendra Mall
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
- Current affiliation: Biotechnology Research Center, Technology Innovation Institute, Abu Dhabi, United Arab Emirates
| | - Jon P Connelly
- Center for Advanced Genome Engineering (CAGE), St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Shondra M Pruett-Miller
- Center for Advanced Genome Engineering (CAGE), St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
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Hassan M, Yasir M, Shahzadi S, Chun W, Kloczkowski A. Molecular Role of Protein Phosphatases in Alzheimer's and Other Neurodegenerative Diseases. Biomedicines 2024; 12:1097. [PMID: 38791058 PMCID: PMC11117500 DOI: 10.3390/biomedicines12051097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/02/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024] Open
Abstract
Alzheimer's disease (AD) is distinguished by the gradual loss of cognitive function, which is associated with neuronal loss and death. Accumulating evidence supports that protein phosphatases (PPs; PP1, PP2A, PP2B, PP4, PP5, PP6, and PP7) are directly linked with amyloid beta (Aβ) as well as the formation of the neurofibrillary tangles (NFTs) causing AD. Published data reported lower PP1 and PP2A activity in both gray and white matters in AD brains than in the controls, which clearly shows that dysfunctional phosphatases play a significant role in AD. Moreover, PP2A is also a major causing factor of AD through the deregulation of the tau protein. Here, we review recent advances on the role of protein phosphatases in the pathology of AD and other neurodegenerative diseases. A better understanding of this problem may lead to the development of phosphatase-targeted therapies for neurodegenerative disorders in the near future.
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Affiliation(s)
- Mubashir Hassan
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA;
| | - Muhammad Yasir
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea; (M.Y.); (W.C.)
| | - Saba Shahzadi
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA;
| | - Wanjoo Chun
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea; (M.Y.); (W.C.)
| | - Andrzej Kloczkowski
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
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Sack T, Dhavarasa P, Szames D, O'Brien S, Angers S, Kelley SO. CRISPR Screening in Tandem with Targeted mtDNA Damage Reveals WRNIP1 Essentiality. ACS Chem Biol 2023; 18:2599-2609. [PMID: 38054633 DOI: 10.1021/acschembio.3c00620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2023]
Abstract
A major impediment to the characterization of mtDNA repair mechanisms in comparison to nuclear DNA repair mechanisms is the difficulty of specifically addressing mitochondrial damage. Using a mitochondria-penetrating peptide, we can deliver DNA-damaging agents directly to mitochondria, bypassing the nuclear compartment. Here, we describe the use of an mtDNA-damaging agent in tandem with CRISPR/Cas9 screening for the genome-wide discovery of factors essential for mtDNA damage response. Using mitochondria-targeted doxorubicin (mtDox), we generate mtDNA double-strand breaks (mtDSBs) specifically in this organelle. Combined with an untargeted doxorubicin (Dox) screen, we identify genes with significantly greater essentiality during mitochondrial versus nuclear DNA damage. We characterize the essentiality of our top hit, WRNIP1─observed here for the first time to respond to mtDNA damage. We further investigate the mitochondrial role of WRNIP1 in innate immune signaling and nuclear genome maintenance, outlining a model that experimentally supports mitochondrial turnover in response to mtDSBs.
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Affiliation(s)
- Tanja Sack
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada
| | - Piriththiv Dhavarasa
- Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Daniel Szames
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada
| | - Siobhan O'Brien
- Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Terrence Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada
| | - Stephane Angers
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada
- Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Terrence Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada
| | - Shana O Kelley
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada
- Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Department of Chemistry, Faculty of Arts and Science, University of Toronto, Toronto, Ontario M5S 3H6, Canada
- Department of Chemistry, Weinberg College of Arts & Sciences, Northwestern University, Evanston, Illinois 60208, United States
- Chan Zuckerberg Biohub Chicago, Chicago, Illinois 60607, United States
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8
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Kuroda M, Halfmann PJ, Thackray LB, Diamond MS, Feldmann H, Marzi A, Kawaoka Y. An Antiviral Role for TRIM14 in Ebola Virus Infection. J Infect Dis 2023; 228:S514-S521. [PMID: 37562033 PMCID: PMC10651195 DOI: 10.1093/infdis/jiad325] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/07/2023] [Accepted: 08/08/2023] [Indexed: 08/12/2023] Open
Abstract
Ebola virus (EBOV) is a highly pathogenic virus that encodes 7 multifunctional structural proteins. Multiple host factors have been reported to interact with the EBOV proteins. Here, we found that tripartite motif-containing 14 (TRIM14), an interferon-stimulated gene that mediates cellular signaling pathways associated with type I interferon and inflammatory cytokine production, interacts with EBOV nucleoprotein to enhance interferon-β (IFN-β) and nuclear factor-κB (NF-κB) promotor activation. Moreover, TRIM14 overexpression reduced viral replication in an infectious but biologically contained EBOVΔVP30 system by approximately 10-fold without affecting viral protein expression. Furthermore, TRM14-deficient mice were more susceptible to mouse-adapted EBOV infection than wild-type mice. Our data suggest that TRIM14 is a host factor with anti-EBOV activity that limits EBOV pathogenesis.
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Affiliation(s)
- Makoto Kuroda
- Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Peter J Halfmann
- Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Larissa B Thackray
- Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
| | - Michael S Diamond
- Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA
- Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri, USA
- The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, Missouri, USA
- Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, St Louis, Missouri, USA
| | - Heinz Feldmann
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
| | - Andrea Marzi
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
| | - Yoshihiro Kawaoka
- Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan
- Pandemic Preparedness, Infection and Advanced Research Center, University of Tokyo, Tokyo, Japan
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9
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Sack T, Dhavarasa P, Szames D, O'Brien S, Angers S, Kelley SO. CRISPR Screening in Tandem with Targeted mtDNA Damage Reveals WRNIP1 Essentiality. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.03.560559. [PMID: 37873237 PMCID: PMC10592966 DOI: 10.1101/2023.10.03.560559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
A major impediment to the characterization of mtDNA repair mechanisms, in comparison to nuclear DNA repair mechanisms, is the difficulty of specifically addressing mitochondrial damage. Using a mitochondria-penetrating peptide, we can deliver DNA-damaging agents directly to mitochondria, bypassing the nuclear compartment. Here, we describe the use of a mtDNA-damaging agent in tandem with CRISPR/Cas9 screening for the genome-wide discovery of factors essential for mtDNA damage response. Using mitochondria-targeted doxorubicin (mtDox) we generate mtDNA double-strand breaks (mtDSBs) specifically in this organelle. Combined with an untargeted Dox screen, we identify genes with significantly greater essentiality during mitochondrial versus nuclear DNA damage. We characterize the essentially of our top hit - WRNIP1 - observed here for the first time to respond to mtDNA damage. We further investigate the mitochondrial role of WRNIP1 in innate immune signaling and nuclear genome maintenance, outlining a model that experimentally supports mitochondrial turnover in response to mtDSBs.
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10
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Jordan BR, Zhai Y, Li Z, Zhao H, Mackmull MT, Glavy JS. Discovering the nuclear localization signal of Werner Helicase Interacting Protein 1. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119502. [PMID: 37268023 DOI: 10.1016/j.bbamcr.2023.119502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/23/2023] [Accepted: 05/18/2023] [Indexed: 06/04/2023]
Abstract
Our study maps the classic nuclear localization signal (cNLS) domain within WRNIP that directs the protein's nuclear positioning.
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Affiliation(s)
- Benjamin R Jordan
- Department of Pharmaceutical Sciences, Fisch College of Pharmacy, The University of Texas At Tyler, Tyler, TX, USA
| | - Yujia Zhai
- Stevens Institute of Technology, Hoboken, NJ, USA; Memorial Sloan Kettering Cancer Center, NY, NY, USA
| | - Zhi Li
- Stevens Institute of Technology, Hoboken, NJ, USA; New York University, Grossman School of Medicine, NY, NY, USA
| | | | - Marie-Therese Mackmull
- New York University, Grossman School of Medicine, NY, NY, USA; European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany; Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Joseph S Glavy
- Department of Pharmaceutical Sciences, Fisch College of Pharmacy, The University of Texas At Tyler, Tyler, TX, USA.
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11
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Ma X, Wang Q, Sun C, Agarwal I, Wu H, Chen J, Zhao C, Qi G, Teng Q, Yuan C, Yan S, Peng J, Li R, Song K, Zhang Q, Kong B. Targeting TCF19 sensitizes MSI endometrial cancer to anti-PD-1 therapy by alleviating CD8 + T cell exhaustion via TRIM14-IFN-β axis. Cell Rep 2023; 42:112944. [PMID: 37566545 DOI: 10.1016/j.celrep.2023.112944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 06/25/2023] [Accepted: 07/21/2023] [Indexed: 08/13/2023] Open
Abstract
Immune checkpoint blockade (ICB) therapies display clinical efficacy in microsatellite instable (MSI) endometrial cancer (EC) treatment, the key mechanism of which is reversing T cell exhaustion and restoration of anti-tumor immunity. Here, we demonstrate that transcription factor 19 (TCF19), one of the most significantly differentially expressed genes between MSI and microsatellite stable (MSS) patients in The Cancer Genome Atlas (TCGA)-EC cohort, is associated with poor prognosis and immune exhaustion signature. Specifically, TCF19 is significantly elevated in MSI EC, which in turn promotes tripartite motif-containing 14 (TRIM14) transcription and correlates with hyperactive signaling of the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3)-interferon β (IFN-β) pathway. The TCF19-TRIM14 axis promotes tumorigenicity under non-immunological background, and the enhanced downstream secretion of IFN-β facilitates CD8+ T cell exhaustion through cell differentiation reprogramming. Finally, using humanized models, we show that a combination of TCF19 inhibition and ICB therapy demonstrates more effective anti-tumor responses. Together, our study indicates that targeting TCF19 is a potent strategy for alleviating CD8+ T cell exhaustion and synergizing with ICB in tumor treatment.
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Affiliation(s)
- Xinyue Ma
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Qiuman Wang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Chenggong Sun
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Indu Agarwal
- Department of Pathology, Northwestern University, Chicago, IL 60208, USA
| | - Huan Wu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Jingying Chen
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Chen Zhao
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Gonghua Qi
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Qiuli Teng
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Cunzhong Yuan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Shi Yan
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Jiali Peng
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Rongrong Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Kun Song
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China
| | - Qing Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.
| | - Beihua Kong
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China; Gynecology Oncology Key Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong 250012, P.R. China.
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12
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Campbell LK, Peery RM, Magor KE. Evolution and expression of the duck TRIM gene repertoire. Front Immunol 2023; 14:1220081. [PMID: 37622121 PMCID: PMC10445537 DOI: 10.3389/fimmu.2023.1220081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 07/05/2023] [Indexed: 08/26/2023] Open
Abstract
Tripartite motif (TRIM) proteins are involved in development, innate immunity, and viral restriction. TRIM gene repertoires vary between species, likely due to diversification caused by selective pressures from pathogens; however, this has not been explored in birds. We mined a de novo assembled transcriptome for the TRIM gene repertoire of the domestic mallard duck (Anas platyrhynchos), a reservoir host of influenza A viruses. We found 57 TRIM genes in the duck, which represent all 12 subfamilies based on their C-terminal domains. Members of the C-IV subfamily with C-terminal PRY-SPRY domains are known to augment immune responses in mammals. We compared C-IV TRIM proteins between reptiles, birds, and mammals and show that many C-IV subfamily members have arisen independently in these lineages. A comparison of the MHC-linked C-IV TRIM genes reveals expansions in birds and reptiles. The TRIM25 locus with related innate receptor modifiers is adjacent to the MHC in reptile and marsupial genomes, suggesting the ancestral organization. Within the avian lineage, both the MHC and TRIM25 loci have undergone significant TRIM gene reorganizations and divergence, both hallmarks of pathogen-driven selection. To assess the expression of TRIM genes, we aligned RNA-seq reads from duck tissues. C-IV TRIMs had high relative expression in immune relevant sites such as the lung, spleen, kidney, and intestine, and low expression in immune privileged sites such as in the brain or gonads. Gene loss and gain in the evolution of the TRIM repertoire in birds suggests candidate immune genes and potential targets of viral subversion.
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Affiliation(s)
- Lee K. Campbell
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada
| | - Rhiannon M. Peery
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
- Department of Biology, Carleton University, Ottawa, ON, Canada
| | - Katharine E. Magor
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada
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13
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Yu B, Zhou Y, He J. TRIM13 inhibits cell proliferation and induces autophagy in lung adenocarcinoma by regulating KEAP1/NRF2 pathway. Cell Cycle 2023; 22:1496-1513. [PMID: 37245083 PMCID: PMC10281484 DOI: 10.1080/15384101.2023.2216504] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/21/2023] [Accepted: 03/22/2023] [Indexed: 05/29/2023] Open
Abstract
Lung adenocarcinoma (LUAD) is the most common type of lung cancer. Tripartite motif 13 (TRIM13) is a member of TRIM protein family and is downregulated in multiple cancers, especially non-small cell lung cancers (NSCLC). In this study, we investigated anti-tumor mechanism of TRIM13 in non-small cell lung cancer tissues and cell lines. First, the mRNA and protein levels of TRIM13 in LUAD tissue and cells were measured. TRIM13 was overexpressed on LUAD cells to investigate the effects on cell proliferation, apoptosis, oxidative stress, p62 ubiquitination, and autophagy activation. Finally, mechanistic role of TRIM13 in regulating the Keap1/Nrf2 pathway was investigated. Results indicated that low level of TRIM13 mRNA and protein expression was found in LUAD tissue and cells. Overexpression of TRIM13 in LUAD cancer cells suppressed their proliferation, increased apoptosis, and oxidative stress, ubiquitinated p62, and activated autophagy via the RING finger domain of TRIM13. Furthermore, TRIM13 showed interaction with p62 and mediated its ubiquitination and degradation in LUAD cells. Mechanistically, TRIM13 exerted the tumor suppressor functions in LUAD cells by negatively regulating Nrf2 signaling and downstream antioxidants, which was further confirmed by in vivo data from xenografts. In conclusion, TRIM13 behaves like a tumor suppressor and triggers autophagy in LUAD cells by mediating p62 ubiquitination via KEAP1/Nrf2 pathway. Our findings provide a novel insight into targeted therapy plans for LUAD.
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Affiliation(s)
- Bo Yu
- Department of thoracic surgery, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yu Zhou
- Department of Scientific Research, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Jinxi He
- Department of thoracic surgery, The General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
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14
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Casanova A, Wevers A, Navarro-Ledesma S, Pruimboom L. Mitochondria: It is all about energy. Front Physiol 2023; 14:1114231. [PMID: 37179826 PMCID: PMC10167337 DOI: 10.3389/fphys.2023.1114231] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/29/2023] [Indexed: 05/15/2023] Open
Abstract
Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases.
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Affiliation(s)
- Amaloha Casanova
- Department of Physiotherapy, University of Granada, Granada, Spain
- Faculty of Health Sciences, Melilla, Spain
- PNI Europe, The Hague, Netherlands
- Chair of Clinical Psychoneuroimmunology, University of Granada and PNI Europe, Granada, Spain
| | - Anne Wevers
- Department of Physiotherapy, University of Granada, Granada, Spain
- Faculty of Health Sciences, Melilla, Spain
- PNI Europe, The Hague, Netherlands
- Chair of Clinical Psychoneuroimmunology, University of Granada and PNI Europe, Granada, Spain
| | - Santiago Navarro-Ledesma
- Department of Physiotherapy, University of Granada, Granada, Spain
- Faculty of Health Sciences, Melilla, Spain
- PNI Europe, The Hague, Netherlands
- Chair of Clinical Psychoneuroimmunology, University of Granada and PNI Europe, Granada, Spain
| | - Leo Pruimboom
- PNI Europe, The Hague, Netherlands
- Chair of Clinical Psychoneuroimmunology, University of Granada and PNI Europe, Granada, Spain
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15
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Aslanyan MG, Doornbos C, Diwan GD, Anvarian Z, Beyer T, Junger K, van Beersum SEC, Russell RB, Ueffing M, Ludwig A, Boldt K, Pedersen LB, Roepman R. A targeted multi-proteomics approach generates a blueprint of the ciliary ubiquitinome. Front Cell Dev Biol 2023; 11:1113656. [PMID: 36776558 PMCID: PMC9908615 DOI: 10.3389/fcell.2023.1113656] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/17/2023] [Indexed: 01/27/2023] Open
Abstract
Establishment and maintenance of the primary cilium as a signaling-competent organelle requires a high degree of fine tuning, which is at least in part achieved by a variety of post-translational modifications. One such modification is ubiquitination. The small and highly conserved ubiquitin protein possesses a unique versatility in regulating protein function via its ability to build mono and polyubiquitin chains onto target proteins. We aimed to take an unbiased approach to generate a comprehensive blueprint of the ciliary ubiquitinome by deploying a multi-proteomics approach using both ciliary-targeted ubiquitin affinity proteomics, as well as ubiquitin-binding domain-based proximity labelling in two different mammalian cell lines. This resulted in the identification of several key proteins involved in signaling, cytoskeletal remodeling and membrane and protein trafficking. Interestingly, using two different approaches in IMCD3 and RPE1 cells, respectively, we uncovered several novel mechanisms that regulate cilia function. In our IMCD3 proximity labeling cell line model, we found a highly enriched group of ESCRT-dependent clathrin-mediated endocytosis-related proteins, suggesting an important and novel role for this pathway in the regulation of ciliary homeostasis and function. In contrast, in RPE1 cells we found that several structural components of caveolae (CAV1, CAVIN1, and EHD2) were highly enriched in our cilia affinity proteomics screen. Consistently, the presence of caveolae at the ciliary pocket and ubiquitination of CAV1 specifically, were found likely to play a role in the regulation of ciliary length in these cells. Cilia length measurements demonstrated increased ciliary length in RPE1 cells stably expressing a ubiquitination impaired CAV1 mutant protein. Furthermore, live cell imaging in the same cells revealed decreased CAV1 protein turnover at the cilium as the possible cause for this phenotype. In conclusion, we have generated a comprehensive list of cilia-specific proteins that are subject to regulation via ubiquitination which can serve to further our understanding of cilia biology in health and disease.
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Affiliation(s)
- Mariam G. Aslanyan
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Cenna Doornbos
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Gaurav D. Diwan
- BioQuant, Heidelberg University, Heidelberg, Germany
- Biochemistry Center (BZH), Heidelberg University, Heidelberg, Germany
| | - Zeinab Anvarian
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Tina Beyer
- Institute for Ophthalmic Research, Eberhard Karl University of Tübingen, Tübingen, Germany
| | - Katrin Junger
- Institute for Ophthalmic Research, Eberhard Karl University of Tübingen, Tübingen, Germany
| | - Sylvia E. C. van Beersum
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Robert B. Russell
- BioQuant, Heidelberg University, Heidelberg, Germany
- Biochemistry Center (BZH), Heidelberg University, Heidelberg, Germany
| | - Marius Ueffing
- Institute for Ophthalmic Research, Eberhard Karl University of Tübingen, Tübingen, Germany
| | - Alexander Ludwig
- School of Biological Sciences, NTU Institute of Structural Biology, Nanyang Technological University, Singapore City, Singapore
| | - Karsten Boldt
- Institute for Ophthalmic Research, Eberhard Karl University of Tübingen, Tübingen, Germany
| | - Lotte B. Pedersen
- Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Ronald Roepman
- Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
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16
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Li W, Song Y, Du Y, Huang Z, Zhang M, Chen Z, He Z, Ding Y, Zhang J, Zhao L, Sun H, Jiao P. Duck TRIM29 negatively regulates type I IFN production by targeting MAVS. Front Immunol 2023; 13:1016214. [PMID: 36685538 PMCID: PMC9853200 DOI: 10.3389/fimmu.2022.1016214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023] Open
Abstract
The innate immune response is a host defense mechanism that induces type I interferon and proinflammatory cytokines. Tripartite motif (TRIM) family proteins have recently emerged as pivotal regulators of type I interferon production in mammals. Here, we first identified duck TRIM29, which encodes 571 amino acids and shows high sequence homology with other bird TRIM29 proteins. DuTRIM29 inhibited IFN-β and IRF7 promoter activation in a dose-dependent manner and downregulated the mRNA expression of IFN-β, IRF7, Mx and IL-6 mediated by duRIG-I. Moreover, duTRIM29 interacted and colocalized with duMAVS in the cytoplasm. DuTRIM29 interacted with duMAVS via its C-terminal domains. In addition, duTRIM29 inhibited IFN-β and IRF7 promoter activation and significantly downregulated IFN-β and immune-related gene expression mediated by duMAVS in ducks. Furthermore, duTRIM29 induced K29-linked polyubiquitination and degradation of duMAVS to suppress the expression of IFN-β. Overall, our results demonstrate that duTRIM29 negatively regulates type I IFN production by targeting duMAVS in ducks. This study will contribute to a better understanding of the molecular mechanism regulating the innate immune response by TRIM proteins in ducks.
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Affiliation(s)
- Weiqiang Li
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Yating Song
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Yuqing Du
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Zhanhong Huang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Meng Zhang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Zuxian Chen
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Zhuoliang He
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Yangbao Ding
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Junsheng Zhang
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Luxiang Zhao
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Hailiang Sun
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
| | - Peirong Jiao
- Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
- Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, Guangzhou, China
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17
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Ciuffa R, Uliana F, Mannion J, Mehnert M, Tenev T, Marulli C, Satanowski A, Keller LML, Rodilla Ramírez PN, Ori A, Gstaiger M, Meier P, Aebersold R. Novel biochemical, structural, and systems insights into inflammatory signaling revealed by contextual interaction proteomics. Proc Natl Acad Sci U S A 2022; 119:e2117175119. [PMID: 36179048 PMCID: PMC9546619 DOI: 10.1073/pnas.2117175119] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 07/28/2022] [Indexed: 12/03/2022] Open
Abstract
Protein-protein interactions (PPIs) represent the main mode of the proteome organization in the cell. In the last decade, several large-scale representations of PPI networks have captured generic aspects of the functional organization of network components but mostly lack the context of cellular states. However, the generation of context-dependent PPI networks is essential for structural and systems-level modeling of biological processes-a goal that remains an unsolved challenge. Here we describe an experimental/computational strategy to achieve a modeling of PPIs that considers contextual information. This strategy defines the composition, stoichiometry, temporal organization, and cellular requirements for the formation of target assemblies. We used this approach to generate an integrated model of the formation principles and architecture of a large signalosome, the TNF-receptor signaling complex (TNF-RSC). Overall, we show that the integration of systems- and structure-level information provides a generic, largely unexplored link between the modular proteome and cellular function.
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Affiliation(s)
- Rodolfo Ciuffa
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Federico Uliana
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Jonathan Mannion
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, SW3 6JB London, United Kingdom
| | - Martin Mehnert
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Tencho Tenev
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, SW3 6JB London, United Kingdom
| | - Cathy Marulli
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Ari Satanowski
- Max Planck Institute of Molecular Plant Physiology, 14476 Potsdam, Germany
| | | | | | - Alessandro Ori
- Leibniz Institute on Aging, Fritz Lipmann Institute, 07745 Jena, Germany
| | - Matthias Gstaiger
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
| | - Pascal Meier
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, SW3 6JB London, United Kingdom
| | - Ruedi Aebersold
- Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
- Faculty of Science, University of Zurich, 8093 Zurich, Switzerland
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18
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Kumar D, Shepherd FK, Springer NL, Mwangi W, Marthaler DG. Rotavirus Infection in Swine: Genotypic Diversity, Immune Responses, and Role of Gut Microbiome in Rotavirus Immunity. Pathogens 2022; 11:pathogens11101078. [PMID: 36297136 PMCID: PMC9607047 DOI: 10.3390/pathogens11101078] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/13/2022] [Accepted: 09/17/2022] [Indexed: 11/16/2022] Open
Abstract
Rotaviruses (RVs) are endemic in swine populations, and all swine herds certainly have a history of RV infection and circulation. Rotavirus A (RVA) and C (RVC) are the most common among all RV species reported in swine. RVA was considered most prevalent and pathogenic in swine; however, RVC has been emerging as a significant cause of enteritis in newborn piglets. RV eradication from swine herds is not practically achievable, hence producers’ mainly focus on minimizing the production impact of RV infections by reducing mortality and diarrhea. Since no intra-uterine passage of immunoglobulins occur in swine during gestation, newborn piglets are highly susceptible to RV infection at birth. Boosting lactogenic immunity in gilts by using vaccines and natural planned exposure (NPE) is currently the only way to prevent RV infections in piglets. RVs are highly diverse and multiple RV species have been reported from swine, which also contributes to the difficulties in preventing RV diarrhea in swine herds. Human RV-gut microbiome studies support a link between microbiome composition and oral RV immunogenicity. Such information is completely lacking for RVs in swine. It is not known how RV infection affects the functionality or structure of gut microbiome in swine. In this review, we provide a detailed overview of genotypic diversity of swine RVs, host-ranges, innate and adaptive immune responses to RVs, homotypic and heterotypic immunity to RVs, current methods used for RV management in swine herds, role of maternal immunity in piglet protection, and prospects of investigating swine gut microbiota in providing immunity against rotaviruses.
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Affiliation(s)
- Deepak Kumar
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
- Correspondence: (D.K.); (W.M.); (D.G.M.); Tel.: +1-804-503-1241 (D.K.)
| | - Frances K Shepherd
- Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55108, USA
| | - Nora L. Springer
- Clinical Pathology, Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA
| | - Waithaka Mwangi
- Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA
- Correspondence: (D.K.); (W.M.); (D.G.M.); Tel.: +1-804-503-1241 (D.K.)
| | - Douglas G. Marthaler
- Indical Inc., 1317 Edgewater Dr #3722, Orlando, FL 32804, USA
- Correspondence: (D.K.); (W.M.); (D.G.M.); Tel.: +1-804-503-1241 (D.K.)
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19
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Chen Q, Zhou L, Ma D, Hou J, Lin Y, Wu J, Tao M. LncRNA GAS6-AS1 facilitates tumorigenesis and metastasis of colorectal cancer by regulating TRIM14 through miR-370-3p/miR-1296-5p and FUS. J Transl Med 2022; 20:356. [PMID: 35962353 PMCID: PMC9373365 DOI: 10.1186/s12967-022-03550-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/19/2022] [Indexed: 12/24/2022] Open
Abstract
Background Long non-coding RNAs (lncRNAs) are essential regulators of tumorigenesis and the development of colorectal cancer (CRC). Here, we aimed to investigate the role of lncRNA GAS6-AS1 in CRC and its potential mechanisms. Methods Bioinformatics analyses evaluated the level of GAS6-AS1 in colon cancer, its correlation with clinicopathological factors, survival curve and diagnostic value. qRT-PCR were performed to detect the GAS6-AS1 level in CRC samples and cell lines. The CCK8, EdU, scratch healing, transwell assays and animal experiments were conducted to investigate the function of GAS6-AS1 in CRC. RNA immunoprecipitation (RIP) and dual-luciferase reporter gene analyses were carried out to reveal interaction between GAS6-AS1, TRIM14, FUS, and miR-370-3p/miR-1296-5p. Results GAS6-AS1 was greatly elevated in CRC and positively associated with unfavorable prognosis of CRC patients. Functionally, GAS6-AS1 positively regulates CRC proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and induces CRC growth and metastasis in vivo. Moreover, GAS6-AS1 exerted oncogenic function by competitively binding to miR-370-3p and miR-1296-5p, thereby upregulating TRIM14. Furthermore, we verified that GAS6-AS1 and TRIM14 both interact with FUS and that GAS6-AS1 stabilized TRIM14 mRNA by recruiting FUS. Besides, rescue experiments furtherly demonstrated that GAS6-AS1 facilitate progression of CRC by regulating TRIM14. Conclusion Collectively, these findings demonstrate that GAS6-AS1 promotes TRIM14-mediated cell proliferation, migration, invasion, and EMT of CRC via ceRNA network and FUS-dependent manner, suggesting that GAS6-AS1 could be utilized as a novel biomarker and therapeutic target for CRC. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03550-0.
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Affiliation(s)
- Qing Chen
- Department of Oncology, Jingjiang People's Hospital, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang, Jiangsu, China.,Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Lin Zhou
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - De Ma
- Department of Oncology, Jingjiang People's Hospital, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang, Jiangsu, China
| | - Juan Hou
- Department of Oncology, Jingjiang People's Hospital, The Seventh Affiliated Hospital of Yangzhou University, Jingjiang, Jiangsu, China
| | - Yuxin Lin
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jie Wu
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Min Tao
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. .,Department of Oncology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China.
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20
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Xing C, Du Y, Duan T, Nim K, Chu J, Wang HY, Wang RF. Interaction between microbiota and immunity and its implication in colorectal cancer. Front Immunol 2022; 13:963819. [PMID: 35967333 PMCID: PMC9373904 DOI: 10.3389/fimmu.2022.963819] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the world. Besides genetic causes, colonic inflammation is one of the major risk factors for CRC development, which is synergistically regulated by multiple components, including innate and adaptive immune cells, cytokine signaling, and microbiota. The complex interaction between CRC and the gut microbiome has emerged as an important area of current CRC research. Metagenomic profiling has identified a number of prominent CRC-associated bacteria that are enriched in CRC patients, linking the microbiota composition to colitis and cancer development. Some microbiota species have been reported to promote colitis and CRC development in preclinical models, while a few others are identified as immune modulators to induce potent protective immunity against colitis and CRC. Mechanistically, microbiota regulates the activation of different immune cell populations, inflammation, and CRC via crosstalk between innate and adaptive immune signaling pathways, including nuclear factor kappa B (NF-κB), type I interferon, and inflammasome. In this review, we provide an overview of the potential interactions between gut microbiota and host immunity and how their crosstalk could synergistically regulate inflammation and CRC, thus highlighting the potential roles and mechanisms of gut microbiota in the development of microbiota-based therapies to prevent or alleviate colitis and CRC.
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Affiliation(s)
- Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Kelly Nim
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Junjun Chu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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21
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Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol 2022. [PMID: 35309296 DOI: 10.3389/fimmu.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.
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Affiliation(s)
- Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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22
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Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol 2022; 13:812774. [PMID: 35309296 PMCID: PMC8927970 DOI: 10.3389/fimmu.2022.812774] [Citation(s) in RCA: 378] [Impact Index Per Article: 126.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/08/2022] [Indexed: 12/13/2022] Open
Abstract
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.
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Affiliation(s)
- Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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23
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Zhang XZ, Li FH, Wang XJ. Regulation of Tripartite Motif-Containing Proteins on Immune Response and Viral Evasion. Front Microbiol 2021; 12:794882. [PMID: 34925304 PMCID: PMC8671828 DOI: 10.3389/fmicb.2021.794882] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/08/2021] [Indexed: 12/21/2022] Open
Abstract
Tripartite motif-containing proteins (TRIMs), exhibiting ubiquitin E3 ligase activity, are involved in regulation of not only autophagy and apoptosis but also pyrotosis and antiviral immune responses of host cells. TRIMs play important roles in modulating signaling pathways of antiviral immune responses via type I interferon, NF-κB, Janus kinase/signal transducer and activator of transcription (JAK/STAT), and Nrf2. However, viruses are able to antagonize TRIM activity or evenly utilize TRIMs for viral replication. This communication presents the current understanding of TRIMs exploited by viruses to evade host immune response.
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Affiliation(s)
- Xiu-Zhong Zhang
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Fu-Huang Li
- Beijing General Station of Animal Husbandry Service (South Section), Beijing, China
| | - Xiao-Jia Wang
- Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, China
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24
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Hsieh YY, Tung SY, Pan HY, Chang TS, Wei KL, Chen WM, Deng YF, Lu CK, Lai YH, Wu CS, Li C. Fusobacterium nucleatum colonization is associated with decreased survival of helicobacter pylori-positive gastric cancer patients. World J Gastroenterol 2021; 27:7311-7323. [PMID: 34876791 PMCID: PMC8611209 DOI: 10.3748/wjg.v27.i42.7311] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/10/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND An increased amount of Fusobacterium nucleatum (F. nucleatum) is frequently detected in the gastric cancer-associated microbiota of the Taiwanese population. F. nucleatum is known to exert cytotoxic effects and play a role in the progression of colorectal cancer, though the impact of F. nucleatum colonization on gastric cancer cells and patient prognosis has not yet been examined.
AIM To identify F. nucleatum-dependent molecular pathways in gastric cancer cells and to determine the impact of F. nucleatum on survival in gastric cancer.
METHODS Coculture of F. nucleatum with a gastric cancer cell line was performed, and changes in gene expression were investigated. Genes with significant changes in expression were identified by RNA sequencing. Pathway analysis was carried out to determine deregulated cellular functions. A cohort of gastric cancer patients undergoing gastrectomy was recruited, and nested polymerase chain reaction was performed to detect the presence of F. nucleatum in resected cancer tissues. Statistical analysis was performed to determine whether F. nucleatum colonization affects patient survival.
RESULTS RNA sequencing and subsequent pathway analysis revealed a drastic interferon response induced by a high colonization load. This response peaked within 24 h and subsided after 72 h of incubation. In contrast, deregulation of actin and its regulators was observed during prolonged incubation under a low colonization load, likely altering the mobility of gastric cancer cells. According to the clinical specimen analysis, approximately one-third of the gastric cancer patients were positive for F. nucleatum, and statistical analysis indicated that the risk for colonization increases in late-stage cancer patients. Survival analysis demonstrated that F. nucleatum colonization was associated with poorer outcomes among patients also positive for Helicobacter pylori (H. pylori).
CONCLUSION F. nucleatum colonization leads to deregulation of actin dynamics and likely changes cancer cell mobility. Cohort analysis demonstrated that F. nucleatum colonization leads to poorer prognosis in H. pylori-positive patients with late-stage gastric cancer. Hence, combined colonization of F. nucleatum and H. pylori is a predictive biomarker for poorer survival in late-stage gastric cancer patients treated with gastrectomy.
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Affiliation(s)
- Yung-Yu Hsieh
- Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 61301, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Shui-Yi Tung
- Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 61301, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Hung-Yu Pan
- Department of Applied Mathematics, National Chiayi University, Chiayi 60035, Taiwan
| | - Te-Sheng Chang
- Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 61301, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Kuo-Liang Wei
- Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 61301, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Wei-Ming Chen
- Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 61301, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yi-Fang Deng
- Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 61301, Taiwan
| | - Chung-Kuang Lu
- Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 61301, Taiwan
| | - Yu-Hsuan Lai
- Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 61301, Taiwan
| | - Cheng-Shyong Wu
- Department of Gastroenterology and Hepatology, Chiayi Chang Gung Memorial Hospital, Chiayi 61301, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chin Li
- Department of Biomedical Sciences, National Chung Cheng University, Chiayi 62130, Taiwan
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25
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Huang Y, Xiao Y, Zhang X, Huang X, Li Y. The Emerging Roles of Tripartite Motif Proteins (TRIMs) in Acute Lung Injury. J Immunol Res 2021; 2021:1007126. [PMID: 34712740 PMCID: PMC8548118 DOI: 10.1155/2021/1007126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/09/2021] [Indexed: 11/21/2022] Open
Abstract
Acute lung injury (ALI) is an inflammatory disorder of the lung that causes high mortality and lacks any pharmacological intervention. Ubiquitination plays a critical role in the pathogenesis of ALI as it regulates the alveolocapillary barrier and the inflammatory response. Tripartite motif (TRIM) proteins are one of the subfamilies of the RING-type E3 ubiquitin ligases, which contains more than 80 distinct members in humans involved in a broad range of biological processes including antivirus innate immunity, development, and tumorigenesis. Recently, some studies have shown that several members of TRIM family proteins play important regulatory roles in inflammation and ALI. Herein, we integrate emerging evidence regarding the roles of TRIMs in ALI. Articles were selected from the searches of PubMed database that had the terms "acute lung injury," "ubiquitin ligases," "tripartite motif protein," "inflammation," and "ubiquitination" using both MeSH terms and keywords. Better understanding of these mechanisms may ultimately lead to novel therapeutic approaches by targeting TRIMs for ALI treatment.
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Affiliation(s)
- Yingjie Huang
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yue Xiao
- The First Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Xuekang Zhang
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xuan Huang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Yong Li
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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26
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Griesemer D, Xue JR, Reilly SK, Ulirsch JC, Kukreja K, Davis JR, Kanai M, Yang DK, Butts JC, Guney MH, Luban J, Montgomery SB, Finucane HK, Novina CD, Tewhey R, Sabeti PC. Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution. Cell 2021; 184:5247-5260.e19. [PMID: 34534445 PMCID: PMC8487971 DOI: 10.1016/j.cell.2021.08.025] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 05/25/2021] [Accepted: 08/19/2021] [Indexed: 12/11/2022]
Abstract
3' untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3'UTR function, suggesting that simple sequences predominately explain 3'UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3'UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.
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Affiliation(s)
- Dustin Griesemer
- Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA; Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - James R Xue
- Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02143, USA.
| | - Steven K Reilly
- Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02143, USA
| | - Jacob C Ulirsch
- Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Kalki Kukreja
- Department of Molecular and Cell Biology, Harvard University, Cambridge, MA 02138, USA
| | - Joe R Davis
- BigHat Biosciences, San Carlos, CA 94070, USA
| | - Masahiro Kanai
- Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA
| | - David K Yang
- Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA
| | - John C Butts
- The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA
| | - Mehmet H Guney
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Jeremy Luban
- Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Stephen B Montgomery
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hilary K Finucane
- Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Carl D Novina
- Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Ryan Tewhey
- The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA; Tufts University School of Medicine, Boston, MA 02111, USA
| | - Pardis C Sabeti
- Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02143, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
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27
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Roy M, Singh R. TRIMs: selective recruitment at different steps of the NF-κB pathway-determinant of activation or resolution of inflammation. Cell Mol Life Sci 2021; 78:6069-6086. [PMID: 34283248 PMCID: PMC11072854 DOI: 10.1007/s00018-021-03900-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 07/04/2021] [Accepted: 07/13/2021] [Indexed: 12/25/2022]
Abstract
TNF-α-induced NF-κB pathway is an essential component of innate and adaptive immune pathway, and it is tightly regulated by various post-translational modifications including ubiquitination. Oscillations in NF-κB activation and temporal gene expression are emerging as critical determinants of inflammatory response, however, the regulators of unique outcomes in different patho-physiological conditions are not well understood. Tripartite Motif-containing proteins (TRIMs) are RING domain-containing E3 ligases involved in the regulation of cellular homeostasis, metabolism, cell death, inflammation, and host defence. Emerging reports suggest that TRIMs are recruited at different steps of TNF-α-induced NF-κB pathway and modulate via their E3 ligase activity. TRIMs show synergy and antagonism in the regulation of the NF-κB pathway and also regulate it in a feedback manner. TRIMs also regulate pattern recognition receptors (PRRs) mediated inflammatory pathways and may have evolved to directly regulate a specific arm of immune signalling. The review emphasizes TRIM-mediated ubiquitination and modulation of TNF-α-regulated temporal and NF-κB signaling and its possible impact on unique transcriptional and functional outcomes.
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Affiliation(s)
- Milton Roy
- Department of Biochemistry, Faculty of Science, The MS University of Baroda, Vadodara, Gujarat, 390002, India
- Institute for Cell Engineering, The Johns Hopkins University School of Medicine, 733 North Broadway, MRB 731, Baltimore, MD, 21205, USA
| | - Rajesh Singh
- Department of Biochemistry, Faculty of Science, The MS University of Baroda, Vadodara, Gujarat, 390002, India.
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28
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Jin Z, Zhu Z. The role of TRIM proteins in PRR signaling pathways and immune-related diseases. Int Immunopharmacol 2021; 98:107813. [PMID: 34126340 DOI: 10.1016/j.intimp.2021.107813] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 05/13/2021] [Accepted: 05/23/2021] [Indexed: 12/25/2022]
Abstract
Pattern recognition receptors (PRRs) are a kind of recognition molecules mainly expressed on innate immune cells. PRRs recognize one or more kinds of pathogen-associated molecular patterns (PAMPs), inducing the production of interleukin (IL), tumor necrosis factor (TNF), interferon (IFN) and other related cytokines to aggravate immune-related diseases. PPR signaling pathways play an important role in both innate and adaptive immune system, and they are easy to be activated or regulated. Tripartite motif (TRIM) proteins are a group of highly conserved proteins in structure. Most of TRIM proteins contain RING domain, which is thought to play a role in ubiquitination. TRIM proteins are involved in viral immunity, inflammatory response, autophagy, and tumor growth. In this review, we focus on the regulation of TRIM proteins on PRR signaling pathways and their roles in immune-related diseases.
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Affiliation(s)
- Zheng Jin
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Zhenhua Zhu
- Department of Orthopaedic Trauma, The Third Affiliated Hospital of Southern, Medical University, Guangzhou, Guangdong Province, China.
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29
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Tan P, He L, Zhou Y. Engineering Supramolecular Organizing Centers for Optogenetic Control of Innate Immune Responses. Adv Biol (Weinh) 2021; 5:e2000147. [PMID: 34028210 PMCID: PMC8144545 DOI: 10.1002/adbi.202000147] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 09/18/2020] [Indexed: 12/20/2022]
Abstract
The spatiotemporal organization of oligomeric protein complexes, such as the supramolecular organizing centers (SMOCs) made of MyDDosome and MAVSome, is essential for transcriptional activation of host inflammatory responses and immunometabolism. Light-inducible assembly of MyDDosome and MAVSome is presented herein to induce activation of nuclear factor-kB and type-I interferons. Engineering of SMOCs and the downstream transcription factor permits programmable and customized innate immune operations in a light-dependent manner. These synthetic molecular tools will likely enable optical and user-defined modulation of innate immunity at a high spatiotemporal resolution to facilitate mechanistic studies of distinct modes of innate immune activations and potential intervention of immune disorders and cancer.
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Affiliation(s)
- Peng Tan
- Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX, 77030, USA
| | - Lian He
- Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX, 77030, USA
| | - Yubin Zhou
- Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX, 77030, USA
- Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX, 77030, USA
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Zhang J, Lin X, Sun Y, Wei J, Wu J. Trim14 promotes osteoclastogenesis and noncanonical NF-κB activation by targeting p100/p52 in chronic periodontitis. Oral Dis 2021; 28:1958-1967. [PMID: 33901321 DOI: 10.1111/odi.13888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 04/07/2021] [Accepted: 04/19/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Periodontitis disease infection initiates host immune response, and alveolar bone damage is a hallmark of periodontitis. Bone damage occurs due to changes in osteoclast activity in response to local inflammation. Nuclear factor κB (NF-κB) signaling is essential for inflammatory responses and plays a pivotal role in osteoclast formation and activation. Tripartite motif 14 (Trim14) is a crucial regulator of the noncanonical NF-κB signaling. Here, we investigated the role of Trim14 in chronic periodontitis. METHODS The development of immune cells and osteoclast formation was evaluated with flow cytometry, qRT-PCR, and histochemical staining. Proinflammatory cytokines were checked by ELISA and qRT-PCR. Protein expression was determined by immunoblotting. Also, the cemento-enamel junction-alveolar bone crest distance was evaluated in the mouse model. RESULTS Development of innate and adaptive cells was not impaired from the deletion of Trim14. However, the genetic loss of Trim14 remarkably suppressed RANKL-induced osteoclastogenesis, without affecting TLR-induced proinflammatory cytokines except for Il-23a expression. The Trim14 deletion also suppressed the activation of noncanonical NF-κB signaling by targeting p100/p52. Importantly, the deletion of NIK diminished the effects of Trim14 on the inflammatory responses in vivo on chronic periodontitis responses. CONCLUSION TRIM14 may be a positive regulator to promote osteoclastogenesis and proinflammatory cytokine secretion.
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Affiliation(s)
- Jian Zhang
- Department of Dental Clinic, Cangzhou Central Hospital, Cangzhou, China
| | - Xiuya Lin
- Department of Dental Clinic, Cangzhou Central Hospital, Cangzhou, China
| | - Yang Sun
- Department of Dental Clinic, Cangzhou Central Hospital, Cangzhou, China
| | - Jianming Wei
- Department of Dental Clinic, Cangzhou Central Hospital, Cangzhou, China
| | - Jiankun Wu
- Department of Dental Clinic, Cangzhou Central Hospital, Cangzhou, China
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31
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Pérez-Pulido AJ, Asencio-Cortés G, Brokate-Llanos AM, Brea-Calvo G, Rodríguez-Griñolo R, Garzón A, Muñoz MJ. Serial co-expression analysis of host factors from SARS-CoV viruses highly converges with former high-throughput screenings and proposes key regulators. Brief Bioinform 2021; 22:1038-1052. [PMID: 33458747 PMCID: PMC7929451 DOI: 10.1093/bib/bbaa419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 11/11/2020] [Accepted: 12/19/2020] [Indexed: 11/14/2022] Open
Abstract
The current genomics era is bringing an unprecedented growth in the amount of gene expression data, only comparable to the exponential growth of sequences in databases during the last decades. This data allow the design of secondary analyses that take advantage of this information to create new knowledge. One of these feasible analyses is the evaluation of the expression level for a gene through a series of different conditions or cell types. Based on this idea, we have developed Automatic and Serial Analysis of CO-expression, which performs expression profiles for a given gene along hundreds of heterogeneous and normalized transcriptomics experiments and discover other genes that show either a similar or an inverse behavior. It might help to discover co-regulated genes, and common transcriptional regulators in any biological model. The present severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is an opportunity to test this novel approach due to the wealth of data that are being generated, which could be used for validating results. Thus, we have identified 35 host factors in the literature putatively involved in the infectious cycle of SARS-CoV viruses and searched for genes tightly co-expressed with them. We have found 1899 co-expressed genes whose assigned functions are strongly related to viral cycles. Moreover, this set of genes heavily overlaps with those identified by former laboratory high-throughput screenings (with P-value near 0). Our results reveal a series of common regulators, involved in immune and inflammatory responses that might be key virus targets to induce the coordinated expression of SARS-CoV-2 host factors.
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Affiliation(s)
- Antonio J Pérez-Pulido
- Centro Andaluz de Biologia del Desarrollo (CABD, UPO-CSIC-JA). Facultad de Ciencias Experimentales (Área de Genética), Universidad Pablo de Olavide, 41013, Sevilla, Spain
| | | | - Ana M Brokate-Llanos
- Centro Andaluz de Biologia del Desarrollo (CABD, UPO-CSIC-JA). Facultad de Ciencias Experimentales (Área de Genética), Universidad Pablo de Olavide, 41013, Sevilla, Spain
| | - Gloria Brea-Calvo
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013, Sevilla, Spain
- CIBERER, Instituto de Salud Carlos III, 28000, Madrid, Spain
| | - Rosario Rodríguez-Griñolo
- Dpto. de Economía, Métodos Cuantitativos e Historia Económica. Universidad Pablo de Olavide, 41013 Sevilla, Spain
| | - Andrés Garzón
- Centro Andaluz de Biologia del Desarrollo (CABD, UPO-CSIC-JA). Facultad de Ciencias Experimentales (Área de Genética), Universidad Pablo de Olavide, 41013, Sevilla, Spain
| | - Manuel J Muñoz
- Centro Andaluz de Biologia del Desarrollo (CABD, UPO-CSIC-JA). Facultad de Ciencias Experimentales (Área de Genética), Universidad Pablo de Olavide, 41013, Sevilla, Spain
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32
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Shen Z, Wei L, Yu ZB, Yao ZY, Cheng J, Wang YT, Song XT, Li M. The Roles of TRIMs in Antiviral Innate Immune Signaling. Front Cell Infect Microbiol 2021; 11:628275. [PMID: 33791238 PMCID: PMC8005608 DOI: 10.3389/fcimb.2021.628275] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 02/02/2021] [Indexed: 01/06/2023] Open
Abstract
The Tripartite motif (TRIM) protein family, which contains over 80 members in human sapiens, is the largest subfamily of the RING-type E3 ubiquitin ligase family. It is implicated in regulating various cellular functions, including cell cycle process, autophagy, and immune response. The dysfunction of TRIMs may lead to numerous diseases, such as systemic lupus erythematosus (SLE). Lots of studies in recent years have demonstrated that many TRIM proteins exert antiviral roles. TRIM proteins could affect viral replication by regulating the signaling pathways of antiviral innate immune responses. Besides, TRIM proteins can directly target viral components, which can lead to the degradation or functional inhibition of viral protein through degradative or non-degradative mechanisms and consequently interrupt the viral lifecycle. However, new evidence suggests that some viruses may manipulate TRIM proteins for their replication. Here, we summarize the latest discoveries on the interactions between TRIM protein and virus, especially TRIM proteins’ role in the signaling pathway of antiviral innate immune response and the direct “game” between them.
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Affiliation(s)
- Zhou Shen
- Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang, China.,Center Laboratory, Affiliated Hospital of Hebei University, Baoding, China
| | - Lin Wei
- Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang, China
| | - Zhi-Bo Yu
- Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang, China
| | - Zhi-Yan Yao
- Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang, China
| | - Jing Cheng
- Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang, China
| | - Yu-Tong Wang
- Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang, China
| | - Xiao-Tian Song
- Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang, China
| | - Miao Li
- Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Department of Immunology, Hebei Medical University, Shijiazhuang, China
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33
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Xie X, Wang F, Li X. Inhibition of TRIM14 protects cerebral ischemia/reperfusion injury through regulating NF-κB/NLRP3 pathway-mediated inflammation and apoptosis. J Recept Signal Transduct Res 2021; 42:197-205. [PMID: 33691569 DOI: 10.1080/10799893.2021.1887218] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
PURPOSE Many proteins in tripartite motif (TRIM) family have been reported to play an important role in cerebral ischemia/reperfusion (I/R) injury. This study was designed to investigate the effect of TRIM14 on the cerebral I/R injury in rats. METHODS The rat model was constructed through inserting thread into the middle cerebral artery. The expression of TRIM14 was measured by qRT-PCR, immunoblotting, and immunofluorescence. The hippocampal sections were stained with 2,3,5-triphenyltetrazolium chloride (TTC) to determine infarct volume and used for measuring the neurologic deficit score and brain water content. The H&E staining was used for immunohistochemical (IHC) staining. The number of apoptotic cells was measured by fluorescence microscopy. The levels of IL-6, IL-1β, and TNFα were detected by qRT-PCR and ELISA. The swimming speed, latency time, and number of platform crossings were measured by the water maze test. RESULTS TRIM14 was significantly enhanced in rats with cerebral I/R injury compared to Sham rats, showing its highest level at 24 h after I/R. TRIM14 inhibition reduced ischemic brain injury, suppressed neuron apoptosis, suppressed inflammation, and improved cognitive dysfunction in rats with cerebral I/R injury. TRIM14 inhibition also suppressed the activation of NF-κB/NLRP3 pathway in rats with cerebral I/R injury. CONCLUSION In conclusion, the expression of TRIM14 was increased in rats with cerebral I/R injury, the protective effect of TRIM14 inhibitor on cerebral I/R injury in rats depends on its anti-apoptotic and anti-inflammatory effect. The underlying mechanism was, at least partially, through regulating NF-κB/NLRP3 pathway.
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Affiliation(s)
- Xianlong Xie
- Department of Geriatrics, Wuhan No. 1 Hospital, Wuhan, China
| | - Fan Wang
- Department of Geriatrics, Wuhan No. 1 Hospital, Wuhan, China
| | - Xiujuan Li
- Department of Geriatrics, Wuhan No. 1 Hospital, Wuhan, China
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34
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Cho E, Lou HJ, Kuruvilla L, Calderwood DA, Turk BE. PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK. Cell Rep 2021; 34:108928. [PMID: 33789117 PMCID: PMC8068315 DOI: 10.1016/j.celrep.2021.108928] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 01/26/2021] [Accepted: 03/10/2021] [Indexed: 12/21/2022] Open
Abstract
Flux through the RAF-MEK-ERK protein kinase cascade is shaped by phosphatases acting on the core components of the pathway. Despite being an established drug target and a hub for crosstalk regulation, little is known about dephosphorylation of MEK, the central kinase within the cascade. Here, we identify PPP6C, a phosphatase frequently mutated or downregulated in melanoma, as a major MEK phosphatase in cells exhibiting oncogenic ERK pathway activation. Recruitment of MEK to PPP6C occurs through an interaction with its associated regulatory subunits. Loss of PPP6C causes hyperphosphorylation of MEK at activating and crosstalk phosphorylation sites, promoting signaling through the ERK pathway and decreasing sensitivity to MEK inhibitors. Recurrent melanoma-associated PPP6C mutations cause MEK hyperphosphorylation, suggesting that they promote disease at least in part by activating the core oncogenic pathway driving melanoma. Collectively, our studies identify a key negative regulator of ERK signaling that may influence susceptibility to targeted cancer therapies. Through an shRNA screen, Cho et al. identify PPP6C as a phosphatase that inactivates the kinase MEK, sensitizing tumor cells to clinical MEK inhibitors. This study suggests that cancer-associated loss-of-function PPP6C mutations prevalent in melanoma serve to activate the core oncogenic RAF-MEK-ERK pathway that drives the disease.
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Affiliation(s)
- Eunice Cho
- Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Hua Jane Lou
- Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Leena Kuruvilla
- Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA
| | - David A Calderwood
- Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Benjamin E Turk
- Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA.
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35
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Wang HT, Hur S. Substrate recognition by TRIM and TRIM-like proteins in innate immunity. Semin Cell Dev Biol 2021; 111:76-85. [PMID: 33092958 PMCID: PMC7572318 DOI: 10.1016/j.semcdb.2020.09.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 09/28/2020] [Indexed: 12/23/2022]
Abstract
TRIM (Tripartite motif) and TRIM-like proteins have emerged as an important class of E3 ligases in innate immunity. Their functions range from activation or regulation of innate immune signaling pathway to direct detection and restriction of pathogens. Despite the importance, molecular mechanisms for many TRIM/TRIM-like proteins remain poorly characterized, in part due to challenges of identifying their substrates. In this review, we discuss several TRIM/TRIM-like proteins in RNA sensing pathways and viral restriction functions. We focus on those containing PRY-SPRY, the domain most frequently used for substrate recognition, and discuss emerging mechanisms that are commonly utilized by several TRIM/TRIM-like proteins to tightly control their interaction with the substrates.
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Affiliation(s)
- Hai-Tao Wang
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA
| | - Sun Hur
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
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36
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Kato K, Ahmad S, Zhu Z, Young JM, Mu X, Park S, Malik HS, Hur S. Structural analysis of RIG-I-like receptors reveals ancient rules of engagement between diverse RNA helicases and TRIM ubiquitin ligases. Mol Cell 2021; 81:599-613.e8. [PMID: 33373584 PMCID: PMC8183676 DOI: 10.1016/j.molcel.2020.11.047] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/17/2020] [Accepted: 11/23/2020] [Indexed: 01/28/2023]
Abstract
RNA helicases and E3 ubiquitin ligases mediate many critical functions in cells, but their actions have largely been studied in distinct biological contexts. Here, we uncover evolutionarily conserved rules of engagement between RNA helicases and tripartite motif (TRIM) E3 ligases that lead to their functional coordination in vertebrate innate immunity. Using cryoelectron microscopy and biochemistry, we show that RIG-I-like receptors (RLRs), viral RNA receptors with helicase domains, interact with their cognate TRIM/TRIM-like E3 ligases through similar epitopes in the helicase domains. Their interactions are avidity driven, restricting the actions of TRIM/TRIM-like proteins and consequent immune activation to RLR multimers. Mass spectrometry and phylogeny-guided biochemical analyses further reveal that similar rules of engagement may apply to diverse RNA helicases and TRIM/TRIM-like proteins. Our analyses suggest not only conserved substrates for TRIM proteins but also, unexpectedly, deep evolutionary connections between TRIM proteins and RNA helicases, linking ubiquitin and RNA biology throughout animal evolution.
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MESH Headings
- Cryoelectron Microscopy
- DEAD Box Protein 58/genetics
- DEAD Box Protein 58/metabolism
- DEAD Box Protein 58/ultrastructure
- Epitopes
- Evolution, Molecular
- HEK293 Cells
- Humans
- Immunity, Innate
- Interferon-Induced Helicase, IFIH1/genetics
- Interferon-Induced Helicase, IFIH1/metabolism
- Interferon-Induced Helicase, IFIH1/ultrastructure
- Models, Molecular
- Phylogeny
- Protein Binding
- Protein Conformation, alpha-Helical
- Protein Interaction Domains and Motifs
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
- Receptors, Immunologic/ultrastructure
- Tripartite Motif Proteins/genetics
- Tripartite Motif Proteins/metabolism
- Tripartite Motif Proteins/ultrastructure
- Ubiquitin-Protein Ligases/genetics
- Ubiquitin-Protein Ligases/metabolism
- Ubiquitin-Protein Ligases/ultrastructure
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Affiliation(s)
- Kazuki Kato
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA
| | - Sadeem Ahmad
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA
| | - Zixiang Zhu
- State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China
| | - Janet M Young
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Xin Mu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA
| | - Sehoon Park
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA
| | - Harmit S Malik
- Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Sun Hur
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
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Carty M, Guy C, Bowie AG. Detection of Viral Infections by Innate Immunity. Biochem Pharmacol 2020; 183:114316. [PMID: 33152343 DOI: 10.1016/j.bcp.2020.114316] [Citation(s) in RCA: 236] [Impact Index Per Article: 47.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 12/12/2022]
Abstract
Pattern recognition receptors (PRRs) and inflammasomes are a key part of the anti-viral innate immune system as they detect conserved viral pathogen-associated molecular patterns (PAMPs). A successful host response to viral infections critically depend on the initial activation of PRRs by viruses, mainly by viral DNA and RNA. The signalling pathways activated by PRRs leads to the expression of pro-inflammatory cytokines, to recruit immune cells, and type I and type III interferons which leads to the induction of interferon stimulated genes (ISG), powerful virus restriction factors that establish the "antiviral state". Inflammasomes contribute to anti-viral responses through the maturation of interleukin (IL)-1 and IL-18 and through triggering pyroptotic cell death. The activity of the innate immune system along with the adaptive immune response normally leads to successful virus elimination, although disproportionate innate responses contribute to viral pathology. In this review we will discuss recent insights into the influence of PRR activation and inflammasomes on viral infections and what this means for the mammalian host. We will also comment on how specific PRRs and inflammasomes may be relevant to how SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, interacts with host innate immunity.
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Affiliation(s)
- Michael Carty
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
| | - Coralie Guy
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Andrew G Bowie
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
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Chong W, Wang Z, Shang L, Jia S, Liu J, Fang Z, Du F, Wu H, Liu Y, Chen Y, Chen H. Association of clock-like mutational signature with immune checkpoint inhibitor outcome in patients with melanoma and NSCLC. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 23:89-100. [PMID: 33335795 PMCID: PMC7723771 DOI: 10.1016/j.omtn.2020.10.033] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 10/21/2020] [Indexed: 12/15/2022]
Abstract
Immune checkpoint inhibitor (ICI) therapy has achieved remarkable clinical benefit in melanoma and non-small cell lung cancer (NSCLC). Tumor mutational signatures are the fingerprints of endogenous and exogenous factors that have acted throughout tumorigenesis and heterogeneity; however, their association with immune response in ICI-treated samples remains unclear. Here, we leveraged whole-exome sequencing (WES)-based mutational profiles combined with clinicopathologic characteristics from melanoma and NSCLC datasets to examine whether tumor genomic features contribute to clinical benefit of ICI treatment. Mutational data acquired from targeted next-generation sequencing (NGS) assays (MSK-IMPACT panels) were also employed for further corroboration. A mutational signature (known as age-related clock-like processing) characterized by enrichment of C>T mutations at NpCpG trinucleotides were identified to be associated with a worse prognosis and lower tumor mutation load (TML) in both WES and targeted NGS immunotherapy cohorts. We also analyzed gene transcriptomic profiles and identified immune regulation-related gene pathways that were significantly altered in samples with different clock-like signature grouping. Leucocyte subset analysis further revealed that clock-like signature was associated with the reduction of cytotoxic cell infiltration and elevation of regulatory T cells. Overall, our work re-annotated that the age-related clock-like signature was associated with worse prognosis and lower immune activity, offering opportunities to stratify patients into optimal immunotherapy plans based on genomic subtyping.
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Affiliation(s)
- Wei Chong
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.,Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong 250021, China
| | - Zhe Wang
- Tianjin Sino-US Diagnostics Co., Ltd, Tianjin 300060, China
| | - Liang Shang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.,Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong 250021, China
| | - Shengtao Jia
- Department of Tumor Cell Biology, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
| | - Jin Liu
- Department of Gastroenterology, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong 250021, China
| | - Zhen Fang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong 250021, China
| | - Fengying Du
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong 250021, China
| | - Hao Wu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong 250021, China
| | - Yang Liu
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.,Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong 250021, China
| | - Yang Chen
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Hao Chen
- Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong 250021, China
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Emilia M, Roman N, Barbara SM, Urszula M, Krzysztof Ł, Paweł O. Expression profile of Tripartite motif family (TRIM) in human fibroblasts (NHDF) infected with porcine endogenous retrovirus (PERV). Xenotransplantation 2020; 28:e12650. [PMID: 33037648 DOI: 10.1111/xen.12650] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 08/31/2020] [Accepted: 09/07/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Understanding the interactions between the microRNA (miRNA) and mRNA of genes encoding restriction factors (RFs) can lead to the development of new antiretroviral strategies aimed at providing the resistance and reducing susceptibility of human cells to potential PERV infection. Among RFs TRIM family play an important role in shaping the immune response during various stages of infection. The aim of the study was to evaluate in vitro the transcriptional profile of TRIM family genes and identify complementary miRNAs in NHDF cells infected with PERVs and induced by gram negative lipopolysacharide (LPS). METHODS Human dermal fibroblasts cells were cultured in four separate conditions- 2 monocultures: control (N), treated with LPS (NL) and 2 co-cultures with porcine PK15 cells: without LPS (NP) and treated with LPS (NLP). Bacterial LPS was used in this study as an inducer of inflammation in NHDF cells. After extraction of DNA and RNA from cells PERV infection was confirmed in co-cultures by qPCR and RTqPCR. RNA extracts served as a matrix for HGU 133A 2.0 and miRNA 2.0 microarrays to evaluate the expression profile of the selected TRIM family genes and miRNAs adequately. TRIM 2, 14, 22, and 28 were selected for the validation of HGU 133A 2.0 results. Statistical analyses were performed with the use of REST© 2009 and Genespring GX 13.0. Transcriptome Analysis Console 4.0 program (Affymetrix) was used to identify miRNAs that differentiate the studied genes in all conditions. RESULTS Porcine endogenous retrovirus infection at DNA and RNA level was confirmed in NHDF cells in each of the tested groups (NP and NLP). Contamination was excluded in N and NL groups. Based on the analysis of HGU 133A 2.0 results 93 mRNA IDs of TRIM family genes differentiating analyzed conditions were selected P < .05. HGU 133A 2.0 mRNA fluorescence profile was confirmed with RTqPCR of TRIM2, TRIM14, TRIM22 and TRIM28 P < .05. TRIM14 down regulation was specific only in PERV monoinfection (group NP). In miRNA 2.0 microarray 346 miRNAs were identified as differentiating NHDF cells in all analyzed conditions, P < .05. According to the analysis with mirTAR platform and Microrna.org datatbase none of the selected miRNAs had the potential to regulate the selected genes of the TRIM family. CONCLUSION Porcine endogenous retrovirus infection of NHDF cells is accompanied by TRIM14 down regulation suggesting TRIM14 as a possible marker of retroviral infection. None of the selected miRNAs had statistically significant potential to regulate the expression of the selected TRIMs in any of the analyzed conditions.
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Affiliation(s)
- Morawiec Emilia
- Department of Microbiology, Faculty of Medicine in Zabrze, University of Technology in Katowice, Katowice, Poland.,Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland.,Gyncentrum, Laboratory of Molecular Biology and Virology, Katowice, Poland.,Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland
| | - Nowak Roman
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland.,Orthopaedic Clinical Unit No 5 Sosnowiec, Silesian Medical University Sosnowiec, Poland
| | - Strzałka-Mrozik Barbara
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland
| | - Mazurek Urszula
- Jozef Tyszkiewicz Higher School in Bielsko-Biała, Bielsko-Biała, Poland.,Karol Godula Upper Silesian Academy of Entrepreneurship Chorzów, Chorzów, Poland
| | - Łopata Krzysztof
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland.,HYDREX DIAGNOSTICS Sp. z o.o. Sp.k, Warszawa, Poland
| | - Olczyk Paweł
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec Medical University of Silesia, Katowice, Poland
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Pérez-Pulido AJ, Asencio-Cortés G, Brokate-Llanos AM, Brea-Calvo G, Rodríguez-Griñolo R, Garzón A, Muñoz MJ. Serial co-expression analysis of host factors from SARS-CoV viruses highly converges with former high-throughput screenings and proposes key regulators and co-option of cellular pathways. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2020:2020.07.28.225078. [PMID: 34013266 PMCID: PMC8132222 DOI: 10.1101/2020.07.28.225078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The current genomics era is bringing an unprecedented growth in the amount of gene expression data, only comparable to the exponential growth of sequences in databases during the last decades. This data now allows the design of secondary analyses that take advantage of this information to create new knowledge through specific computational approaches. One of these feasible analyses is the evaluation of the expression level for a gene through a series of different conditions or cell types. Based on this idea, we have developed ASACO, Automatic and Serial Analysis of CO-expression, which performs expression profiles for a given gene along hundreds of normalized and heterogeneous transcriptomics experiments and discover other genes that show either a similar or an inverse behavior. It might help to discover co-regulated genes, and even common transcriptional regulators in any biological model, including human diseases or microbial infections. The present SARS-CoV-2 pandemic is an opportunity to test this novel approach due to the wealth of data that is being generated, which could be used for validating results. In addition, new cell mechanisms identified could become new therapeutic targets. Thus, we have identified 35 host factors in the literature putatively involved in the infectious cycle of SARS-CoV and/or SARS-CoV-2 and searched for genes tightly co-expressed with them. We have found around 1900 co-expressed genes whose assigned functions are strongly related to viral cycles. Moreover, this set of genes heavily overlap with those identified by former laboratory high-throughput screenings (with p-value near 0). Some of these genes aim to cellular structures such as the stress granules, which could be essential for the virus replication and thereby could constitute potential targets in the current fight against the virus. Additionally, our results reveal a series of common transcription regulators, involved in immune and inflammatory responses, that might be key virus targets to induce the coordinated expression of SARS-CoV-2 host factors. All of this proves that ASACO can discover gene co-regulation networks with potential for proposing new genes, pathways and regulators participating in particular biological systems. Highlights ASACO identifies regulatory associations of genes using public transcriptomics data.ASACO highlights new cell functions likely involved in the infection of coronavirus.Comparison with high-throughput screenings validates candidates proposed by ASACO.Genes co-expressed with host's genes used by SARS-CoV-2 are related to stress granules.
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41
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Ni G, Ma Z, Wong JP, Zhang Z, Cousins E, Major MB, Damania B. PPP6C Negatively Regulates STING-Dependent Innate Immune Responses. mBio 2020; 11:e01728-20. [PMID: 32753499 PMCID: PMC7407089 DOI: 10.1128/mbio.01728-20] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 06/30/2020] [Indexed: 12/17/2022] Open
Abstract
Stimulator of interferon genes (STING) is an essential adaptor protein of the innate DNA-sensing signaling pathway, which recognizes genomic DNA from invading pathogens to establish antiviral responses in host cells. STING activity is tightly regulated by several posttranslational modifications, including phosphorylation. However, specifically how the phosphorylation status of STING is modulated by kinases and phosphatases remains to be fully elucidated. In this study, we identified protein phosphatase 6 catalytic subunit (PPP6C) as a binding partner of Kaposi's sarcoma-associated herpesvirus (KSHV) open reading frame 48 (ORF48), which is a negative regulator of the cyclic GMP-AMP synthase (cGAS)-STING pathway. PPP6C depletion enhances double-stranded DNA (dsDNA)-induced and 5'ppp double-stranded RNA (dsRNA)-induced but not poly(I:C)-induced innate immune responses. PPP6C negatively regulates dsDNA-induced IRF3 activation but not NF-κB activation. Deficiency of PPP6C greatly inhibits the replication of herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) as well as the reactivation of KSHV, due to increased type I interferon production. We further demonstrated that PPP6C interacts with STING and that loss of PPP6C enhances STING phosphorylation. These data demonstrate the important role of PPP6C in regulating STING phosphorylation and activation, which provides an additional mechanism by which the host responds to viral infection.IMPORTANCE Cytosolic DNA, which usually comes from invading microbes, is a dangerous signal to the host. The cGAS-STING pathway is the major player that detects cytosolic DNA and then evokes the innate immune response. As an adaptor protein, STING plays a central role in controlling activation of the cGAS-STING pathway. Although transient activation of STING is essential to trigger the host defense during pathogen invasion, chronic STING activation has been shown to be associated with several autoinflammatory diseases. Here, we report that PPP6C negatively regulates the cGAS-STING pathway by removing STING phosphorylation, which is required for its activation. Dephosphorylation of STING by PPP6C helps prevent the sustained production of STING-dependent cytokines, which would otherwise lead to severe autoimmune disorders. This work provides additional mechanisms on the regulation of STING activity and might facilitate the development of novel therapeutics designed to prevent a variety of autoinflammatory disorders.
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Affiliation(s)
- Guoxin Ni
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Zhe Ma
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jason P Wong
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Zhigang Zhang
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Emily Cousins
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - M Ben Major
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Blossom Damania
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Huang X, Li Y, Li X, Fan D, Xin HB, Fu M. TRIM14 promotes endothelial activation via activating NF-κB signaling pathway. J Mol Cell Biol 2020; 12:176-189. [PMID: 31070748 PMCID: PMC7181718 DOI: 10.1093/jmcb/mjz040] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 04/18/2019] [Accepted: 04/28/2019] [Indexed: 12/12/2022] Open
Abstract
Endothelial activation by proinflammatory cytokines is closely associated to the pathogenesis of atherosclerosis and other vascular diseases; however, the molecular mechanisms controlling endothelial activation are not fully understood. Here we identify TRIM14 as a new positive regulator of endothelial activation via activating NF-κB signal pathway. TRIM14 is highly expressed in human vascular endothelial cells (ECs) and markedly induced by inflammatory stimuli such as TNF-α, IL-1β, and LPS. Overexpression of TRIM14 significantly increased the expression of adhesion molecules such as VCAM-1, ICAM-1, E-selectin, and cytokines such as CCL2, IL-8, CXCL-1, and TNF-α in activated ECs and by which it facilitated monocyte adhesion to ECs. Conversely, knockdown of TRIM14 has opposite effect on endothelial activation. Upon TNF-α stimulation, TRIM14 is recruited to IKK complex via directly binding to NEMO and promotes the phosphorylation of IκBα and p65, which is dependent on its K63-linked ubiquitination. Meanwhile, p65 can directly bind to the promoter regions of human TRIM14 gene and control its mRNA transcription. Finally, TRIM14 protein level is significantly upregulated in mouse and human atheroma compared to normal arteries. Taken together, these results indicate that TRIM14-NF-κB forms a positive feedback loop to enhance EC activation and TRIM14 may be a potential therapeutic target for vascular inflammatory diseases such as atherosclerosis.
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Affiliation(s)
- Xuan Huang
- Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
- Department of Biomedical Science and Shock/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Yong Li
- Department of Biomedical Science and Shock/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA
| | - Xiuzhen Li
- Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
- Department of Biomedical Science and Shock/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Daping Fan
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA
| | - Hong-Bo Xin
- Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
| | - Mingui Fu
- Department of Biomedical Science and Shock/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA
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Refolo G, Vescovo T, Piacentini M, Fimia GM, Ciccosanti F. Mitochondrial Interactome: A Focus on Antiviral Signaling Pathways. Front Cell Dev Biol 2020; 8:8. [PMID: 32117959 PMCID: PMC7033419 DOI: 10.3389/fcell.2020.00008] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/10/2020] [Indexed: 01/10/2023] Open
Abstract
In the last years, proteomics has represented a valuable approach to elucidate key aspects in the regulation of type I/III interferons (IFNs) and autophagy, two main processes involved in the response to viral infection, to unveil the molecular strategies that viruses have evolved to counteract these processes. Besides their main metabolic roles, mitochondria are well recognized as pivotal organelles in controlling signaling pathways essential to restrain viral infections. In particular, a major role in antiviral defense is played by mitochondrial antiviral signaling (MAVS) protein, an adaptor protein that coordinates the activation of IFN inducing pathways and autophagy at the mitochondrial level. Here, we provide an overview of how mass spectrometry-based studies of protein–protein interactions and post-translational modifications (PTMs) have fostered our understanding of the molecular mechanisms that control the mitochondria-mediated antiviral immunity.
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Affiliation(s)
- Giulia Refolo
- Lazzaro Spallanzani, National Institute for Infectious Diseases - IRCCS, Rome, Italy
| | - Tiziana Vescovo
- Lazzaro Spallanzani, National Institute for Infectious Diseases - IRCCS, Rome, Italy
| | - Mauro Piacentini
- Lazzaro Spallanzani, National Institute for Infectious Diseases - IRCCS, Rome, Italy.,Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Gian Maria Fimia
- Lazzaro Spallanzani, National Institute for Infectious Diseases - IRCCS, Rome, Italy.,Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Fabiola Ciccosanti
- Lazzaro Spallanzani, National Institute for Infectious Diseases - IRCCS, Rome, Italy
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Zerbe CM, Mouser DJ, Cole JL. Oligomerization of RIG-I and MDA5 2CARD domains. Protein Sci 2020; 29:521-526. [PMID: 31697400 PMCID: PMC6954692 DOI: 10.1002/pro.3776] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/17/2019] [Accepted: 11/01/2019] [Indexed: 12/25/2022]
Abstract
The innate immune system is the first line of defense against invading pathogens. The retinoic acid-inducible gene I (RIG-I) like receptors (RLRs), RIG-I and melanoma differentiation-associated protein 5 (MDA5), are critical for host recognition of viral RNAs. These receptors contain a pair of N-terminal tandem caspase activation and recruitment domains (2CARD), an SF2 helicase core domain, and a C-terminal regulatory domain. Upon RLR activation, 2CARD associates with the CARD domain of MAVS, leading to the oligomerization of MAVS, downstream signaling and interferon induction. Unanchored K63-linked polyubiquitin chains (polyUb) interacts with the 2CARD domain, and in the case of RIG-I, induce tetramer formation. However, the nature of the MDA5 2CARD signaling complex is not known. We have used sedimentation velocity analytical ultracentrifugation to compare MDA5 2CARD and RIG-I 2CARD binding to polyUb and to characterize the assembly of MDA5 2CARD oligomers in the absence of polyUb. Multi-signal sedimentation velocity analysis indicates that Ub4 binds to RIG-I 2CARD with a 3:4 stoichiometry and cooperatively induces formation of an RIG-I 2CARD tetramer. In contrast, Ub4 and Ub7 interact with MDA5 2CARD weakly and form complexes with 1:1 and 2:1 stoichiometries but do not induce 2CARD oligomerization. In the absence of polyUb, MDA5 2CARD self-associates to forms large oligomers in a concentration-dependent manner. Thus, RIG-I and MDA5 2CARD assembly processes are distinct. MDA5 2CARD concentration-dependent self-association, rather than polyUb binding, drives oligomerization and MDA5 2CARD forms oligomers larger than tetramer. We propose a mechanism where MDA5 2CARD oligomers, rather than a stable tetramer, function to nucleate MAVS polymerization.
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Affiliation(s)
- Cassie M. Zerbe
- Department of Molecular and Cell BiologyUniversity of ConnecticutStorrsConnecticut
| | - David J. Mouser
- Department of Molecular and Cell BiologyUniversity of ConnecticutStorrsConnecticut
| | - James L. Cole
- Department of Molecular and Cell BiologyUniversity of ConnecticutStorrsConnecticut
- Department of ChemistryUniversity of ConnecticutStorrsConnecticut
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Chen M, Zhao Z, Meng Q, Liang P, Su Z, Wu Y, Huang J, Cui J. TRIM14 Promotes Noncanonical NF-κB Activation by Modulating p100/p52 Stability via Selective Autophagy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:1901261. [PMID: 31921549 PMCID: PMC6947505 DOI: 10.1002/advs.201901261] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 09/29/2019] [Indexed: 05/15/2023]
Abstract
The noncanonical NF-κB signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF-κB signaling largely relies on the abundance as well as the processing of the NF-κB family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF-κB signaling pathway. TRIM14 promotes noncanonical NF-κB activation by targeting p100/p52 in vitro and in vivo. Furthermore, a mechanistic study shows that TRIM14 recruits deubiquitinase USP14 to cleave the K63-linked ubiquitin chains of p100/p52 at multiple sites, thereby preventing p100/p52 from cargo receptor p62-mediated autophagic degradation. TRIM14 deficiency in mice significantly impairs noncanonical NF-κB-mediated inflammatory responses as well as acute colitis and colitis-associated colon cancer development. Taken together, these findings establish the TRIM14-USP14 axis as a crucial checkpoint that controls noncanonical NF-κB signaling and highlight the crosstalk between autophagy and innate immunity.
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Affiliation(s)
- Meixin Chen
- State Key Laboratory of Oncology in South ChinaMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat‐Sen UniversityGuangzhouGuangdong510006China
| | - Zhiyao Zhao
- State Key Laboratory of Oncology in South ChinaMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat‐Sen UniversityGuangzhouGuangdong510006China
- Department of Internal MedicineGuangzhou Institute of PediatricsGuangzhou Women and Children's Medical CenterGuangzhouGuangdong510623China
| | - Qingcai Meng
- State Key Laboratory of Oncology in South ChinaMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat‐Sen UniversityGuangzhouGuangdong510006China
| | - Puping Liang
- State Key Laboratory of Oncology in South ChinaMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat‐Sen UniversityGuangzhouGuangdong510006China
| | - Zexiong Su
- State Key Laboratory of Oncology in South ChinaMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat‐Sen UniversityGuangzhouGuangdong510006China
| | - Yaoxing Wu
- State Key Laboratory of Oncology in South ChinaMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat‐Sen UniversityGuangzhouGuangdong510006China
| | - Junjiu Huang
- State Key Laboratory of Oncology in South ChinaMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat‐Sen UniversityGuangzhouGuangdong510006China
| | - Jun Cui
- State Key Laboratory of Oncology in South ChinaMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat‐Sen UniversityGuangzhouGuangdong510006China
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Lee HC, Chathuranga K, Lee JS. Intracellular sensing of viral genomes and viral evasion. Exp Mol Med 2019; 51:1-13. [PMID: 31827068 PMCID: PMC6906418 DOI: 10.1038/s12276-019-0299-y] [Citation(s) in RCA: 415] [Impact Index Per Article: 69.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/15/2019] [Accepted: 05/22/2019] [Indexed: 12/11/2022] Open
Abstract
During viral infection, virus-derived cytosolic nucleic acids are recognized by host intracellular specific sensors. The efficacy of this recognition system is crucial for triggering innate host defenses, which then stimulate more specific adaptive immune responses against the virus. Recent studies show that signal transduction pathways activated by sensing proteins are positively or negatively regulated by many modulators to maintain host immune homeostasis. However, viruses have evolved several strategies to counteract/evade host immune reactions. These systems involve viral proteins that interact with host sensor proteins and prevent them from detecting the viral genome or from initiating immune signaling. In this review, we discuss key regulators of cytosolic sensor proteins and viral proteins based on experimental evidence.
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Affiliation(s)
- Hyun-Cheol Lee
- College of Veterinary Medicine, Chungnam National University, Daejeon, 34134, Korea
- Central Research Institute, Komipharm International Co., Ltd, Shiheung, 15094, Korea
| | - Kiramage Chathuranga
- College of Veterinary Medicine, Chungnam National University, Daejeon, 34134, Korea
| | - Jong-Soo Lee
- College of Veterinary Medicine, Chungnam National University, Daejeon, 34134, Korea.
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Porebski B, Wild S, Kummer S, Scaglione S, Gaillard PHL, Gari K. WRNIP1 Protects Reversed DNA Replication Forks from SLX4-Dependent Nucleolytic Cleavage. iScience 2019; 21:31-41. [PMID: 31654852 PMCID: PMC6820244 DOI: 10.1016/j.isci.2019.10.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 04/15/2019] [Accepted: 10/02/2019] [Indexed: 11/30/2022] Open
Abstract
During DNA replication stress, stalled replication forks need to be stabilized to prevent fork collapse and genome instability. The AAA + ATPase WRNIP1 (Werner Helicase Interacting Protein 1) has been implicated in the protection of stalled replication forks from nucleolytic degradation, but the underlying molecular mechanism has remained unclear. Here we show that WRNIP1 exerts its protective function downstream of fork reversal. Unexpectedly though, WRNIP1 is not part of the well-studied BRCA2-dependent branch of fork protection but seems to protect the junction point of reversed replication forks from SLX4-mediated endonucleolytic degradation, possibly by directly binding to reversed replication forks. This function is specific to the shorter, less abundant, and less conserved variant of WRNIP1. Overall, our data suggest that in the absence of BRCA2 and WRNIP1 different DNA substrates are generated at reversed forks but that nascent strand degradation in both cases depends on the activity of exonucleases and structure-specific endonucleases.
WRNIP1, as BRCA2, protects stalled replication forks downstream of fork reversal WRNIP1 and BRCA2 act in two different branches of the fork protection pathway WRNIP1 protects from SLX4-mediated nucleolytic cleavage, possibly by direct binding Fork protection function is specific to the shorter isoform of WRNIP1
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Affiliation(s)
- Bartlomiej Porebski
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
| | - Sebastian Wild
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
| | - Sandra Kummer
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
| | - Sarah Scaglione
- Centre de Recherche en Cancérologie de Marseille, CNRS, INSERM, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France
| | - Pierre-Henri L Gaillard
- Centre de Recherche en Cancérologie de Marseille, CNRS, INSERM, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France
| | - Kerstin Gari
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
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Brisse M, Ly H. Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5. Front Immunol 2019; 10:1586. [PMID: 31379819 PMCID: PMC6652118 DOI: 10.3389/fimmu.2019.01586] [Citation(s) in RCA: 238] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 06/25/2019] [Indexed: 12/12/2022] Open
Abstract
RIG-I (Retinoic acid-inducible gene I) and MDA5 (Melanoma Differentiation-Associated protein 5), collectively known as the RIG-I-like receptors (RLRs), are key protein sensors of the pathogen-associated molecular patterns (PAMPs) in the form of viral double-stranded RNA (dsRNA) motifs to induce expression of type 1 interferons (IFN1) (IFNα and IFNβ) and other pro-inflammatory cytokines during the early stage of viral infection. While RIG-I and MDA5 share many genetic, structural and functional similarities, there is increasing evidence that they can have significantly different strategies to recognize different pathogens, PAMPs, and in different host species. This review article discusses the similarities and differences between RIG-I and MDA5 from multiple perspectives, including their structures, evolution and functional relationships with other cellular proteins, their differential mechanisms of distinguishing between host and viral dsRNAs and interactions with host and viral protein factors, and their immunogenic signaling. A comprehensive comparative analysis can help inform future studies of RIG-I and MDA5 in order to fully understand their functions in order to optimize potential therapeutic approaches targeting them.
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Affiliation(s)
- Morgan Brisse
- Biochemistry, Molecular Biology, and Biophysics Graduate Program, University of Minnesota, Twin Cities, St. Paul, MN, United States
- Department of Veterinary & Biomedical Sciences, University of Minnesota, Twin Cities, St. Paul, MN, United States
| | - Hinh Ly
- Department of Veterinary & Biomedical Sciences, University of Minnesota, Twin Cities, St. Paul, MN, United States
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Cui J, Xu X, Li Y, Hu X, Xie Y, Tan J, Qiao W. TRIM14 expression is regulated by IRF-1 and IRF-2. FEBS Open Bio 2019; 9:1413-1420. [PMID: 31150153 PMCID: PMC6668374 DOI: 10.1002/2211-5463.12682] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 05/01/2019] [Accepted: 05/30/2019] [Indexed: 12/20/2022] Open
Abstract
Tripartite motif‐containing 14 (TRIM14) is a mitochondrial adaptor that promotes innate immune signaling and plays important roles in antiviral defense. Expression of TRIM14 is induced by interferon (IFN)‐I. However, the mechanism by which IFN‐I induces TRIM14 production is not yet determined. In this study, we have examined the function of TRIM14 promoter and found that a GC box and an IFN‐stimulated response element (ISRE) are necessary for the basal level transcription of TRIM14. We further observed that IFN‐I activates the TRIM14 promoter through the ISRE. In particular, interferon regulatory factor (IRF)‐1 and IRF‐2 bind to the TRIM14 promoter and activate transcription of TRIM14. Moreover, knockdown of IRF‐1 reduces the stimulation of TRIM14 transcription by IFN‐α, suggesting that IRF‐1 is involved in the activation of TRIM14 by IFN‐I. IRF‐2 has little effect on IFN‐α‐induced TRIM14 transcription but is essential for the basal transcription of TRIM14.
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Affiliation(s)
- Jingang Cui
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Xiao Xu
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Yutong Li
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Xiaomei Hu
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Yingpeng Xie
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Juan Tan
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Wentao Qiao
- Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
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Shen W, Jin Z, Tong X, Wang H, Zhuang L, Lu X, Wu S. TRIM14 promotes cell proliferation and inhibits apoptosis by suppressing PTEN in colorectal cancer. Cancer Manag Res 2019; 11:5725-5735. [PMID: 31296997 PMCID: PMC6598940 DOI: 10.2147/cmar.s210782] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 05/23/2019] [Indexed: 12/13/2022] Open
Abstract
Background Colorectal cancer (CRC) is among the most frequent and lethal malignancies worldwide. Although great advances have been made in the treatment of CRC, prognosis remains poor. Our previous study indicated that tripartite motif-containing 14 (TRIM14) was upregulated in CRC samples. Methods In the current study, the association between TRIM14 and CRC was investigated. Protein expression was determined by Western blotting and immunohistochemistry. Further, the biological roles of TRIM14 in CRC cell proliferation and apoptosis were explored both in vitro and in vivo. Results We observed that increased TRIM14 expression in CRC tissues was closely related with aggressive clinicopathological characteristics and poor prognosis. TRIM14 knockdown markedly reduced proliferation and increased apoptosis in HT-29 and SW620 cells, whereas TRIM14 overexpression in LoVo cells displayed opposite results. Xenograft experiments using HT-29 cells confirmed suppression of tumor growth and induction of apoptosis upon TRIM14 knockdown in vivo. Furthermore, downregulation of TRIM14 inhibited the AKT pathway, as indicated by reduced levels of phosphorylated AKT, Bcl-2 and Cyclin D1, and elevated levels of phosphatase and
tensin homology (PTEN) and p27. In addition, TRIM14 colocalized with PTEN in the cytoplasm and induced PTEN ubiquitination. Moreover, PTEN overexpression significantly inhibited pro-proliferative effects of TRIM14, indicating an involvement of PTEN/AKT signaling in mediating TRIM14 functions. Conclusions The present data demonstrate that TRIM14 overexpression promotes CRC cell proliferation, suggesting TRIM14 as an attractive therapeutic target for CRC.
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Affiliation(s)
- Weidong Shen
- Department of Gastroenterology, Jiangyin Hospital Affiliated to Nantong University, Jiangyin, People's Republic of China
| | - Zhonghai Jin
- Department of Gastroenterology, Yiwu Hospital, Wenzhou Medical University, Yiwu, People's Republic of China
| | - Xiuping Tong
- Department of Gastroenterology, Yiwu Hospital, Wenzhou Medical University, Yiwu, People's Republic of China
| | - Haiying Wang
- Department of Gastroenterology, Yiwu Hospital, Wenzhou Medical University, Yiwu, People's Republic of China
| | - Lilei Zhuang
- Department of Gastroenterology, Yiwu Hospital, Wenzhou Medical University, Yiwu, People's Republic of China
| | - Xiaofeng Lu
- Department of Gastroenterology, Yiwu Hospital, Wenzhou Medical University, Yiwu, People's Republic of China
| | - Shenbao Wu
- Department of Gastroenterology, Yiwu Hospital, Wenzhou Medical University, Yiwu, People's Republic of China
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