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Xue F, Liu YK, Chen XY, Chen SS, Yu XR, Li HW, Lu LG, Chen MH. Targeting cGAS-STING: modulating the immune landscape of hepatic diseases. Front Immunol 2025; 16:1498323. [PMID: 40098962 PMCID: PMC11911377 DOI: 10.3389/fimmu.2025.1498323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 02/11/2025] [Indexed: 03/19/2025] Open
Abstract
Liver diseases, including viral hepatitis, alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC), represent a significant threat to global health due to their high mortality rates. The cGAS-STING pathway, a critical part of the innate immune system, plays a crucial role in detecting cytoplasmic DNA and initiating immune responses, including autoimmune inflammation and antitumor immunity. Genomic instability during cancer progression can trigger this pathway by releasing DNA into the cytoplasm. Emerging research indicates that cGAS-STING signaling is intricately involved in maintaining liver homeostasis and contributes to the pathogenesis of various liver diseases. This review outlines the cGAS-STING pathway, with a particular focus on its activation mechanism and its roles in several notable liver conditions. Specifically, we explore the complex interplay of cGAS-STING signaling in viral hepatitis, ALD, MASLD, and HCC, and discuss its potential as a therapeutic target. For example, in HCC, strategies targeting cGAS-STING include using nanomaterials to deliver STING agonists, combining radiofrequency ablation (RFA) with cGAS-STING activation, and leveraging radiotherapy to enhance pathway activation. Furthermore, modulating cGAS-STING activity may offer therapeutic avenues for viral hepatitis and chronic liver diseases like MASLD and ALD, either by boosting antiviral responses or mitigating inflammation. This review highlights the complex role of cGAS-STING signaling in these specific liver diseases and underscores the need for further research to fully realize its therapeutic potential.
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Affiliation(s)
- Feng Xue
- Department of Radiology, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital, The Affiliated Hospital of Beijing Institute of Technology), Zhuhai, Guangdong, China
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai, Guangdong, China
| | - Yong-Kang Liu
- Department of Radiology, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital, The Affiliated Hospital of Beijing Institute of Technology), Zhuhai, Guangdong, China
- Guangzhou First People's Hospital, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Xiao-Ying Chen
- Department of Radiology, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital, The Affiliated Hospital of Beijing Institute of Technology), Zhuhai, Guangdong, China
| | - Shan-Shan Chen
- Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital, The Affiliated Hospital of Beijing Institute of Technology), Zhuhai, Guangdong, China
| | - Xiang-Rong Yu
- Department of Radiology, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital, The Affiliated Hospital of Beijing Institute of Technology), Zhuhai, Guangdong, China
| | - Hua-Wen Li
- Department of Gynecology, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital, The Affiliated Hospital of Beijing Institute of Technology), Zhuhai, Guangdong, China
| | - Li-Gong Lu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai, Guangdong, China
- Guangzhou First People's Hospital, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Mu-He Chen
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai, Guangdong, China
- Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital, The Affiliated Hospital of Beijing Institute of Technology), Zhuhai, Guangdong, China
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Wang YY, Wang XL, Li ZC, Zhang C, Xu X, Cui BJ, Tian MZ, Zhou CJ, Xu N, Wu Y, Yang XL, Chen DD, Lu LF, Li S. Grass carp reovirus VP4 manipulates TOLLIP to degrade STING for inhibition of IFN production. J Virol 2025; 99:e0158324. [PMID: 39807855 PMCID: PMC11853074 DOI: 10.1128/jvi.01583-24] [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: 09/08/2024] [Accepted: 12/12/2024] [Indexed: 01/16/2025] Open
Abstract
Although fish possess an effective interferon (IFN) system to defend against viral infection, grass carp reovirus (GCRV) still causes epidemic hemorrhagic disease and tremendous economic loss in grass carp. Therefore, it is necessary to investigate the immune escape strategies employed by GCRV. In this study, we show that the structural protein VP4 of GCRV (encoded by the S6 segment) significantly restricts IFN expression by degrading stimulator of IFN genes (STING) through the autophagy-lysosome-dependent pathway. First, overexpression of VP4 inhibited the expression of IFN induced by GCRV and polyinosinic-polycytidylic acid (poly I:C) at both the promoter and mRNA levels. Second, VP4 was found to associate with STING, and the N-terminal transmembrane domain is essential for this interaction. Additionally, VP4 dramatically blocked STING-induced IFN expression and weakened its antiviral capacity. Further mechanistic studies revealed that VP4 degrades STING via the autophagy-lysosome pathway in a dose-dependent manner. Interestingly, toll-interacting protein (TOLLIP), a selective autophagy receptor, was found to interact with VP4 and reduce VP4-mediated STING degradation after tollip knockdown. Finally, overexpression of VP4 facilitated GCRV proliferation, while its depletion had the opposite effect. These findings indicate that GCRV VP4 recruits TOLLIP to degrade STING and achieve immune escape. This enhances our comprehension of aquatic virus pathogenesis. IMPORTANCE Upon virus invasion, fish cells employ a multitude of strategies to defend against infection. Consequently, viruses have evolved a plethora of tactics to evade host antiviral mechanisms. To date, fewer studies have been conducted on the immune evasion mechanism of grass carp reovirus (GCRV). In this study, we demonstrate that VP4 of GCRV-873 inhibits interferon expression by interacting with stimulator of IFN gene and degrading it in an autophagy-lysosome-dependent manner through the manipulation of the selective autophagy receptor toll-interacting protein. The findings of this study contribute to our understanding of the novel evasion mechanisms of GCRV and widen our knowledge of the virus-host interactions in lower vertebrates.
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Affiliation(s)
- Yang-Yang Wang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, Beijing, China
| | - Xue-Li Wang
- TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, Tianjin, China
| | - Zhuo-Cong Li
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, Beijing, China
| | - Can Zhang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, Beijing, China
| | - Xiao Xu
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, Liaoning, China
| | - Bao-Jie Cui
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, Liaoning, China
| | - Meng-Ze Tian
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, Liaoning, China
| | - Chu-Jing Zhou
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- College of Fisheries and Life Science, Dalian Ocean University, Dalian, Liaoning, China
| | - Na Xu
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, Beijing, China
| | - Yue Wu
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, Beijing, China
| | - Xiao-Li Yang
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, Beijing, China
| | - Dan-Dan Chen
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, Beijing, China
| | - Long-Feng Lu
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, Beijing, China
- Key Laboratory of Aquaculture Disease Control, Ministry of Agriculture, Wuhan, China
| | - Shun Li
- Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, Beijing, China
- Key Laboratory of Aquaculture Disease Control, Ministry of Agriculture, Wuhan, China
- Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Wuhan, China
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3
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Rui Y, Shen S, Wang Y, Cheng L, Chen S, Hu Y, Cai Y, Wei W, Su J, Yu XF. HIV-1 Vpu and SARS-CoV-2 ORF3a proteins disrupt STING-mediated activation of antiviral NF-κB signaling. Sci Signal 2025; 18:eadd6593. [PMID: 39836751 DOI: 10.1126/scisignal.add6593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 09/12/2023] [Accepted: 12/19/2024] [Indexed: 01/30/2025]
Abstract
Activation of the stimulator of interferon genes (STING) pathway by cytosolic DNA leads to the activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB). Although many viruses produce proteins that inhibit IRF3-dependent antiviral responses, some viruses produce proteins that inhibit STING-induced NF-κB activation without blocking IRF3 activation. Here, we found that STING-activated, NF-κB-dependent, and IRF3-independent innate immunity inhibited the replication of the DNA virus herpes simplex virus type 1 (HSV-1), the RNA virus coxsackievirus A16 (CV-A16), and the retrovirus HIV-1. The HIV-1 nonstructural protein Vpu bound to STING and prevented it from interacting with the upstream NF-κB pathway kinase inhibitor of NF-κB subunit β (IKKβ), thus blocking NF-κB signaling. This function of Vpu was conserved among Vpu proteins from diverse HIV-1 and simian immunodeficiency virus strains and was distinct from its action in disrupting other host antiviral pathways. Furthermore, the ORF3a protein from the coronavirus SARS-CoV-2 also promoted viral replication by interacting with STING and blocking STING-induced activity of NF-κB but not of IRF3. These findings demonstrate that diverse viral proteins have convergently evolved to selectively inhibit NF-κB-mediated innate immunity downstream of STING activation, suggesting that targeting this pathway may represent a promising antiviral strategy.
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Affiliation(s)
- Yajuan Rui
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
- Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310000, China
| | - Si Shen
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
- Department of Respiratory Disease, Thoracic Disease Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Yanpu Wang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
- Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310000, China
| | - Leyi Cheng
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Shiqi Chen
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Ying Hu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
| | - Yong Cai
- School of Life Science, Jilin University, Changchun 130012, China
| | - Wei Wei
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Translational Medicine and Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin 130021, China
| | - Jiaming Su
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
- Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310000, China
| | - Xiao-Fang Yu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
- Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310000, China
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4
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Delli Ponti R, Vandelli A, Tartaglia GG. Subgenomic flaviviral RNAs and human proteins: in silico exploration of anti-host defense mechanisms. Comput Struct Biotechnol J 2024; 23:3527-3536. [PMID: 39435344 PMCID: PMC11492465 DOI: 10.1016/j.csbj.2024.09.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/29/2024] [Accepted: 09/29/2024] [Indexed: 10/23/2024] Open
Abstract
Flaviviruses pose significant global health threats, infecting over 300 million people annually. Among their evasion strategies, the production of subgenomic flaviviral RNAs (sfRNAs) from the 3' UTR of viral genomes is particularly notable. Utilizing a comprehensive in silico approach with the catRAPID algorithm, we analyzed over 300,000 interactions between sfRNAs and human proteins derived from more than 8000 flavivirus genomes, including Dengue, Zika, Yellow Fever, West Nile, and Japanese Encephalitis viruses. By providing the first extensive atlas of sfRNA interactions, we offer new insights into how flaviviruses can manipulate host cellular machinery to facilitate viral survival and persistence. Our study not only validated known interactions but also revealed novel human proteins that could be involved in sfRNA-mediated host defense evasion, including helicases, splicing factors, and chemokines. These findings significantly expand the known interactome of sfRNAs with human proteins, underscoring their role in modulating host cellular pathways. Intriguingly, we predict interaction with stress granules, a critical component of the cellular response to viral infection, suggesting a mechanism by which flaviviruses inhibit their formation to evade host defenses. Moreover, a set of highly-interacting proteins in common among the sfRNAs showed predictive power to identify sfRNA-forming regions, highlighting how protein signatures could be used to annotate viruses. This atlas not only serves as a resource for exploring therapeutic targets but also aids in the identification of sfRNA biomarkers for improved flavivirus diagnostics.
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Affiliation(s)
- Riccardo Delli Ponti
- Centre for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, Genova GE 16152, Italy
| | - Andrea Vandelli
- Centre for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, Genova GE 16152, Italy
| | - Gian Gaetano Tartaglia
- Centre for Human Technologies, Istituto Italiano di Tecnologia, Via Enrico Melen, 83, Genova GE 16152, Italy
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5
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Sharma AK, Mal S, Sahu SK, Bagchi S, Majumder D, Chakravorty D, Saha S, Kundu M, Basu J. Mycobacterial peptidyl prolyl isomerase A activates STING-TBK1-IRF3 signaling to promote IFNβ release in macrophages. FEBS J 2024. [PMID: 39288201 DOI: 10.1111/febs.17261] [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: 12/07/2023] [Revised: 06/23/2024] [Accepted: 08/21/2024] [Indexed: 09/19/2024]
Abstract
Peptidyl prolyl isomerases (PPIases) are well-conserved protein-folding enzymes that moonlight as regulators of bacterial virulence. Peptidyl prolyl isomerase A, PPiA (Rv0009) is a secretory protein of Mycobacterium tuberculosis that possesses sequence and structural similarity to eukaryotic cyclophilins. In this study, we validated the interaction of PPiA with stimulator of interferon genes (STING) using both, Escherichia coli-based and mammalian in vitro expression systems. In vitro pull-down assays confirmed that the cytosolic domain of STING interacts with PPiA, and moreover, we found that PPiA could induce dimerization of STING in macrophages. In silico docking analyses suggested that the PXXP (PDP) motif of PPiA is crucial for interaction with STING, and concordantly, mutations in the PDP domain (PPiA MUT-II) abrogated this interaction, as well as the ability of PPiA to facilitate STING dimerization. In agreement with these observations, fluorescence microscopy demonstrated that STING and wild-type PPiA, but not PPiA MUT-II, could colocalize when expressed in HEK293 cells. Highlighting the importance of the PDP domain further, PPiA, but not PPiA MUT-II could activate Tank binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) signaling to promote the release of interferon-beta (IFNβ). PPiA, but not PPiA MUT-II expressed in Mycobacterium smegmatis induced IFNβ release and facilitated bacterial survival in macrophages in a STING-dependent manner. The PPiA-induced release of IFNβ was c-GAS independent. We conclude that PPiA is a previously undescribed mycobacterial regulator of STING-dependent type I interferon production from macrophages.
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Affiliation(s)
| | - Soumya Mal
- Department of Biological Sciences, Bose Institute, Kolkata, India
| | | | - Shreya Bagchi
- Department of Chemical Sciences, Bose Institute, Kolkata, India
| | | | | | - Sudipto Saha
- Department of Biological Sciences, Bose Institute, Kolkata, India
| | | | - Joyoti Basu
- Department of Chemical Sciences, Bose Institute, Kolkata, India
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Al Hamrashdi M, Sanchez Perez C, Haas DA, Vishwakarma J, Pichlmair A, Bowie AG, Brady G. Molluscum contagiosum virus protein MC089 inhibits interferon regulatory factor 3 activation. J Gen Virol 2024; 105:002015. [PMID: 39167082 PMCID: PMC11338640 DOI: 10.1099/jgv.0.002015] [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: 03/27/2024] [Accepted: 07/30/2024] [Indexed: 08/23/2024] Open
Abstract
Molluscum contagiosum virus (MCV) is a human-specific poxvirus that causes a highly common but mild infection characterized by distinctive and persistent papular skin lesions. These lesions can persist for long periods without an effective clearance response from the host. MCV, like all poxviruses, encodes multiple known immunosuppressive proteins which target innate immune signalling pathways involved in viral nucleic acid sensing, interferon production and inflammation which should trigger antiviral immunity leading to clearance. Two major families of transcription factors responsible for driving the immune response to viruses are the NF-κB and the interferon regulatory factor (IRF) families. While NF-κB broadly drives pro-inflammatory gene expression and IRFs chiefly drive interferon induction, both collaborate in transactivating many of the same genes in a concerted immune response to viral infection. Here, we report that the MCV protein MC089 specifically inhibits IRF activation from both DNA- and RNA-sensing pathways, making it the first characterized MCV inhibitor to selectively target IRF activation to date. MC089 interacts with proteins required for IRF activation, namely IKKε, TBKBP1 and NAP1. Additionally, MC089 targets RNA sensing by associating with the RNA-sensing adaptor protein mitochondrial antiviral-signalling protein on mitochondria. MC089 displays specificity in its inhibition of IRF3 activation by suppressing immunostimulatory nucleic acid-induced serine 396 phosphorylation without affecting the phosphorylation of serine 386. The selective interaction of MC089 with IRF-regulatory proteins and site-specific inhibition of IRF3 phosphorylation may offer a tool to provide novel insights into the biology of IRF3 regulation.
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Affiliation(s)
- Mariya Al Hamrashdi
- Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, St. James’ Hospital Campus, Dublin, Ireland
| | - Carla Sanchez Perez
- Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, St. James’ Hospital Campus, Dublin, Ireland
| | - Darya A. Haas
- Technical University of Munich, School of Medicine, Institute of Virology, Munich, Germany
| | - Jyoti Vishwakarma
- Technical University of Munich, School of Medicine, Institute of Virology, Munich, Germany
| | - Andreas Pichlmair
- Technical University of Munich, School of Medicine, Institute of Virology, Munich, Germany
- German Centre for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Andrew G. Bowie
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Gareth Brady
- Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, St. James’ Hospital Campus, Dublin, Ireland
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Xie F, Zhu Q. The regulation of cGAS-STING signaling by RNA virus-derived components. Virol J 2024; 21:101. [PMID: 38693578 PMCID: PMC11064393 DOI: 10.1186/s12985-024-02359-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 04/04/2024] [Indexed: 05/03/2024] Open
Abstract
The Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) serves as a key innate immune signaling axis involved in the regulation of various human diseases. It has been found that cGAS-STING pathway can recognize a variety of cytosolic double-stranded DNA (dsDNA), contributing to cause a robust type I interferon response thereby affecting the occurrence and progression of viral infection. Accumulating evidence indicates RNA virus-derived components play an important role in regulating cGAS-STING signaling, either as protective or pathogenic factors in the pathogenesis of diseases. Thus, a comprehensive understanding of the function of RNA virus-derived components in regulating cGAS-STING signaling will provide insights into developing novel therapies. Here, we review the existing literature on cGAS-STING pathway regulated by RNA virus-derived components to propose insights into pharmacologic strategies targeting the cGAS-STING pathway.
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Affiliation(s)
- Feiting Xie
- Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, China.
| | - Qiugang Zhu
- Department of Laboratory Medicine, Shangyu People's Hospital of Shaoxing, Shaoxing, China
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Mondelli MU, Ottolini S, Oliviero B, Mantovani S, Cerino A, Mele D, Varchetta S. Hepatitis C Virus and the Host: A Mutual Endurance Leaving Indelible Scars in the Host's Immunity. Int J Mol Sci 2023; 25:268. [PMID: 38203436 PMCID: PMC10779088 DOI: 10.3390/ijms25010268] [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: 11/28/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatitis C virus (HCV) has spread worldwide, and it is responsible for potentially severe chronic liver disease and primary liver cancer. Chronic infection remains for life if not spontaneously eliminated and viral persistence profoundly impairs the efficiency of the host's immunity. Attempts have been made to develop an effective vaccine, but efficacy trials have met with failure. The availability of highly efficacious direct-acting antivirals (DAA) has created hope for the progressive elimination of chronic HCV infections; however, this approach requires a monumental global effort. HCV elicits a prompt innate immune response in the host, characterized by a robust production of interferon-α (IFN-α), although interference in IFN-α signaling by HCV proteins may curb this effect. The late appearance of largely ineffective neutralizing antibodies and the progressive exhaustion of T cells, particularly CD8 T cells, result in the inability to eradicate the virus in most infected patients. Moreover, an HCV cure resulting from DAA treatment does not completely restore the normal immunologic homeostasis. Here, we discuss the main immunological features of immune responses to HCV and the epigenetic scars that chronic viral persistence leaves behind.
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Affiliation(s)
- Mario U. Mondelli
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Sabrina Ottolini
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;
| | - Barbara Oliviero
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Stefania Mantovani
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Antonella Cerino
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Dalila Mele
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Stefania Varchetta
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
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Barik S. Suppression of Innate Immunity by the Hepatitis C Virus (HCV): Revisiting the Specificity of Host-Virus Interactive Pathways. Int J Mol Sci 2023; 24:16100. [PMID: 38003289 PMCID: PMC10671098 DOI: 10.3390/ijms242216100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 10/31/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
The hepatitis C virus (HCV) is a major causative agent of hepatitis that may also lead to liver cancer and lymphomas. Chronic hepatitis C affects an estimated 2.4 million people in the USA alone. As the sole member of the genus Hepacivirus within the Flaviviridae family, HCV encodes a single-stranded positive-sense RNA genome that is translated into a single large polypeptide, which is then proteolytically processed to yield the individual viral proteins, all of which are necessary for optimal viral infection. However, cellular innate immunity, such as type-I interferon (IFN), promptly thwarts the replication of viruses and other pathogens, which forms the basis of the use of conjugated IFN-alpha in chronic hepatitis C management. As a countermeasure, HCV suppresses this form of immunity by enlisting diverse gene products, such as HCV protease(s), whose primary role is to process the large viral polyprotein into individual proteins of specific function. The exact number of HCV immune suppressors and the specificity and molecular mechanism of their action have remained unclear. Nonetheless, the evasion of host immunity promotes HCV pathogenesis, chronic infection, and carcinogenesis. Here, the known and putative HCV-encoded suppressors of innate immunity have been reviewed and analyzed, with a predominant emphasis on the molecular mechanisms. Clinically, the knowledge should aid in rational interventions and the management of HCV infection, particularly in chronic hepatitis.
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Affiliation(s)
- Sailen Barik
- EonBio, 3780 Pelham Drive, Mobile, AL 36619, USA
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Chen F, Kang R, Liu J, Tang D. The ACSL4 Network Regulates Cell Death and Autophagy in Diseases. BIOLOGY 2023; 12:864. [PMID: 37372148 DOI: 10.3390/biology12060864] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/05/2023] [Accepted: 06/11/2023] [Indexed: 06/29/2023]
Abstract
Lipid metabolism, cell death, and autophagy are interconnected processes in cells. Dysregulation of lipid metabolism can lead to cell death, such as via ferroptosis and apoptosis, while lipids also play a crucial role in the regulation of autophagosome formation. An increased autophagic response not only promotes cell survival but also causes cell death depending on the context, especially when selectively degrading antioxidant proteins or organelles that promote ferroptosis. ACSL4 is an enzyme that catalyzes the formation of long-chain acyl-CoA molecules, which are important intermediates in the biosynthesis of various types of lipids. ACSL4 is found in many tissues and is particularly abundant in the brain, liver, and adipose tissue. Dysregulation of ACSL4 is linked to a variety of diseases, including cancer, neurodegenerative disorders, cardiovascular disease, acute kidney injury, and metabolic disorders (such as obesity and non-alcoholic fatty liver disease). In this review, we introduce the structure, function, and regulation of ACSL4; discuss its role in apoptosis, ferroptosis, and autophagy; summarize its pathological function; and explore the potential implications of targeting ACSL4 in the treatment of various diseases.
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Affiliation(s)
- Fangquan Chen
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511436, China
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jiao Liu
- DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511436, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
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11
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Coderch C, Arranz-Herrero J, Nistal-Villan E, de Pascual-Teresa B, Rius-Rocabert S. The Many Ways to Deal with STING. Int J Mol Sci 2023; 24:ijms24109032. [PMID: 37240378 DOI: 10.3390/ijms24109032] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/15/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
The stimulator of interferon genes (STING) is an adaptor protein involved in the activation of IFN-β and many other genes associated with the immune response activation in vertebrates. STING induction has gained attention from different angles such as the potential to trigger an early immune response against different signs of infection and cell damage, or to be used as an adjuvant in cancer immune treatments. Pharmacological control of aberrant STING activation can be used to mitigate the pathology of some autoimmune diseases. The STING structure has a well-defined ligand binding site that can harbor natural ligands such as specific purine cyclic di-nucleotides (CDN). In addition to a canonical stimulation by CDNs, other non-canonical stimuli have also been described, whose exact mechanism has not been well defined. Understanding the molecular insights underlying the activation of STING is important to realize the different angles that need to be considered when designing new STING-binding molecules as therapeutic drugs since STING acts as a versatile platform for immune modulators. This review analyzes the different determinants of STING regulation from the structural, molecular, and cell biology points of view.
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Affiliation(s)
- Claire Coderch
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Boadilla del Monte, Spain
| | - Javier Arranz-Herrero
- Transplant Immunology Unit, National Center of Microbiology, Instituto de Salud Carlos III, 28220 Majadahonda, Spain
- Departamento CC, Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Boadilla del Monte, Spain
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Boadilla del Monte, Spain
| | - Estanislao Nistal-Villan
- Departamento CC, Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Boadilla del Monte, Spain
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Boadilla del Monte, Spain
| | - Beatriz de Pascual-Teresa
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Boadilla del Monte, Spain
| | - Sergio Rius-Rocabert
- Departamento CC, Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Boadilla del Monte, Spain
- Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28668 Boadilla del Monte, Spain
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12
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Amurri L, Horvat B, Iampietro M. Interplay between RNA viruses and cGAS/STING axis in innate immunity. Front Cell Infect Microbiol 2023; 13:1172739. [PMID: 37077526 PMCID: PMC10106766 DOI: 10.3389/fcimb.2023.1172739] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 03/21/2023] [Indexed: 04/05/2023] Open
Abstract
While the function of cGAS/STING signalling axis in the innate immune response to DNA viruses is well deciphered, increasing evidence demonstrates its significant contribution in the control of RNA virus infections. After the first evidence of cGAS/STING antagonism by flaviviruses, STING activation has been detected following infection by various enveloped RNA viruses. It has been discovered that numerous viral families have implemented advanced strategies to antagonize STING pathway through their evolutionary path. This review summarizes the characterized cGAS/STING escape strategies to date, together with the proposed mechanisms of STING signalling activation perpetrated by RNA viruses and discusses possible therapeutic approaches. Further studies regarding the interaction between RNA viruses and cGAS/STING-mediated immunity could lead to major discoveries important for the understanding of immunopathogenesis and for the treatment of RNA viral infections.
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13
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Pan J, Fei CJ, Hu Y, Wu XY, Nie L, Chen J. Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases. Zool Res 2023; 44:183-218. [PMID: 36579404 PMCID: PMC9841179 DOI: 10.24272/j.issn.2095-8137.2022.464] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 12/27/2022] [Indexed: 01/04/2023] Open
Abstract
The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway, comprised of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases. After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2'3'-cGAMP for the activation of endoplasmic reticulum (ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosolic-localized cGAS. Detailed delineation of this pathway, including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.
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Affiliation(s)
- Jing Pan
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, Zhejiang 315832, China
- Zhejiang Key Laboratory of Marine Bioengineering, Ningbo University, Ningbo, Zhejiang 315832, China
| | - Chen-Jie Fei
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, Zhejiang 315832, China
- Zhejiang Key Laboratory of Marine Bioengineering, Ningbo University, Ningbo, Zhejiang 315832, China
| | - Yang Hu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, Zhejiang 315832, China
- Zhejiang Key Laboratory of Marine Bioengineering, Ningbo University, Ningbo, Zhejiang 315832, China
| | - Xiang-Yu Wu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, Zhejiang 315832, China
- Zhejiang Key Laboratory of Marine Bioengineering, Ningbo University, Ningbo, Zhejiang 315832, China
| | - Li Nie
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, Zhejiang 315832, China
- Zhejiang Key Laboratory of Marine Bioengineering, Ningbo University, Ningbo, Zhejiang 315832, China. E-mail:
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, Zhejiang 315832, China
- Zhejiang Key Laboratory of Marine Bioengineering, Ningbo University, Ningbo, Zhejiang 315832, China. E-mail:
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Haridevamuthu B, Guru A, Velayutham M, Snega Priya P, Arshad A, Arockiaraj J. Long non‐coding RNA, a supreme post‐transcriptional immune regulator of bacterial or virus‐driven immune evolution in teleost. REVIEWS IN AQUACULTURE 2023; 15:163-178. [DOI: 10.1111/raq.12709] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 06/18/2022] [Indexed: 10/16/2023]
Abstract
AbstractThe global aquaculture boom, fuelled by a reduction in wild population and detection of novel viruses, has created a demanding market, hence, there is a pressing need to investigate the immune system of fish, further. As the most diverse community of vertebrates and a central contributor to the progressing global aquaculture market, teleost continues to draw vast scientific interest. Recent breakthroughs in multi‐omics technologies have provided a platform to understand the role of long non‐coding RNA (lncRNA) in the host immune system during infection. Emerging evidence shows that teleost lncRNA might have a regulatory role in immune responses, mostly through lncRNA–microRNA (miRNA) sponging. Teleost lncRNA shares a functionally active short sequence complement to target the miRNA which is conserved among the several fish species. Recent report suggests that rhabdovirus exploits a lncRNA in teleost and, to dodge the host immune mechanism and negatively regulate the immune system. This observation reveals the essentiality of lncRNA in pathogen‐driven immunity in teleost. Reports available on the function of teleost lncRNA are still in early stages and experimental verifications are a limiting factor. Unravelling the lncRNA‐mediated immune regulation in fishes could be used against the invading pathogens to strengthen the aquaculture production. This review elaborates on the experimentally identified and functionally characterized lncRNA and its regulatory role in the teleost immune response during infection and pathogen‐driven host immune evolution, which could eventually lead to achieving high standards in aquaculture productivity.
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Affiliation(s)
- B. Haridevamuthu
- Department of Biotechnology, College of Science and Humanities SRM Institute of Science and Technology Chennai Tamil Nadu India
| | - Ajay Guru
- Department of Biotechnology, College of Science and Humanities SRM Institute of Science and Technology Chennai Tamil Nadu India
| | - Manikandan Velayutham
- Department of Biotechnology, College of Science and Humanities SRM Institute of Science and Technology Chennai Tamil Nadu India
| | - P. Snega Priya
- Department of Biotechnology, College of Science and Humanities SRM Institute of Science and Technology Chennai Tamil Nadu India
| | - Aziz Arshad
- International Institute of Aquaculture and Aquatic Sciences (I‐AQUAS) Universiti Putra Malaysia Port Dickson Malaysia
| | - Jesu Arockiaraj
- Department of Biotechnology, College of Science and Humanities SRM Institute of Science and Technology Chennai Tamil Nadu India
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15
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Impact of eradication of hepatitis C virus on liver-related and -unrelated diseases: morbidity and mortality of chronic hepatitis C after SVR. J Gastroenterol 2022; 58:299-310. [PMID: 36585501 DOI: 10.1007/s00535-022-01940-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/05/2022] [Indexed: 12/31/2022]
Abstract
Hepatitis C virus infection is characterized by chronic liver inflammation and fibrogenesis, leading to end-stage liver failure and hepatocellular carcinoma over the course of 20 to 30 years. It seems not only the chronicity of hepatitis C but also the presence of the virus in non-hepatic tissues creates a favorable environment for the potential development of pathogenic impacts on extrahepatic systems and organs. Numerous extra-hepatic manifestations have been reported in association with HCV infection, all of which can substantially affect morbidity, mortality, and quality of life. With the recent development of DAAs, antiviral treatment can cure almost all patients with HCV infection, even those intolerant of or unresponsive to IFN treatment, and several large multicenter studies have confirmed the association of DAA-induced SVR with reductions in liver-related and liver-unrelated complications, such as cardiovascular events, end stage renal disease, and so on. Because, in addition to liver-related diseases, extrahepatic lesions are threatening for patients, it is important to eradicate the virus before these progress and affect life prognosis; in other words, patients should be treated before reaching the point of no return. Tailored surveillance with biomarkers such as M2BPGi and Ang-2, which can be used to identify patients with an elevated risk of EHM, and early prevention or treatment for these patients could improve the morbidity, mortality and QOL. Advancement of both basic and clinical research in this field including the development of more precise biomarkers is highly anticipated.
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16
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Diaz O, Vidalain PO, Ramière C, Lotteau V, Perrin-Cocon L. What role for cellular metabolism in the control of hepatitis viruses? Front Immunol 2022; 13:1033314. [PMID: 36466918 PMCID: PMC9713817 DOI: 10.3389/fimmu.2022.1033314] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/02/2022] [Indexed: 11/26/2023] Open
Abstract
Hepatitis B, C and D viruses (HBV, HCV, HDV, respectively) specifically infect human hepatocytes and often establish chronic viral infections of the liver, thus escaping antiviral immunity for years. Like other viruses, hepatitis viruses rely on the cellular machinery to meet their energy and metabolite requirements for replication. Although this was initially considered passive parasitism, studies have shown that hepatitis viruses actively rewire cellular metabolism through molecular interactions with specific enzymes such as glucokinase, the first rate-limiting enzyme of glycolysis. As part of research efforts in the field of immunometabolism, it has also been shown that metabolic changes induced by viruses could have a direct impact on the innate antiviral response. Conversely, detection of viral components by innate immunity receptors not only triggers the activation of the antiviral defense but also induces in-depth metabolic reprogramming that is essential to support immunological functions. Altogether, these complex triangular interactions between viral components, innate immunity and hepatocyte metabolism may explain why chronic hepatitis infections progressively lead to liver inflammation and progression to cirrhosis, fibrosis and hepatocellular carcinoma (HCC). In this manuscript, we first present a global overview of known connections between the innate antiviral response and cellular metabolism. We then report known molecular mechanisms by which hepatitis viruses interfere with cellular metabolism in hepatocytes and discuss potential consequences on the innate immune response. Finally, we present evidence that drugs targeting hepatocyte metabolism could be used as an innovative strategy not only to deprive viruses of key metabolites, but also to restore the innate antiviral response that is necessary to clear infection.
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Affiliation(s)
- Olivier Diaz
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Pierre-Olivier Vidalain
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Christophe Ramière
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
- Laboratoire de Virologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Vincent Lotteau
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Laure Perrin-Cocon
- CIRI, Centre International de Recherche en Infectiologie, Team VIRal Infection, Metabolism and Immunity, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
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17
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Zheng W, Zeng Z, Lin S, Hou P. Revisiting potential value of antitumor drugs in the treatment of COVID-19. Cell Biosci 2022; 12:165. [PMID: 36182930 PMCID: PMC9526459 DOI: 10.1186/s13578-022-00899-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 09/12/2022] [Indexed: 01/08/2023] Open
Abstract
Since an outbreak started in China in 2019, coronavirus disease 2019 (COVID-19) has rapidly become a worldwide epidemic with high contagiousness and caused mass mortalities of infected cases around the world. Currently, available treatments for COVID-19, including supportive care, respiratory support and antiviral therapy, have shown limited efficacy. Thus, more effective therapeutic modalities are highly warranted. Drug repurposing, as an efficient strategy to explore a potential broader scope of the application of approved drugs beyond their original indications, accelerates the process of discovering safe and effective agents for a given disease. Since the outbreak of COVID-19 pandemic, drug repurposing strategy has been widely used to discover potential antiviral agents, and some of these drugs have advanced into clinical trials. Antitumor drugs compromise a vast variety of compounds and exhibit extensive mechanism of action, showing promising properties in drug repurposing. In this review, we revisit the potential value of antitumor drugs in the treatment of COVID-19 and systematically discuss their possible underlying mechanisms of the antiviral actions.
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Affiliation(s)
- Wenfang Zheng
- grid.452438.c0000 0004 1760 8119Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 People’s Republic of China
| | - Zekun Zeng
- grid.452438.c0000 0004 1760 8119Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 People’s Republic of China
| | - Shumei Lin
- grid.452438.c0000 0004 1760 8119Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 People’s Republic of China
| | - Peng Hou
- grid.452438.c0000 0004 1760 8119Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 People’s Republic of China ,grid.452438.c0000 0004 1760 8119Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 People’s Republic of China
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Post-Translational Modifications of cGAS-STING: A Critical Switch for Immune Regulation. Cells 2022; 11:cells11193043. [PMID: 36231006 PMCID: PMC9563579 DOI: 10.3390/cells11193043] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 09/13/2022] [Accepted: 09/24/2022] [Indexed: 12/02/2022] Open
Abstract
Innate immune mechanisms initiate immune responses via pattern-recognition receptors (PRRs). Cyclic GMP-AMP synthase (cGAS), a member of the PRRs, senses diverse pathogenic or endogenous DNA and activates innate immune signaling pathways, including the expression of stimulator of interferon genes (STING), type I interferon, and other inflammatory cytokines, which, in turn, instructs the adaptive immune response development. This groundbreaking discovery has rapidly advanced research on host defense, cancer biology, and autoimmune disorders. Since cGAS/STING has enormous potential in eliciting an innate immune response, understanding its functional regulation is critical. As the most widespread and efficient regulatory mode of the cGAS-STING pathway, post-translational modifications (PTMs), such as the covalent linkage of functional groups to amino acid chains, are generally considered a regulatory mechanism for protein destruction or renewal. In this review, we discuss cGAS-STING signaling transduction and its mechanism in related diseases and focus on the current different regulatory modalities of PTMs in the control of the cGAS-STING-triggered innate immune and inflammatory responses.
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19
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Ge Z, Ding S. Regulation of cGAS/STING signaling and corresponding immune escape strategies of viruses. Front Cell Infect Microbiol 2022; 12:954581. [PMID: 36189363 PMCID: PMC9516114 DOI: 10.3389/fcimb.2022.954581] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/25/2022] [Indexed: 11/13/2022] Open
Abstract
Innate immunity is the first line of defense against invading external pathogens, and pattern recognition receptors (PRRs) are the key receptors that mediate the innate immune response. Nowadays, there are various PRRs in cells that can activate the innate immune response by recognizing pathogen-related molecular patterns (PAMPs). The DNA sensor cGAS, which belongs to the PRRs, plays a crucial role in innate immunity. cGAS detects both foreign and host DNA and generates a second-messenger cGAMP to mediate stimulator of interferon gene (STING)-dependent antiviral responses, thereby exerting an antiviral immune response. However, the process of cGAS/STING signaling is regulated by a wide range of factors. Multiple studies have shown that viruses directly target signal transduction proteins in the cGAS/STING signaling through viral surface proteins to impede innate immunity. It is noteworthy that the virus utilizes these cGAS/STING signaling regulators to evade immune surveillance. Thus, this paper mainly summarized the regulatory mechanism of the cGAS/STING signaling pathway and the immune escape mechanism of the corresponding virus, intending to provide targeted immunotherapy ideas for dealing with specific viral infections in the future.
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Affiliation(s)
- Zhe Ge
- School of Sport, Shenzhen University, Shenzhen, China
| | - Shuzhe Ding
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, China
- *Correspondence: Shuzhe Ding,
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20
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Latanova A, Starodubova E, Karpov V. Flaviviridae Nonstructural Proteins: The Role in Molecular Mechanisms of Triggering Inflammation. Viruses 2022; 14:v14081808. [PMID: 36016430 PMCID: PMC9414172 DOI: 10.3390/v14081808] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 12/24/2022] Open
Abstract
Members of the Flaviviridae family are posing a significant threat to human health worldwide. Many flaviviruses are capable of inducing severe inflammation in humans. Flaviviridae nonstructural proteins, apart from their canonical roles in viral replication, have noncanonical functions strongly affecting antiviral innate immunity. Among these functions, antagonism of type I IFN is the most investigated; meanwhile, more data are accumulated on their role in the other pathways of innate response. This review systematizes the last known data on the role of Flaviviridae nonstructural proteins in molecular mechanisms of triggering inflammation, with an emphasis on their interactions with TLRs and RLRs, interference with NF-κB and cGAS-STING signaling, and activation of inflammasomes.
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21
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Toll-like Receptor Response to Hepatitis C Virus Infection: A Recent Overview. Int J Mol Sci 2022; 23:ijms23105475. [PMID: 35628287 PMCID: PMC9141274 DOI: 10.3390/ijms23105475] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) infection remains a major global health burden, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors that detect pathogen-associated molecular patterns and activate downstream signaling to induce proinflammatory cytokine and chemokine production. An increasing number of studies have suggested the importance of TLR responses in the outcome of HCV infection. However, the exact role of innate immune responses, including TLR response, in controlling chronic HCV infection remains to be established. A proper understanding of the TLR response in HCV infection is essential for devising new therapeutic approaches against HCV infection. In this review, we discuss the progress made in our understanding of the host innate immune response to HCV infection, with a particular focus on the TLR response. In addition, we discuss the mechanisms adopted by HCV to avoid immune surveillance mediated by TLRs.
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22
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Xue C, Dong N, Shan A. Putative role of STING-mitochondria associated membrane crosstalk in immunity. Trends Immunol 2022; 43:513-522. [DOI: 10.1016/j.it.2022.04.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 04/29/2022] [Accepted: 04/29/2022] [Indexed: 01/03/2023]
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23
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Fan YM, Zhang YL, Luo H, Mohamud Y. Crosstalk between RNA viruses and DNA sensors: Role of the cGAS‐STING signalling pathway. Rev Med Virol 2022; 32:e2343. [DOI: 10.1002/rmv.2343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/17/2022] [Accepted: 02/22/2022] [Indexed: 12/13/2022]
Affiliation(s)
- Yiyun Michelle Fan
- Center for Heart Lung Innovation St. Paul's Hospital University of British Columbia Vancouver British Columbia Canada
- Department of Cellular & Physiological Sciences University of British Columbia Vancouver British Columbia Canada
| | - Yizhuo Lyanne Zhang
- Center for Heart Lung Innovation St. Paul's Hospital University of British Columbia Vancouver British Columbia Canada
- Department of Cellular & Physiological Sciences University of British Columbia Vancouver British Columbia Canada
| | - Honglin Luo
- Center for Heart Lung Innovation St. Paul's Hospital University of British Columbia Vancouver British Columbia Canada
- Department of Pathology and Laboratory Medicine University of British Columbia Vancouver British Columbia Canada
| | - Yasir Mohamud
- Center for Heart Lung Innovation St. Paul's Hospital University of British Columbia Vancouver British Columbia Canada
- Department of Pathology and Laboratory Medicine University of British Columbia Vancouver British Columbia Canada
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24
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Webb LG, Fernandez-Sesma A. RNA viruses and the cGAS-STING pathway: reframing our understanding of innate immune sensing. Curr Opin Virol 2022; 53:101206. [PMID: 35180533 DOI: 10.1016/j.coviro.2022.101206] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 12/12/2022]
Abstract
The past decade has provided critical information about the cytoplasmic innate immune sensing pathway of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). These discoveries have broadened our understanding of the interconnectedness of the cGAS-STING pathway with autophagy, programmed cell death, Rig-I-like receptor (RLR) signaling, DNA independent interferon induction, and how this pathway responds to RNA virus infection. These advances highlight how multiple families of RNA viruses are restricted by and in turn have mechanisms to inhibit cGAS-STING dependent type-I interferon (IFN-I) induction. Here we review recent discoveries of how and why the cGAS-STING pathway responds to infection with RNA viruses, novel findings of RNA viral antagonism of the cGAS-STING innate immune sensing pathway, and attempt to provide context for a shift in thinking as to how critical this DNA sensing pathway is for the restriction of a wide range of RNA viruses.
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Affiliation(s)
- Laurence G Webb
- The Icahn School of Medicine at Mount Sinai, United States; Mount Sinai Department of Microbiology, United States
| | - Ana Fernandez-Sesma
- The Icahn School of Medicine at Mount Sinai, United States; Mount Sinai Department of Microbiology, United States.
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25
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Wahaab A, Mustafa BE, Hameed M, Stevenson NJ, Anwar MN, Liu K, Wei J, Qiu Y, Ma Z. Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review. Viruses 2021; 14:44. [PMID: 35062249 PMCID: PMC8781031 DOI: 10.3390/v14010044] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 02/07/2023] Open
Abstract
Flaviviruses are known to cause a variety of diseases in humans in different parts of the world. There are very limited numbers of antivirals to combat flavivirus infection, and therefore new drug targets must be explored. The flavivirus NS2B-NS3 proteases are responsible for the cleavage of the flavivirus polyprotein, which is necessary for productive viral infection and for causing clinical infections; therefore, they are a promising drug target for devising novel drugs against different flaviviruses. This review highlights the structural details of the NS2B-NS3 proteases of different flaviviruses, and also describes potential antiviral drugs that can interfere with the viral protease activity, as determined by various studies. Moreover, optimized in vitro reaction conditions for studying the NS2B-NS3 proteases of different flaviviruses may vary and have been incorporated in this review. The increasing availability of the in silico and crystallographic/structural details of flavivirus NS2B-NS3 proteases in free and drug-bound states can pave the path for the development of promising antiflavivirus drugs to be used in clinics. However, there is a paucity of information available on using animal cells and models for studying flavivirus NS2B-NS3 proteases, as well as on the testing of the antiviral drug efficacy against NS2B-NS3 proteases. Therefore, on the basis of recent studies, an effort has also been made to propose potential cellular and animal models for the study of flavivirus NS2B-NS3 proteases for the purposes of exploring flavivirus pathogenesis and for testing the efficacy of possible drugs targets, in vitro and in vivo.
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Affiliation(s)
- Abdul Wahaab
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China; (A.W.); (M.H.); (M.N.A.); (K.L.); (J.W.)
| | - Bahar E Mustafa
- Sub Campus Toba Tek Singh, University of Agriculture, Faisalabad 36050, Pakistan;
| | - Muddassar Hameed
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China; (A.W.); (M.H.); (M.N.A.); (K.L.); (J.W.)
- Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Polytechnic Institute, State University, Fralin Life Sciences Building, 360 W Campus Blacksburg, Blacksburg, VA 24061, USA
| | - Nigel J. Stevenson
- Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen, Adliya 15503, Bahrain;
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland
| | - Muhammad Naveed Anwar
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China; (A.W.); (M.H.); (M.N.A.); (K.L.); (J.W.)
| | - Ke Liu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China; (A.W.); (M.H.); (M.N.A.); (K.L.); (J.W.)
| | - Jianchao Wei
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China; (A.W.); (M.H.); (M.N.A.); (K.L.); (J.W.)
| | - Yafeng Qiu
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China; (A.W.); (M.H.); (M.N.A.); (K.L.); (J.W.)
| | - Zhiyong Ma
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China; (A.W.); (M.H.); (M.N.A.); (K.L.); (J.W.)
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26
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Shukla A, Rastogi M, Singh SK. Zika virus NS1 suppresses the innate immune responses via miR-146a in human microglial cells. Int J Biol Macromol 2021; 193:2290-2296. [PMID: 34798192 DOI: 10.1016/j.ijbiomac.2021.11.061] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 11/10/2021] [Accepted: 11/10/2021] [Indexed: 12/27/2022]
Abstract
Zika virus (ZIKV) is a positive-single strand RNA virus that belongs to the Flaviviridae family. ZIKV infection causes congenital ZIKV syndrome (CZS) in children and Guillain Barre Syndrome (GBS) in adults. ZIKV infected cells secrete non-structural protein 1 (sNS1), which plays an important role in viral replication and immune evasion. The microglial cells are the brain resident macrophages that mediate the immune responses in CNS. The miRNAs are small non-coding RNAs that regulate the expression of their target genes by binding to the 3'UTR region. The present study highlights the bystander effect of ZIKV-NS1 via miR-146a. The Real-Time PCR, Immunoblotting, overexpression, knockdown studies, and reactive oxygen species measurement have been done to study the immunomodulatory effects of ZIKV-NS1 in human microglial cells. ZIKV-NS1 induced the expression of miR-146a and suppressed the ROS activity in human microglial cells. The up-regulated miR-146a led to the decreased expression of TRAF6 and STAT-1. The reduced expression of TRAF6 in turn led to the suppression of pNF-κBp65 and TNF-α downstream. The miR-146a suppressed the pro-inflammatory and cellular antiviral responses in microglial cells. Our findings demonstrate the bystander role of ZIKV-NS1 in suppressing the pro-inflammatory and cellular antiviral responses through miR-146a in human microglial cells.
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Affiliation(s)
- Astha Shukla
- Molecular Biology Unit, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Meghana Rastogi
- Molecular Biology Unit, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Sunit K Singh
- Molecular Biology Unit, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
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27
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INMI1 Zika Virus NS4B Antagonizes the Interferon Signaling by Suppressing STAT1 Phosphorylation. Viruses 2021; 13:v13122448. [PMID: 34960717 PMCID: PMC8705506 DOI: 10.3390/v13122448] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/22/2021] [Accepted: 12/02/2021] [Indexed: 12/17/2022] Open
Abstract
The evasion of the Interferon response has important implications in Zika virus (ZIKV) disease. Mutations in ZIKV viral protein NS4B, associated with modulation of the interferon (IFN) system, have been linked to increased pathogenicity in animal models. In this study, we unravel ZIKV NS4B as antagonist of the IFN signaling cascade. Firstly, we reported the genomic characterization of NS4B isolated from a strain of the 2016 outbreak, ZIKV Brazil/2016/INMI1, and we predicted its membrane topology. Secondly, we analyzed its phylogenetic correlation with other flaviviruses, finding a high similarity with dengue virus 2 (DEN2) strains; in particular, the highest conservation was found when NS4B was aligned with the IFN inhibitory domain of DEN2 NS4B. Hence, we asked whether ZIKV NS4B was also able to inhibit the IFN signaling cascade, as reported for DEN2 NS4B. Our results showed that ZIKV NS4B was able to strongly inhibit the IFN stimulated response element and the IFN-γ-activated site transcription, blocking IFN-I/-II responses. mRNA expression levels of the IFN stimulated genes ISG15 and OAS1 were also strongly reduced in presence of NS4B. We found that the viral protein was acting by suppressing the STAT1 phosphorylation and consequently blocking the nuclear transport of both STAT1 and STAT2.
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28
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Xu C, Chen J, Chen X. Host Innate Immunity Against Hepatitis Viruses and Viral Immune Evasion. Front Microbiol 2021; 12:740464. [PMID: 34803956 PMCID: PMC8598044 DOI: 10.3389/fmicb.2021.740464] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/29/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatitis viruses are primary causative agents of hepatitis and represent a major source of public health problems in the world. The host innate immune system forms the first line of defense against hepatitis viruses. Hepatitis viruses are sensed by specific pathogen recognition receptors (PRRs) that subsequently trigger the innate immune response and interferon (IFN) production. However, hepatitis viruses evade host immune surveillance via multiple strategies, which help compromise the innate immune response and create a favorable environment for viral replication. Therefore, this article reviews published findings regarding host innate immune sensing and response against hepatitis viruses. Furthermore, we also focus on how hepatitis viruses abrogate the antiviral effects of the host innate immune system.
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Affiliation(s)
- Chonghui Xu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jizheng Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
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29
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Yin D, Shao Y, Yang K, Tu J, Song X, Qi K, Pan X. Fowl adenovirus serotype 4 uses gga-miR-181a-5p expression to facilitate viral replication via targeting of STING. Vet Microbiol 2021; 263:109276. [PMID: 34785478 DOI: 10.1016/j.vetmic.2021.109276] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/26/2021] [Accepted: 10/30/2021] [Indexed: 12/26/2022]
Abstract
Fowl adenovirus serotype 4 (FAdV-4) has caused substantial economic losses to the poultry industry and it has become a serious pathogen of poultry in China since 2015. MicroRNAs (miRNAs) play vital roles in regulating viral infection. However, how miRNAs regulate FAdV-4 replication in Leghorn male hepatocellular (LMH) cells remains unclear. This study aimed to elucidate the role of gga-miR-181a-5p in regulating FAdV-4 replication. The findings indicated that the expression of gga-miR-181a-5p was significantly upregulated in LMH cells during FAdV-4 infection. Also, the transfection of gga-miR-181a-5p mimics promoted FAdV-4 replication, while the opposite result was observed when gga-miR-181a-5p inhibitor was transfected in LMH cells. Moreover, the stimulator of interferon genes (STING) was found to be the target gene of gga-miR-181a-5p using software analysis, further confirming that STING was the target of gga-miR-181a-5p and gga-miR-181a-5p could negatively regulate the expression of STING at the mRNA and protein levels. Finally, the results showed that the overexpression of STING inhibited FAdV-4 replication and the knockout of STING promoted FAdV-4 replication. The collective findings revealed a novel host evasion mechanism adopted by FAdV-4 via gga-miR-181a-5p, suggesting novel strategies for designing miRNA-based vaccines and therapies.
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Affiliation(s)
- Dongdong Yin
- Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China; Institute of Animal Husbandry and Veterinary Science, Anhui Academy of Agricultural Sciences, Livestock and Poultry Epidemic Diseases Research Center of Anhui Province, Anhui Province Key Laboratory of Livestock and Poultry Product Safety Engineering, Hefei, 230031, PR China
| | - Ying Shao
- Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China
| | - Kankan Yang
- Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China
| | - Jian Tu
- Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China
| | - Xiangjun Song
- Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China
| | - Kezong Qi
- Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, PR China.
| | - Xiaocheng Pan
- Institute of Animal Husbandry and Veterinary Science, Anhui Academy of Agricultural Sciences, Livestock and Poultry Epidemic Diseases Research Center of Anhui Province, Anhui Province Key Laboratory of Livestock and Poultry Product Safety Engineering, Hefei, 230031, PR China.
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30
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Su H, Liao Z, Yang C, Zhang Y, Su J. Grass Carp Reovirus VP56 Allies VP4, Recruits, Blocks, and Degrades RIG-I to More Effectively Attenuate IFN Responses and Facilitate Viral Evasion. Microbiol Spectr 2021; 9:e0100021. [PMID: 34523975 PMCID: PMC8557896 DOI: 10.1128/spectrum.01000-21] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 08/16/2021] [Indexed: 12/14/2022] Open
Abstract
Grass carp reovirus (GCRV), the most virulent aquareovirus, causes epidemic hemorrhagic disease and tremendous economic loss in freshwater aquaculture industry. VP56, a putative fibrin inlaying the outer surface of GCRV-II and GCRV-III, is involved in cell attachment. In the present study, we found that VP56 localizes at the early endosome, lysosome, and endoplasmic reticulum, recruits the cytoplasmic viral RNA sensor retinoic acid-inducible gene I (RIG-I) and binds to it. The interaction between VP56 and RIG-I was detected by endogenous coimmunoprecipitation (co-IP), glutathione S-transferase (GST) pulldown, and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) and was then confirmed by traditional co-IPs and a novel far-red mNeptune-based bimolecular fluorescence complementation system. VP56 binds to the helicase domain of RIG-I. VP56 enhances K48-linked ubiquitination of RIG-I to degrade it by the proteasomal pathway. Thus, VP56 impedes the initial immune function of RIG-I by dual mechanisms (blockade and degradation) and attenuates signaling from RIG-I recognizing viral RNA, subsequently weakening downstream signaling transduction and interferon (IFN) responses. Accordingly, host antiviral effectors are reduced, and cytopathic effects are increased. These findings were corroborated by RNA sequencing (RNA-seq) and VP56 knockdown. Finally, we found that VP56 and the major outer capsid protein VP4 bind together in the cytosol to enhance the degradation of RIG-I and more efficiently facilitate viral replication. Collectively, the results indicated that VP56 allies VP4, recruits, blocks, and degrades RIG-I, thereby attenuating IFNs and antiviral effectors to facilitate viral evasion more effectively. This study reveals a virus attacking target and an escaping strategy from host antiviral immunity for GCRV and will help understand mechanisms of infection of reoviruses. IMPORTANCE Grass carp reovirus (GCRV) fibrin VP56 and major outer capsid protein VP4 inlay and locate on the outer surface of GCRV-II and GCRV-III, which causes tremendous loss in grass carp and black carp industries. Fibrin is involved in cell attachment and plays an important role in reovirus infection. The present study identified the interaction proteins of VP56 and found that VP56 and VP4 bind to the different domains of the viral RNA sensor retinoic acid-inducible gene I (RIG-I) in grass carp to block RIG-I sensing of viral RNA and induce RIG-I degradation by the proteasomal pathway to attenuate signaling transduction, thereby suppressing interferons (IFNs) and antiviral effectors, facilitating viral replication. VP56 and VP4 bind together in the cytosol to more efficiently facilitate viral evasion. This study reveals a virus attacking a target and an escaping strategy from host antiviral immunity for GCRV and will be helpful in understanding the mechanisms of infection of reoviruses.
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Affiliation(s)
- Hang Su
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, China
- Laboratory for Marine Biology and Biotechnology, Pilot Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
- Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, China
| | - Zhiwei Liao
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, China
| | - Chunrong Yang
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Yongan Zhang
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, China
- Laboratory for Marine Biology and Biotechnology, Pilot Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
- Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, China
| | - Jianguo Su
- Department of Aquatic Animal Medicine, College of Fisheries, Huazhong Agricultural University, Wuhan, China
- Laboratory for Marine Biology and Biotechnology, Pilot Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
- Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Wuhan, China
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31
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Anwar S, Ul Islam K, Azmi MI, Iqbal J. cGAS-STING-mediated sensing pathways in DNA and RNA virus infections: crosstalk with other sensing pathways. Arch Virol 2021; 166:3255-3268. [PMID: 34622360 DOI: 10.1007/s00705-021-05211-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 07/04/2021] [Indexed: 12/25/2022]
Abstract
Viruses cause a variety of diseases in humans and other organisms. The most important defense mechanism against viral infections is initiated when the viral genome is sensed by host proteins, and this results in interferon production and pro-inflammatory cytokine responses. The sensing of the viral genome or its replication intermediates within host cells is mediated by cytosolic proteins. For example, cGAS and IFI16 recognize non-self DNA, and RIG-I and MDA5 recognize non-self RNA. Once these sensors are activated, they trigger a cascade of reactions activating downstream molecules, which eventually results in the transcriptional activation of type I and III interferons, which play a critical role in suppressing viral propagation, either by directly limiting their replication or by inducing host cells to inhibit viral protein synthesis. The immune response against viruses relies solely upon sensing of viral genomes and their downstream signaling molecules. Although DNA and RNA viruses are sensed by distinct classes of receptor proteins, there is a possibility of overlap between the viral DNA and viral RNA sensing mechanisms. In this review, we focus on various host sensing molecules and discuss the associated signaling pathways that are activated in response to different viral infections. We further highlight the possibility of crosstalk between the cGAS-STING and the RIG-I-MAVS pathways to limit viral infections. This comprehensive review delineates the mechanisms by which different viruses evade host cellular responses to sustain within the host cells.
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Affiliation(s)
- Saleem Anwar
- Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Khursheed Ul Islam
- Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Md Iqbal Azmi
- Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Jawed Iqbal
- Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
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32
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Virus-Induced Tumorigenesis and IFN System. BIOLOGY 2021; 10:biology10100994. [PMID: 34681093 PMCID: PMC8533565 DOI: 10.3390/biology10100994] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/01/2021] [Accepted: 09/27/2021] [Indexed: 01/11/2023]
Abstract
Oncogenic viruses favor the development of tumors in mammals by persistent infection and specific cellular pathways modifications by deregulating cell proliferation and inhibiting apoptosis. They counteract the cellular antiviral defense through viral proteins as well as specific cellular effectors involved in virus-induced tumorigenesis. Type I interferons (IFNs) are a family of cytokines critical not only for viral interference but also for their broad range of properties that go beyond the antiviral action. In fact, they can inhibit cell proliferation and modulate differentiation, apoptosis, and migration. However, their principal role is to regulate the development and activity of most effector cells of the innate and adaptive immune responses. Various are the mechanisms by which IFNs exert their effects on immune cells. They can act directly, through IFN receptor triggering, or indirectly by the induction of chemokines, the secretion of further cytokines, or by the stimulation of cells useful for the activation of particular immune cells. All the properties of IFNs are crucial in the host defense against viruses and bacteria, as well as in the immune surveillance against tumors. IFNs may be affected by and, in turn, affect signaling pathways to mediate anti-proliferative and antiviral responses in virus-induced tumorigenic context. New data on cellular and viral microRNAs (miRNAs) machinery, as well as cellular communication and microenvironment modification via classical secretion mechanisms and extracellular vesicles-mediated delivery are reported. Recent research is reviewed on the tumorigenesis induced by specific viruses with RNA or DNA genome, belonging to different families (i.e., HPV, HTLV-1, MCPyV, JCPyV, Herpesviruses, HBV, HCV) and the IFN system involvement.
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Dixon CR, Malik P, de las Heras JI, Saiz-Ros N, de Lima Alves F, Tingey M, Gaunt E, Richardson AC, Kelly DA, Goldberg MW, Towers GJ, Yang W, Rappsilber J, Digard P, Schirmer EC. STING nuclear partners contribute to innate immune signaling responses. iScience 2021; 24:103055. [PMID: 34541469 PMCID: PMC8436130 DOI: 10.1016/j.isci.2021.103055] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/19/2021] [Accepted: 08/25/2021] [Indexed: 02/08/2023] Open
Abstract
STimulator of INterferon Genes (STING) is an adaptor for cytoplasmic DNA sensing by cGAMP/cGAS that helps trigger innate immune responses (IIRs). Although STING is mostly localized in the ER, we find a separate inner nuclear membrane pool of STING that increases mobility and redistributes to the outer nuclear membrane upon IIR stimulation by transfected dsDNA or dsRNA mimic poly(I:C). Immunoprecipitation of STING from isolated nuclear envelopes coupled with mass spectrometry revealed a distinct nuclear envelope-STING proteome consisting of known nuclear membrane proteins and enriched in DNA- and RNA-binding proteins. Seventeen of these nuclear envelope STING partners are known to bind direct interactors of IRF3/7 transcription factors, and testing a subset of these revealed STING partners SYNCRIP, MEN1, DDX5, snRNP70, RPS27a, and AATF as novel modulators of dsDNA-triggered IIRs. Moreover, we find that SYNCRIP is a novel antagonist of the RNA virus, influenza A, potentially shedding light on reports of STING inhibition of RNA viruses.
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Affiliation(s)
- Charles R. Dixon
- Institute of Cell Biology, University of Edinburgh, Kings Buildings, Swann 5.22, Mayfield Road, Edinburgh EH9 3BF, UK
| | - Poonam Malik
- Institute of Cell Biology, University of Edinburgh, Kings Buildings, Swann 5.22, Mayfield Road, Edinburgh EH9 3BF, UK
| | - Jose I. de las Heras
- Institute of Cell Biology, University of Edinburgh, Kings Buildings, Swann 5.22, Mayfield Road, Edinburgh EH9 3BF, UK
| | - Natalia Saiz-Ros
- Institute of Cell Biology, University of Edinburgh, Kings Buildings, Swann 5.22, Mayfield Road, Edinburgh EH9 3BF, UK
| | - Flavia de Lima Alves
- Institute of Cell Biology, University of Edinburgh, Kings Buildings, Swann 5.22, Mayfield Road, Edinburgh EH9 3BF, UK
| | - Mark Tingey
- Department of Biology, Temple University, Philadelphia 19121, USA
| | - Eleanor Gaunt
- Division of Infection and Immunity, Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK
| | | | - David A. Kelly
- Institute of Cell Biology, University of Edinburgh, Kings Buildings, Swann 5.22, Mayfield Road, Edinburgh EH9 3BF, UK
| | - Martin W. Goldberg
- School of Biological and Biomedical Sciences, Durham University, Durham DH1 3LE, UK
| | - Greg J. Towers
- Department of Infection and Immunity, University College London, London WC1E 6BT, UK
| | - Weidong Yang
- Department of Biology, Temple University, Philadelphia 19121, USA
| | - Juri Rappsilber
- Institute of Cell Biology, University of Edinburgh, Kings Buildings, Swann 5.22, Mayfield Road, Edinburgh EH9 3BF, UK
- Department of Bioanalytics, Institute of Biotechnology, Technische Universitat Berlin, 13355 Berlin, Germany
| | - Paul Digard
- Division of Infection and Immunity, Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, UK
| | - Eric C. Schirmer
- Institute of Cell Biology, University of Edinburgh, Kings Buildings, Swann 5.22, Mayfield Road, Edinburgh EH9 3BF, UK
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34
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Abstract
STING (stimulator of interferon genes) also known as transmembrane protein 173 (TMEM173) is a cytoplasmic DNA sensor which can be activated by the upstream cyclic dinucleotides (CDNs). This activation produces cytokines such as interferons and pro-inflammatory factors via the downstream IRF3 and NF-κB pathways, triggering an innate immune response and adaptive immunity to maintain homeostasis. STING is mainly expressed and activated in non-parenchymal cells, thus exerting a corresponding effect to maintain the homeostasis of the liver. In viral hepatitis, interferons and pro-inflammatory factors produced after STING activation initiate the immune response to inhibit virus replication and assembly. In the case of metabolic diseases of the liver, the activation of STING in kupffer cells and hepatic stellate cells leads to inflammation, the proliferation of connective tissue, and metabolic disorders in the hepatocytes, promoting the occurrence and development of the disease. In hepatocellular carcinoma, STING has two contradictory roles. When STING is activated in dendritic cells and macrophages, a large number of cytokines can be produced to initiate innate immune effects directly and to exert adaptive immunity through the recruitment and activation of T cells; however, aberrant activation of the STING pathway leads to a weakening of immune function and promotes oncogenesis and metastasis. Here, we summarize the interactions between STING and liver disease that have currently been identified and how to achieve therapeutic goals by modulating the activity of the STING pathway.
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Affiliation(s)
- Can Chen
- Department of Laboratory Medicine, The First Affiliated Hospital, Nanjing Medical University, 300 Guang Zhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Rui-Xia Yang
- Department of Laboratory Medicine, The First Affiliated Hospital, Nanjing Medical University, 300 Guang Zhou Road, Nanjing, 210029, Jiangsu Province, China
| | - Hua-Guo Xu
- Department of Laboratory Medicine, The First Affiliated Hospital, Nanjing Medical University, 300 Guang Zhou Road, Nanjing, 210029, Jiangsu Province, China.
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35
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Wang Z, Chen N, Li Z, Xu G, Zhan X, Tang J, Xiao X, Bai Z. The Cytosolic DNA-Sensing cGAS-STING Pathway in Liver Diseases. Front Cell Dev Biol 2021; 9:717610. [PMID: 34386500 PMCID: PMC8353273 DOI: 10.3389/fcell.2021.717610] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/05/2021] [Indexed: 12/23/2022] Open
Abstract
Inflammation is regulated by the host and is a protective response activated by the evolutionarily conserved immune system in response to harmful stimuli, such as dead cells or pathogens. cGAS-STING pathway is a vital natural sensor of host immunity that can defend various tissues and organs against pathogenic infection, metabolic syndrome, cellular stress and cancer metastasis. The potential impact of cGAS-STING pathway in hepatic ischemia reperfusion (I/R) injury, alcoholic/non-alcoholic steatohepatitis (ASH), hepatic B virus infection, and other liver diseases has recently attracted widespread attention. In this review, the relationship between cGAS-STING pathway and the pathophysiological mechanisms and progression of liver diseases is summarized. Additionally, we discuss various pharmacological agonists and antagonists of cGAS-STING signaling as novel therapeutics for the treatment of liver diseases. A detailed understanding of mechanisms and biology of this pathway will lay a foundation for the development and clinical application of therapies for related liver diseases.
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Affiliation(s)
- Zhilei Wang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Department of Liver Diseases, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China.,State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Nian Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhiyong Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Guang Xu
- Department of Liver Diseases, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Xiaoyan Zhan
- Department of Liver Diseases, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Jianyuan Tang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaohe Xiao
- Department of Liver Diseases, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China.,State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Zhaofang Bai
- Department of Liver Diseases, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
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36
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Chen R, Du J, Zhu H, Ling Q. The role of cGAS-STING signalling in liver diseases. JHEP Rep 2021; 3:100324. [PMID: 34381984 PMCID: PMC8340306 DOI: 10.1016/j.jhepr.2021.100324] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 05/20/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
The recently identified novel cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) activates the downstream adaptor protein stimulator of interferon genes (STING) by catalysing the synthesis of cyclic GMP-AMP. This in turn initiates an innate immune response through the release of various cytokines, including type I interferon. Foreign DNA (microbial infection) or endogenous DNA (nuclear or mitochondrial leakage) can serve as cGAS ligands and lead to the activation of cGAS-STING signalling. Therefore, the cGAS-STING pathway plays essential roles in infectious diseases, sterile inflammation, tumours, and autoimmune diseases. In addition, cGAS-STING signalling affects the progression of liver inflammation through other mechanisms, such as autophagy and metabolism. In this review, we summarise recent advances in our understanding of the role of cGAS-STING signalling in the innate immune modulation of different liver diseases. Furthermore, we discuss the therapeutic potential of targeting the cGAS-STING pathway in the treatment of liver diseases.
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Key Words
- AIM2, absent in melanoma 2
- ALD, alcohol-related liver disease
- APCs, antigen-presenting cells
- CDNs, cyclic dinucleotides
- DAMPs, damage-associated molecular patterns
- DCs, dendritic cells
- ER, endoplasmic reticulum
- GVHD, graft-versus-host disease
- HCC, hepatocellular carcinoma
- HSCs, hepatic stellate cells
- IFN-I, type I interferon
- IL, interleukin
- IRF3, interferon regulatory factor 3
- IRI, ischaemia refusion injury
- KCs, Kupffer cells
- LSECs, liver sinusoidal endothelial cells
- MHC, major histocompatibility complex
- NAFLD, non-alcoholic fatty liver disease
- NK cells, natural killer cells
- NPCs, non-parenchymal cells
- PAMPs, pathogen-associated molecular patterns
- PD-1, programmed cell death protein-1
- PD-L1, programmed cell death protein ligand-1
- PPRs, pattern recognition receptors
- SAVI, STING-associated vasculopathy with onset in infancy
- STING, stimulator of interferon genes
- TBK1, TANK-binding kinase 1
- TGF-β1, transforming growth factor-β1
- TLR, Toll-like receptor
- TNF, tumour necrosis factor
- XRCC, X-ray repair cross complementing
- aHSCT, allogeneic haematopoietic stem cell transplantation
- cGAMP, cyclic guanosine monophosphate-adenosine monophosphate
- cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase
- cGAS-STING signalling
- dsDNA, double-strand DNA
- hepatocellular carcinoma
- innate immune response
- liver injury
- mTOR, mammalian target of rapamycin
- mtDNA, mitochondrial DNA
- nonalcoholic fatty liver disease
- siRNA, small interfering RNA
- ssRNA, single-stranded RNA
- viral hepatitis
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Affiliation(s)
- Ruihan Chen
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiamin Du
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hong Zhu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qi Ling
- Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Awogbindin IO, Ben-Azu B, Olusola BA, Akinluyi ET, Adeniyi PA, Di Paolo T, Tremblay MÈ. Microglial Implications in SARS-CoV-2 Infection and COVID-19: Lessons From Viral RNA Neurotropism and Possible Relevance to Parkinson's Disease. Front Cell Neurosci 2021; 15:670298. [PMID: 34211370 PMCID: PMC8240959 DOI: 10.3389/fncel.2021.670298] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/05/2021] [Indexed: 12/24/2022] Open
Abstract
Since December 2019, humankind has been experiencing a ravaging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, the second coronavirus pandemic in a decade after the Middle East respiratory syndrome coronavirus (MERS-CoV) disease in 2012. Infection with SARS-CoV-2 results in Coronavirus disease 2019 (COVID-19), which is responsible for over 3.1 million deaths worldwide. With the emergence of a second and a third wave of infection across the globe, and the rising record of multiple reinfections and relapses, SARS-CoV-2 infection shows no sign of abating. In addition, it is now evident that SARS-CoV-2 infection presents with neurological symptoms that include early hyposmia, ischemic stroke, meningitis, delirium and falls, even after viral clearance. This may suggest chronic or permanent changes to the neurons, glial cells, and/or brain vasculature in response to SARS-CoV-2 infection or COVID-19. Within the central nervous system (CNS), microglia act as the central housekeepers against altered homeostatic states, including during viral neurotropic infections. In this review, we highlight microglial responses to viral neuroinfections, especially those with a similar genetic composition and route of entry as SARS-CoV-2. As the primary sensor of viral infection in the CNS, we describe the pathogenic and neuroinvasive mechanisms of RNA viruses and SARS-CoV-2 vis-à-vis the microglial means of viral recognition. Responses of microglia which may culminate in viral clearance or immunopathology are also covered. Lastly, we further discuss the implication of SARS-CoV-2 CNS invasion on microglial plasticity and associated long-term neurodegeneration. As such, this review provides insight into some of the mechanisms by which microglia could contribute to the pathophysiology of post-COVID-19 neurological sequelae and disorders, including Parkinson's disease, which could be pervasive in the coming years given the growing numbers of infected and re-infected individuals globally.
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Affiliation(s)
- Ifeoluwa O. Awogbindin
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Neuroimmunology Group, Molecular Drug Metabolism and Toxicology Laboratory, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Benneth Ben-Azu
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, College of Health Sciences, Delta State University, Abraka, Nigeria
| | - Babatunde A. Olusola
- Department of Virology, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Elizabeth T. Akinluyi
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Nigeria
| | - Philip A. Adeniyi
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States
| | - Therese Di Paolo
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec, QC, Canada
| | - Marie-Ève Tremblay
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, QC, Canada
- Neurology and Neurosurgery Department, McGill University, Montréal, QC, Canada
- Department of Molecular Medicine, Université Laval, Québec, QC, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada
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38
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Hsin F, Hsu YC, Tsai YF, Lin SW, Liu HM. The transmembrane serine protease hepsin suppresses type I interferon induction by cleaving STING. Sci Signal 2021; 14:14/687/eabb4752. [PMID: 34131022 DOI: 10.1126/scisignal.abb4752] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Many viral proteases mediate the evasion of antiviral innate immunity by cleaving adapter proteins in the interferon (IFN) induction pathway. Host proteases are also involved in innate immunity and inflammation. Here, we report that the transmembrane protease hepsin (also known as TMPRSS1), which is predominantly present in hepatocytes, inhibited the induction of type I IFN during viral infections. Knocking out hepsin in mouse embryonic fibroblasts (MEFs) increased the viral infection-induced expression of Ifnb1, an Ifnb1 promoter reporter, and an IFN-sensitive response element promoter reporter. Ectopic expression of hepsin in cultured human hepatocytes and HEK293T cells suppressed the induction of IFNβ during viral infections by reducing the abundance of STING. These effects depended on the protease activity of hepsin. We identified a putative hepsin target site in STING and showed that mutating this site protected STING from hepsin-mediated cleavage. In addition to hepatocytes, several hepsin-producing prostate cancer cell lines showed reduced STING-mediated type I IFN induction and responses. These results reveal a role for hepsin in suppressing STING-mediated type I IFN induction, which may contribute to the vulnerability of hepatocytes to chronic viral infections.
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Affiliation(s)
- Fu Hsin
- Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei City, Taiwan.,Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Yu-Chen Hsu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei City, Taiwan.,Liver Disease Prevention and Treatment Research Foundation, Taipei City, Taiwan
| | - Yu-Fei Tsai
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Shu-Wha Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Helene Minyi Liu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei City, Taiwan.
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39
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Xu D, Tian Y, Xia Q, Ke B. The cGAS-STING Pathway: Novel Perspectives in Liver Diseases. Front Immunol 2021; 12:682736. [PMID: 33995425 PMCID: PMC8117096 DOI: 10.3389/fimmu.2021.682736] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 04/19/2021] [Indexed: 12/18/2022] Open
Abstract
Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.
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Affiliation(s)
- Dongwei Xu
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yizhu Tian
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Bibo Ke
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
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40
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A Highly Conserved Circular RNA circRasGEF1B Enhances Antiviral Immunity by Regulating miR-21-3p/MITA Pathway in Lower Vertebrates. J Virol 2021; 95:JVI.02145-20. [PMID: 33441345 PMCID: PMC8092700 DOI: 10.1128/jvi.02145-20] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Circular RNAs (circRNAs) represent a class of widespread, diverse, and covalently closed circRNAs that function as microRNA (miRNA) sponges and crucial regulators of gene expression in mammals. However, the regulation and function of circRNAs in lower vertebrates are still unknown. Here, we first discover a highly conserved circRNA termed circRasGEF1B, which displays a high conservation from mammals to fish and serves as key regulator in eliciting antiviral immunity in teleost fish. Results indicate that circRasGEF1B was highly expressed in Siniperca chuatsi rhabdovirus-infected tissues and cells. Functionally, miR-21-3p could inhibit cellular antiviral responses significantly, whereas circRasGEF1B counteract the effects of miR-21-3p. In mechanism, the results demonstrate that circRasGEF1B acts as a competing endogenous RNA (ceRNA) of miR-21-3p to relieve the repressive effect of miR-21-3p on its target MITA, then enhance the innate antiviral responses. Our results not only provide a novel insight into the functions of circRNAs in lower vertebrates, but broaden our understanding of circRNAs in viral infection.IMPORTANCE Siniperca chuatsi rhabdovirus (SCRV) is a typical fish RNA rhabdovirus, which is one of the most significant viral pathogens in teleost fish and can cause severe hemorrhagic septicemia in freshwater and marine fishes. Here, we discovered a highly conserved circRNAs called circRasGEF1B, which acts as a key regulator for innate antiviral responses upon SCRV infection. circRasGEF1B acts as an endogenous sponge of miR-21-3p that downregulates miR-21-3p expression levels. circRasGEF1B is able to bind to miR-21-3p directly and regulates MITA expression. To our knowledge, this report is the first to characterize circRNA-miRNA regulatory networks that exist in lower vertebrates.
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41
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Roca Suarez AA, Testoni B, Baumert TF, Lupberger J. Nucleic Acid-Induced Signaling in Chronic Viral Liver Disease. Front Immunol 2021; 11:624034. [PMID: 33613561 PMCID: PMC7892431 DOI: 10.3389/fimmu.2020.624034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
A hallmark for the development and progression of chronic liver diseases is the persistent dysregulation of signaling pathways related to inflammatory responses, which eventually promotes the development of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The two major etiological agents associated with these complications in immunocompetent patients are hepatitis B virus (HBV) and hepatitis C virus (HCV), accounting for almost 1.4 million liver disease-associated deaths worldwide. Although both differ significantly from the point of their genomes and viral life cycles, they exert not only individual but also common strategies to divert innate antiviral defenses. Multiple virus-modulated pathways implicated in stress and inflammation illustrate how chronic viral hepatitis persistently tweaks host signaling processes with important consequences for liver pathogenesis. The following review aims to summarize the molecular events implicated in the sensing of viral nucleic acids, the mechanisms employed by HBV and HCV to counter these measures and how the dysregulation of these cellular pathways drives the development of chronic liver disease and the progression toward HCC.
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MESH Headings
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- DNA, Viral/immunology
- Hepacivirus/immunology
- Hepatitis B virus/immunology
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/mortality
- Hepatitis B, Chronic/pathology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/mortality
- Hepatitis C, Chronic/pathology
- Humans
- Liver Neoplasms/immunology
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- RNA, Viral/immunology
- Signal Transduction/immunology
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Affiliation(s)
- Armando Andres Roca Suarez
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Thomas F. Baumert
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
- Institut Universitaire de France (IUF), Paris, France
| | - Joachim Lupberger
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
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42
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Sokolova TM. [Hepatitis C virus (Flaviviridae: Hepacivirus: Hepacivirus C): regulation of signaling reactions of innate immunity]. Vopr Virusol 2021; 65:307-316. [PMID: 33533227 DOI: 10.36233/0507-4088-2020-65-6-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 01/07/2021] [Indexed: 12/21/2022]
Abstract
Studying the regulation of signaling reactions of innate immunity by the hepatitis C virus (HCV) will help to reveal the causes of the transition of the acute form of the disease to a chronic course. The molecular mechanisms of activation by HCV RNA of innate immunity receptors TLR and RLR and signal transduction processes leading to the synthesis of IFN and inflammatory cytokines are considered. The inhibitory effects of non-structural and structural HCV proteins on immune signaling reactions are analyzed in detail. The information presented is the result of an analysis of literature data published in international databases mainly over the past 5 years. In conclusion, signaling receptors are proposed as targets for the development of new antiviral drugs with immunotherapeutic activity.
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Affiliation(s)
- T M Sokolova
- D.I. Ivanovsky Institute of Virology of National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya
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43
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Mitochondria Associated Membranes (MAMs): Architecture and physiopathological role. Cell Calcium 2021; 94:102343. [PMID: 33418313 DOI: 10.1016/j.ceca.2020.102343] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/27/2020] [Accepted: 12/27/2020] [Indexed: 12/17/2022]
Abstract
In the last decades, the communication between the Endoplasmic reticulum (ER) and mitochondria has obtained great attention: mitochondria-associated membranes (MAMs), which represent the contact sites between the two organelles, have indeed emerged as central hub involved in different fundamental cell processes, such as calcium signalling, apoptosis, autophagy and lipid biosynthesis. Consistently, dysregulation of ER-mitochondria crosstalk has been associated with different pathological conditions, ranging from diabetes to cancer and neurodegenerative diseases. In this review, we will try to summarize the current knowledge on MAMs' structure and functions in health and their relevance for human diseases.
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44
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Mycobacterium tuberculosis MmsA (Rv0753c) Interacts with STING and Blunts the Type I Interferon Response. mBio 2020; 11:mBio.03254-19. [PMID: 33262262 PMCID: PMC7733952 DOI: 10.1128/mbio.03254-19] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
It is unclear how the type I IFN response is regulated by mycobacterial determinants. Here, we characterized the previously unreported role of M. tuberculosis MmsA in immunological regulation of type I IFN response by targeting the central adaptor STING in the DNA sensing pathway. We identified STING-interacting MmsA by coimmunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis and showed MmsA interacting with STING and autophagy receptor p62 via its N terminus and C terminus, respectively. We also showed that MmsA downregulated type I IFN by promoting p62-mediated STING degradation. Moreover, the MmsA mutant R138W is potentially associated with the virulence of M. tuberculosis clinical strains owing to the modulation of STING protein. Our results provide novel insights into the regulatory mechanism of type I IFN response manipulated by mycobacterial MmsA and the additional cross talk between autophagy and STING in M. tuberculosis infection, wherein a protein from microbial pathogens induces autophagic degradation of host innate immune molecules. Type I interferon (IFN) plays an important role in Mycobacterium tuberculosis persistence and disease pathogenesis. M. tuberculosis has evolved a number of mechanisms to evade host immune surveillance. However, it is unclear how the type I IFN response is tightly regulated by the M. tuberculosis determinants. Stimulator of interferon genes (STING) is an essential adaptor for type I IFN production triggered by M. tuberculosis genomic DNA or cyclic dinucleotides upon infection. To investigate how the type I IFN response is regulated by M. tuberculosis determinants, immunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis was performed to screen proteins interacting with STING in the context of M. tuberculosis infection. Among the many predicted candidates interacting with STING, the M. tuberculosis coding protein Rv0753c (MmsA) was identified. We confirmed that MmsA binds and colocalizes with STING, and the N-terminal regions of MmsA (amino acids [aa] 1 to 251) and STING (aa 1 TO 190) are responsible for MmsA-STING interaction. Type I IFN production was impaired with exogenous expression of MmsA in RAW264.7 cells. MmsA inhibited the STING-TBK1-IRF3 pathway, as evidenced by reduced STING levelS and subsequent IRF3 activation. Furthermore, MmsA facilitated p62-mediated STING autophagic degradation by binding p62 with its C terminus (aa 252 to 455), which may account for the negative regulation of M. tuberculosis MmsA in STING-mediated type I IFN production. Additionally, the M. tuberculosismmsA R138W mutation, detected in a hypervirulent clinical isolate, enhanced the degradation of STING, implying the important relevance of MmsA in disease outcome. Together, we report a novel mechanism where M. tuberculosis MmsA serves as an antagonist of type I IFN response by targeting STING with p62-mediated autophagic degradation.
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Webb LG, Veloz J, Pintado-Silva J, Zhu T, Rangel MV, Mutetwa T, Zhang L, Bernal-Rubio D, Figueroa D, Carrau L, Fenutria R, Potla U, Reid SP, Yount JS, Stapleford KA, Aguirre S, Fernandez-Sesma A. Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS. PLoS Pathog 2020; 16:e1008999. [PMID: 33057424 PMCID: PMC7591055 DOI: 10.1371/journal.ppat.1008999] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 10/27/2020] [Accepted: 09/21/2020] [Indexed: 12/24/2022] Open
Abstract
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathways in the host recognition of CHIKV; however, less is known regarding antagonism of CHIKV by cytosolic DNA sensing pathways like that of cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). With the use of cGAS or STING null cells we demonstrate that the pathway restricts CHIKV replication in fibroblasts and immune cells. We show that DNA accumulates in the cytoplasm of infected cells and that CHIKV blocks DNA dependent IFN-β transcription. This antagonism of DNA sensing is via an early autophagy-mediated degradation of cGAS and expression of the CHIKV capsid protein is sufficient to induce cGAS degradation. Furthermore, we identify an interaction of CHIKV nsP1 with STING and map the interaction to 23 residues in the cytosolic loop of the adaptor protein. This interaction stabilizes the viral protein and increases the level of palmitoylated nsP1 in cells. Together, this work supports previous publications highlighting the relevance of the cGAS-STING pathway in the early detection of (+)ssRNA viruses and provides direct evidence that CHIKV interacts with and antagonizes cGAS-STING signaling.
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Affiliation(s)
- L. G. Webb
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - J. Veloz
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - J. Pintado-Silva
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - T. Zhu
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - M. V. Rangel
- Department of Microbiology, New York University School of Medicine, New York, NY, United States of America
| | - T. Mutetwa
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - L. Zhang
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States of America
- Infectious Diseases Institute, The Ohio State University, Columbus, OH, United States of America
| | - D. Bernal-Rubio
- The Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - D. Figueroa
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - L. Carrau
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - R. Fenutria
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - U. Potla
- The Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - St. P. Reid
- Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - J. S. Yount
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States of America
- Infectious Diseases Institute, The Ohio State University, Columbus, OH, United States of America
| | - K. A. Stapleford
- Department of Microbiology, New York University School of Medicine, New York, NY, United States of America
| | - S. Aguirre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - A. Fernandez-Sesma
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- The Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
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Long noncoding RNA AANCR modulates innate antiviral responses by blocking miR-210-dependent MITA downregulation in teleost fish, Miichthys miiuy. SCIENCE CHINA-LIFE SCIENCES 2020; 64:1131-1148. [PMID: 32997329 DOI: 10.1007/s11427-020-1789-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 08/03/2020] [Indexed: 01/17/2023]
Abstract
Viral infection induces the initiation of antiviral effectors and cytokines which are critical mediators of innate antiviral responses. The critical molecular determinants are responsible for triggering an appropriate immune response. Long noncoding RNAs (lncRNAs) have emerged as new gene modulators involved in various biological processes, while how lncRNAs operate in lower vertebrates are still unknown. Here, we discover a long noncoding RNA, termed antiviral-associated long noncoding RNA (AANCR), as a novel regulator for innate antiviral responses in teleost fish. The results indicate that fish MITA plays an essential role in host antiviral responses and inhibition of Siniperca chuatsi rhabdovirus (SCRV) production. miR-210 reduces MITA expression and suppress MITA-mediated antiviral responses, which may help viruses evade host antiviral responses. Further, AANCR functions as a competing endogenous RNA (ceRNA) for miR-210 to control protein abundance of MITA, thereby inhibiting SCRV replication and promoting antiviral responses. Our data not only shed new light on understanding the function role of lncRNA in biological processes in teleost fish, but confirmed the hypothesis that ceRNA networks exist widely in vertebrates.
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Zhu T, Fernandez-Sesma A. Innate Immune DNA Sensing of Flaviviruses. Viruses 2020; 12:v12090979. [PMID: 32899347 PMCID: PMC7552040 DOI: 10.3390/v12090979] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 08/27/2020] [Accepted: 08/28/2020] [Indexed: 12/13/2022] Open
Abstract
Flaviviruses are arthropod-borne RNA viruses that have been used extensively to study host antiviral responses. Often selected just to represent standard single-stranded positive-sense RNA viruses in early studies, the Flavivirus genus over time has taught us how truly unique it is in its remarkable ability to target not just the RNA sensory pathways but also the cytosolic DNA sensing system for its successful replication inside the host cell. This review summarizes the main developments on the unexpected antagonistic strategies utilized by different flaviviruses, with RNA genomes, against the host cyclic GAMP synthase (cGAS)/stimulator of interferon genes (STING) cytosolic DNA sensing pathway in mammalian systems. On the basis of the recent advancements on this topic, we hypothesize that the mechanisms of viral sensing and innate immunity are much more fluid than what we had anticipated, and both viral and host factors will continue to be found as important factors contributing to the host innate immune system in the future.
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Affiliation(s)
- Tongtong Zhu
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ana Fernandez-Sesma
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Correspondence: ; Tel.: +1-212-241-5182
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Stolz ML, McCormick C. The bZIP Proteins of Oncogenic Viruses. Viruses 2020; 12:v12070757. [PMID: 32674309 PMCID: PMC7412551 DOI: 10.3390/v12070757] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/08/2020] [Accepted: 07/13/2020] [Indexed: 12/20/2022] Open
Abstract
Basic leucine zipper (bZIP) transcription factors (TFs) govern diverse cellular processes and cell fate decisions. The hallmark of the leucine zipper domain is the heptad repeat, with leucine residues at every seventh position in the domain. These leucine residues enable homo- and heterodimerization between ZIP domain α-helices, generating coiled-coil structures that stabilize interactions between adjacent DNA-binding domains and target DNA substrates. Several cancer-causing viruses encode viral bZIP TFs, including human T-cell leukemia virus (HTLV), hepatitis C virus (HCV) and the herpesviruses Marek’s disease virus (MDV), Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV). Here, we provide a comprehensive review of these viral bZIP TFs and their impact on viral replication, host cell responses and cell fate.
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Xu L, Yu D, Peng L, Wu Y, Fan Y, Gu T, Yao YL, Zhong J, Chen X, Yao YG. An Alternative Splicing of Tupaia STING Modulated Anti-RNA Virus Responses by Targeting MDA5-LGP2 and IRF3. THE JOURNAL OF IMMUNOLOGY 2020; 204:3191-3204. [DOI: 10.4049/jimmunol.1901320] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 04/15/2020] [Indexed: 01/01/2023]
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Wan D, Jiang W, Hao J. Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response. Front Immunol 2020; 11:615. [PMID: 32411126 PMCID: PMC7198750 DOI: 10.3389/fimmu.2020.00615] [Citation(s) in RCA: 172] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 03/17/2020] [Indexed: 12/19/2022] Open
Abstract
Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immune-surveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.
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Affiliation(s)
- Dongshan Wan
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.,Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Wei Jiang
- Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Junwei Hao
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
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