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Ma K, Xu Y, Cheng H, Tang K, Ma J, Huang B. T cell-based cancer immunotherapy: opportunities and challenges. Sci Bull (Beijing) 2025:S2095-9273(25)00337-8. [PMID: 40221316 DOI: 10.1016/j.scib.2025.03.054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/24/2025] [Accepted: 03/25/2025] [Indexed: 04/14/2025]
Abstract
T cells play a central role in the cancer immunity cycle. The therapeutic outcomes of T cell-based intervention strategies are determined by multiple factors at various stages of the cycle. Here, we summarize and discuss recent advances in T cell immunotherapy and potential barriers to it within the framework of the cancer immunity cycle, including T-cell recognition of tumor antigens for activation, T cell trafficking and infiltration into tumors, and killing of target cells. Moreover, we discuss the key factors influencing T cell differentiation and functionality, including TCR stimulation, costimulatory signals, cytokines, metabolic reprogramming, and mechanistic forces. We also highlight the key transcription factors dictating T cell differentiation and discuss how metabolic circuits and specific metabolites shape the epigenetic program of tumor-infiltrating T cells. We conclude that a better understanding of T cell fate decision will help design novel strategies to overcome the barriers to effective cancer immunity.
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Affiliation(s)
- Kaili Ma
- National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China
| | - Yingxi Xu
- Department of Oncology, University of Lausanne, Lausanne, 1015, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, 1066, Switzerland; National Key Laboratory of Blood Science, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science, Tianjin 300070, China
| | - Hongcheng Cheng
- National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China
| | - Ke Tang
- Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Jingwei Ma
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Bo Huang
- Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
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Palzer KA, Bolduan V, Lakus J, Tubbe I, Montermann E, Clausen BE, Bros M, Pautz A. The RNA-binding protein KSRP reduces asthma-like characteristics in a murine model. Inflamm Res 2025; 74:54. [PMID: 40095032 PMCID: PMC11914311 DOI: 10.1007/s00011-025-02024-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 02/24/2025] [Accepted: 03/04/2025] [Indexed: 03/19/2025] Open
Abstract
BACKGROUND AND OBJECTIVE Asthma is a chronic inflammatory disease characterized by dysregulated cytokine expression. The RNA-binding protein KSRP reduces the expression of several pro-inflammatory mediators. Therefore, we investigated whether KSRP modulates Th2-associated immune responses in vivo in an ovalbumin-induced (OVA) allergic asthma model in C57BL/6 KSRP-deficient mice (KSRP-/-). METHODS Asthma severity in OVA-immunized wild type or KSRP-/- mice was determined by airway hyperresponsiveness (AHR), structural changes of lung tissue, and OVA-specific antibody production. Cytokine expression in bronchoalveolar lavage fluid (BALF) was measured by Cytometric Bead Array (CBA) analysis. Cellular signaling pathways involved in KSRP-mediated effects in asthma pathogenesis were analyzed in vitro in cell culture models using specific inhibitors. RESULTS KSRP deficiency exacerbates OVA-induced allergic asthma compared to wild type mice, as indicated by increased AHR, more severe lung damage, goblet cell hyperplasia and increased OVA-specific antibody production. CBA analyses confirmed, that KSRP deficiency enhances IL-4, IL-5 and IL-13 production in BALF. The effect of KSRP on Th2-associated cytokine expression appears to be mediated by modulation of the STAT6 and NFAT signaling pathway rather than by inhibiting the stability of cytokine-encoding mRNA species. CONCLUSION Our data demonstrate that KSRP dampens Th2 immune cell activity and therefore seems to be important for the pathogenesis of Th2-mediated diseases.
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Affiliation(s)
- Kim-Alicia Palzer
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg-University, Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.
| | - Vanessa Bolduan
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Jelena Lakus
- Paul Klein Center for Immune Intervention, Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Ingrid Tubbe
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Evelyn Montermann
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Björn E Clausen
- Paul Klein Center for Immune Intervention, Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Matthias Bros
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Andrea Pautz
- Department of Pharmacology, University Medical Center of the Johannes Gutenberg-University, Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
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Ma S, Dahabieh MS, Mann TH, Zhao S, McDonald B, Song WS, Chung HK, Farsakoglu Y, Garcia-Rivera L, Hoffmann FA, Xu S, Du VY, Chen D, Furgiuele J, LaPorta M, Jacobs E, DeCamp LM, Oswald BM, Sheldon RD, Ellis AE, Liu L, He P, Wang Y, Jang C, Jones RG, Kaech SM. Nutrient-driven histone code determines exhausted CD8 + T cell fates. Science 2025; 387:eadj3020. [PMID: 39666821 PMCID: PMC11881194 DOI: 10.1126/science.adj3020] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 06/30/2024] [Accepted: 11/13/2024] [Indexed: 12/14/2024]
Abstract
Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by down-regulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.
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Affiliation(s)
- Shixin Ma
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Michael S. Dahabieh
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
| | - Thomas H. Mann
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Steven Zhao
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Bryan McDonald
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Won-Suk Song
- Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
| | - H. Kay Chung
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yagmur Farsakoglu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Lizmarie Garcia-Rivera
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Filipe Araujo Hoffmann
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Shihao Xu
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Victor Y. Du
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Dan Chen
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Jesse Furgiuele
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Michael LaPorta
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Emily Jacobs
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Lisa M. DeCamp
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
| | - Brandon M. Oswald
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
| | - Ryan D. Sheldon
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
- Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Abigail E. Ellis
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
- Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA
| | - Longwei Liu
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Peixiang He
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | - Yingxiao Wang
- Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Cholsoon Jang
- Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
| | - Russell G. Jones
- Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA
| | - Susan M. Kaech
- NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA
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Sinha P, Yadav AK. Unraveling the anti-breast cancer activity of Cimicifugae rhizoma using biological network pathways and molecular dynamics simulation. Mol Divers 2025; 29:241-254. [PMID: 38615110 DOI: 10.1007/s11030-024-10847-3] [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: 02/06/2024] [Accepted: 03/12/2024] [Indexed: 04/15/2024]
Abstract
Cimicifugae is a commonly used treatment for breast cancer, but the specific molecular mechanisms underlying its effectiveness remain unclear. In this research, we employ a combination of network pharmacology, molecular docking, and molecular dynamics simulations to uncover the most potent phytochemical within Cimicifugae rhizoma in order to delve into its interaction with the target protein in breast cancer treatment. We identified 18 active compounds and 89 associated targets, primarily associated to various biological processes such as lipid metabolism, the signaling pathway in diabetes, viral infections, and cancer-related pathways. Molecular docking analysis revealed that the two most active compounds, Formononetin and Cimigenol, exhibit strong binding to the target protein AKT1. Through molecular dynamics simulations, we found that the Cimigenol-AKT1 complex exhibits greater structural stability and lower interaction energy compared to the stigmasterol-AKT1 complex. Our study demonstrates that Cimicifugae rhizoma exerts its effects in breast cancer treatment through a multi-component, multi-target synergistic approach. Furthermore, we propose that Cimigenol, targeting AKT-1, represents the most effective compound, offering valuable insights into the molecular mechanisms underpinning its role in breast cancer therapy.
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Affiliation(s)
- Prashasti Sinha
- Department of Physics, School of Physical & Decision Science, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, 226025, India
| | - Anil Kumar Yadav
- Department of Physics, School of Physical & Decision Science, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, 226025, India.
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Yang Z, Krammer S, Mitländer H, Grund JC, Zirlik S, Wirtz S, Rauh M, Shermeh AS, Finotto S. NFATc1 in CD4 + T cells and CD11c + dendritic cells drives T H2-mediated eosinophilic inflammation in allergic asthma. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. GLOBAL 2025; 4:100355. [PMID: 39629220 PMCID: PMC11613943 DOI: 10.1016/j.jacig.2024.100355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/30/2024] [Accepted: 09/03/2024] [Indexed: 12/07/2024]
Abstract
Background Asthma, a chronic lung disease, is a significant public health problem worldwide. It is marked by increased TH2 response resulting in eosinophil accumulation. The pathophysiology of asthma involves various cell types, including epithelial cells, dendritic cells (DCs), innate lymphoid cells, B cells, and effector cells. Nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a critical transcription factor for immune regulation, is known for its role in T cells and, more recently, in myeloid cells. However, the specific contributions of NFATc1 in T cells and DCs in the context of asthma are not well understood. Objective We explored NFATc1's role in T cells and DCs in modulating TH2 immune responses within the pathophysiology of allergic asthma. Methods We induced asthma in mice lacking Nfatc1 in CD4+ T cells or CD11c+ DCs using house dust mite, thereby enabling investigation into NFATc1's role in both cell types in experimental allergic asthma. Additionally, we examined NFATc1 expression in these cell types and its correlation with blood eosinophil levels in an adult asthma cohort. Results In a house dust mite-induced asthma model, we found that Nfatc1 deficiency either in CD4+ T cells or CD11c+ DCs resulted in reduced TH2-driven eosinophilic inflammation, IgE levels, and mast cell presence in the lung of asthmatic mice. Nfatc1's absence in CD4+ T cells directly hampered TH2 cell polarization and functionality, whereas in CD11c+ DCs, it affected DC differentiation and maturation, thereby weakening T-cell priming, proliferation, and subsequent TH2 differentiation. Correspondingly, translational research indicated significant correlations between CD4+NFATc1+ and CD11c+NFATc1+ cell populations and eosinophil levels in asthmatic patients, but not in healthy controls. Conclusion NFATc1 in T cells and DCs modulates TH2-mediated eosinophilic inflammation in allergic asthma, thus offering insight into asthma pathogenesis and identifying NFATc1 as a potential target for therapeutic intervention.
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Affiliation(s)
- Zuqin Yang
- Department of Molecular Pneumology, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Susanne Krammer
- Department of Molecular Pneumology, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Hannah Mitländer
- Department of Molecular Pneumology, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Janina C. Grund
- Department of Molecular Pneumology, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Sabine Zirlik
- Department of Internal Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Stefan Wirtz
- Department of Internal Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Manfred Rauh
- Department of Pediatrics, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Atefeh Sadeghi Shermeh
- Department of Immune Modulation, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Susetta Finotto
- Department of Molecular Pneumology, Friedrich-Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Bavarian Cancer Research Center, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
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Trink J, Li R, Gao B, Lu C, Krepinsky JC. Modulators of Alpha-2 Macroglobulin Upregulation by High Glucose in Glomerular Mesangial Cells. Biomolecules 2024; 14:1444. [PMID: 39595620 PMCID: PMC11592121 DOI: 10.3390/biom14111444] [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: 10/11/2024] [Revised: 11/09/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Up to 40% of patients with diabetes mellitus will develop diabetic kidney disease (DKD), characterized pathologically by the accumulation of extracellular matrix proteins, which leads to the loss of kidney function over time. Our previous studies showed that the pan-protease inhibitor alpha 2-macroglobulin (A2M) is increased in DKD and is a critical regulator of the fibrotic response in glomerular mesangial cells (MC), an initial site of injury during DKD development. How A2M is regulated by high glucose (HG) has not yet been elucidated and is the focus of this investigation. Using serial deletions of the full A2M promoter, we identified the -405 bp region as HG-responsive in MC. Site-directed mutagenesis, siRNA, and ChIP studies showed that the transcription factor, nuclear factor of activated T cells 5 (NFAT5), regulated A2M promoter activity and protein expression in response to HG. Forkhead box P1 (FOXP1) served as a cooperative binding partner for NFAT5, required for A2M upregulation. Lastly, we showed that Smad3, known for its role in kidney fibrosis, regulated A2M promoter activity and protein production independently of HG. The importance of NFAT5, FOXP1, and Smad3 in A2M regulation was confirmed in ex vivo studies using isolated glomeruli. In conclusion, Smad3 is required for basal and HG-induced A2M expression, while NFAT5 and FOXP1 cooperatively regulate increased A2M transcription in response to HG. Inhibition of NFAT5/FOXP1 will be further evaluated as a potential therapeutic strategy to inhibit A2M production and attenuate profibrotic signaling in DKD.
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Affiliation(s)
- Jackie Trink
- Division of Nephrology, McMaster University, Hamilton, ON L8N 1Y3, Canada; (J.T.); (R.L.); (B.G.); (C.L.)
| | - Renzhong Li
- Division of Nephrology, McMaster University, Hamilton, ON L8N 1Y3, Canada; (J.T.); (R.L.); (B.G.); (C.L.)
| | - Bo Gao
- Division of Nephrology, McMaster University, Hamilton, ON L8N 1Y3, Canada; (J.T.); (R.L.); (B.G.); (C.L.)
| | - Chao Lu
- Division of Nephrology, McMaster University, Hamilton, ON L8N 1Y3, Canada; (J.T.); (R.L.); (B.G.); (C.L.)
| | - Joan C. Krepinsky
- Division of Nephrology, McMaster University, Hamilton, ON L8N 1Y3, Canada; (J.T.); (R.L.); (B.G.); (C.L.)
- St. Joseph’s Hospital, 50 Charlton Ave East, Rm T3311, Hamilton, ON L8N 4A6, Canada
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Gao Z, Sun Y, Zhu Z, Ni N, Sun S, Nie M, Du W, Irfan M, Chen L, Zhang L. Transcription factors LvBBX24 and LvbZIP44 coordinated anthocyanin accumulation in response to light in lily petals. HORTICULTURE RESEARCH 2024; 11:uhae211. [PMID: 39372289 PMCID: PMC11450212 DOI: 10.1093/hr/uhae211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 07/23/2024] [Indexed: 10/08/2024]
Abstract
Lily (Lilium spp.), a horticultural crop serving both ornamental and edible functions, derives its coloration primarily from anthocyanins. However, limited studies have been conducted on the accumulation of anthocyanins within lilies. In this study, we cloned a light-induced transcription factor named as LvBBX24 in lilies. Through genetic and biochemical analysis, we determined that LvBBX24 could upregulate the transcription of LvMYB5 and facilitate anthocyanin synthesis. Moreover, we identified that darkness promoted the degradation of LvBBX24 protein. Through screening a yeast library, we identified LvbZIP44 acts as its interacting partner. Genetic testing confirmed that LvbZIP44 also plays a role in promoting lily anthocyanin synthesis. This indicates a potential synergistic regulatory effect between LvBBX24 and LvbZIP44. Our study indicates that LvBBX24 and LvbZIP44 cooperate to regulate anthocyanin accumulation in lily petals. These findings provide compelling evidence supporting the idea that LvBBX24 and LvbZIP44 may form a looped helix surrounding the LvMYB5 promoter region to regulate anthocyanin biosynthesis.
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Affiliation(s)
- Zhenhua Gao
- Key Laboratory of Agriculture Biotechnology, Key Laboratory of Protected Horticulture (Ministry of Education), College of Biosciences and Biotechnology, Shenyang Agricultural University, Shenyang, Liaoning 110161, China
| | - Yibo Sun
- Key Laboratory of Agriculture Biotechnology, Key Laboratory of Protected Horticulture (Ministry of Education), College of Biosciences and Biotechnology, Shenyang Agricultural University, Shenyang, Liaoning 110161, China
| | - Ziman Zhu
- Key Laboratory of Agriculture Biotechnology, Key Laboratory of Protected Horticulture (Ministry of Education), College of Biosciences and Biotechnology, Shenyang Agricultural University, Shenyang, Liaoning 110161, China
| | - Na Ni
- Key Laboratory of Agriculture Biotechnology, Key Laboratory of Protected Horticulture (Ministry of Education), College of Biosciences and Biotechnology, Shenyang Agricultural University, Shenyang, Liaoning 110161, China
| | - Shaokun Sun
- Institute of Vegetable Research, Liaoning Academy of Agricultural Sciences, Shenyang, Liaoning 110161, China
| | - Mengyao Nie
- Key Laboratory of Agriculture Biotechnology, Key Laboratory of Protected Horticulture (Ministry of Education), College of Biosciences and Biotechnology, Shenyang Agricultural University, Shenyang, Liaoning 110161, China
| | - Weifeng Du
- Key Laboratory of Agriculture Biotechnology, Key Laboratory of Protected Horticulture (Ministry of Education), College of Biosciences and Biotechnology, Shenyang Agricultural University, Shenyang, Liaoning 110161, China
| | - Muhammad Irfan
- Department of Biotechnology, University of Sargodha, Sargodha Pakistan
| | - Lijing Chen
- Key Laboratory of Agriculture Biotechnology, Key Laboratory of Protected Horticulture (Ministry of Education), College of Biosciences and Biotechnology, Shenyang Agricultural University, Shenyang, Liaoning 110161, China
| | - Li Zhang
- Key Laboratory of Agriculture Biotechnology, Key Laboratory of Protected Horticulture (Ministry of Education), College of Biosciences and Biotechnology, Shenyang Agricultural University, Shenyang, Liaoning 110161, China
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Maytum A, Obier N, Cauchy P, Bonifer C. Regulation of developmentally controlled enhancer activity by extrinsic signals in normal and malignant cells: AP-1 at the centre. FRONTIERS IN EPIGENETICS AND EPIGENOMICS 2024; 2:freae.2024.1465958. [PMID: 39506987 PMCID: PMC7616781 DOI: 10.3389/freae.2024.1465958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/08/2024]
Abstract
The ability of cells to respond to external stimuli is one of the characteristics of life as we know it. Multicellular organisms have developed a huge machinery that interprets the cellular environment and instigates an appropriate cellular response by changing gene expression, metabolism, proliferation state and motility. Decades of research have studied the pathways transmitting the various signals within the cell. However, whilst we know most of the players, we know surprisingly little about the mechanistic details of how extrinsic signals are interpreted and integrated within the genome. In this article we revisit the long-standing debate of whether factors regulating cellular growth (cytokines) act in an instructive or permissive fashion on cell fate decisions. We touch upon this topic by highlighting the paradigm of AP-1 as one of the most important signaling-responsive transcription factor family and summarize our work and that of others to explain what is known about cytokine responsive cis-regulatory elements driving differential gene expression. We propose that cytokines and, by extension, multiple types of external signals are the main drivers of cell differentiation and act via inducible transcription factors that transmit signaling processes to the genome and are essential for changing gene expression to drive transitions between gene regulatory networks. Importantly, inducible transcription factors cooperate with cell type specific factors within a pre-existing chromatin landscape and integrate multiple signaling pathways at specific enhancer elements, to both maintain and alter cellular identities. We also propose that signaling processes and signaling responsive transcription factors are at the heart of tumor development.
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Affiliation(s)
- Alexander Maytum
- Blood Cell Development Group, Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052 Australia, Country
| | - Nadine Obier
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Pierre Cauchy
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Constanze Bonifer
- Blood Cell Development Group, Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052 Australia, Country
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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Patterson SD, Massett ME, Huang X, Jørgensen HG, Michie AM. The MYC-NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells. Mol Oncol 2024; 18:2234-2254. [PMID: 38459421 PMCID: PMC11467801 DOI: 10.1002/1878-0261.13630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/30/2024] [Accepted: 02/29/2024] [Indexed: 03/10/2024] Open
Abstract
Acute myeloid leukaemia (AML) is a clonal haematological malignancy affecting the myeloid lineage, with generally poor patient outcomes owing to the lack of targeted therapies. The histone lysine demethylase 4A (KDM4A) has been established as a novel therapeutic target in AML, due to its selective oncogenic role within leukaemic cells. We identify that the transcription factor nuclear factor of activated T cells 2 (NFATC2) is a novel binding and transcriptional target of KDM4A in the human AML THP-1 cell line. Furthermore, cytogenetically diverse AML cell lines, including THP-1, were dependent on NFATC2 for colony formation in vitro, highlighting a putative novel mechanism of AML oncogenesis. Our study demonstrates that NFATC2 maintenance of cell cycle progression in human AML cells was driven primarily by CCND1. Through RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq), NFATc2 was shown to bind to the promoter region of genes involved in oxidative phosphorylation and subsequently regulate their gene expression in THP-1 cells. Furthermore, our data show that NFATC2 shares transcriptional targets with the transcription factor c-MYC, with MYC knockdown phenocopying NFATC2 knockdown. These data suggest a newly identified co-ordinated role for NFATC2 and MYC in the maintenance of THP-1 cell function, indicative of a potential means of therapeutic targeting in human AML.
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Affiliation(s)
- Shaun D. Patterson
- Paul O'Gorman Leukaemia Research Centre, Gartnavel General HospitalUniversity of GlasgowUK
| | - Matthew E. Massett
- Paul O'Gorman Leukaemia Research Centre, Gartnavel General HospitalUniversity of GlasgowUK
| | - Xu Huang
- Paul O'Gorman Leukaemia Research Centre, Gartnavel General HospitalUniversity of GlasgowUK
| | - Heather G. Jørgensen
- Paul O'Gorman Leukaemia Research Centre, Gartnavel General HospitalUniversity of GlasgowUK
| | - Alison M. Michie
- Paul O'Gorman Leukaemia Research Centre, Gartnavel General HospitalUniversity of GlasgowUK
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10
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Kim S, Liu TT, Ou F, Murphy TL, Murphy KM. Anatomy of a superenhancer. Adv Immunol 2024; 163:51-96. [PMID: 39271259 DOI: 10.1016/bs.ai.2024.08.001] [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] [Indexed: 09/15/2024]
Abstract
Interferon regulatory factor-8 (IRF8) is the lineage determining transcription factor for the type one classical dendritic cell (cDC1) subset, a terminal selector for plasmacytoid dendritic cells and important for the function of monocytes. Studies of Irf8 gene regulation have identified several enhancers controlling its activity during development of progenitors in the bone marrow that precisely regulate expression at distinct developmental stages. Each enhancer responds to distinct transcription factors that are expressed at each stage. IRF8 is first expressed in early progenitors that form the monocyte dendritic cell progenitor (MDP) in response to induction of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) acting at the Irf8 +56 kb enhancer. IRF8 levels increase further as the MDP transits into the common dendritic cell progenitor (CDP) in response to E protein activity at the Irf8 +41 kb enhancer. Upon Nfil3-induction in CDPs leading to specification of the cDC1 progenitor, abrupt induction of BATF3 forms the JUN/BATF3/IRF8 heterotrimer that activates the Irf8 +32 kb enhancer that sustains Irf8 autoactivation throughout the cDC1 lifetime. Deletions of each of these enhancers has revealed their stage dependent activation. Surprisingly, studies of compound heterozygotes for each combination of enhancer deletions revealed that activation of each subsequent enhancer requires the successful activation of the previous enhancer in strictly cis-dependent mechanism. Successful progression of enhancer activation is finely tuned to alter the functional accessibility of subsequent enhancers to factors active in the next stage of development. The molecular basis for these phenomenon is still obscure but could have implications for genomic regulation in a broader developmental context.
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Affiliation(s)
- Sunkyung Kim
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States.
| | - Tian-Tian Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
| | - Feiya Ou
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
| | - Theresa L Murphy
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
| | - Kenneth M Murphy
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States.
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11
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Rückert T, Romagnani C. Extrinsic and intrinsic drivers of natural killer cell clonality. Immunol Rev 2024; 323:80-106. [PMID: 38506411 DOI: 10.1111/imr.13324] [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] [Indexed: 03/21/2024]
Abstract
Clonal expansion of antigen-specific lymphocytes is the fundamental mechanism enabling potent adaptive immune responses and the generation of immune memory. Accompanied by pronounced epigenetic remodeling, the massive proliferation of individual cells generates a critical mass of effectors for the control of acute infections, as well as a pool of memory cells protecting against future pathogen encounters. Classically associated with the adaptive immune system, recent work has demonstrated that innate immune memory to human cytomegalovirus (CMV) infection is stably maintained as large clonal expansions of natural killer (NK) cells, raising questions on the mechanisms for clonal selection and expansion in the absence of re-arranged antigen receptors. Here, we discuss clonal NK cell memory in the context of the mechanisms underlying clonal competition of adaptive lymphocytes and propose alternative selection mechanisms that might decide on the clonal success of their innate counterparts. We propose that the integration of external cues with cell-intrinsic sources of heterogeneity, such as variegated receptor expression, transcriptional states, and somatic variants, compose a bottleneck for clonal selection, contributing to the large size of memory NK cell clones.
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Affiliation(s)
- Timo Rückert
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, Berlin, Germany
| | - Chiara Romagnani
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, Berlin, Germany
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12
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Ma S, Sandhoff R, Luo X, Shang F, Shi Q, Li Z, Wu J, Ming Y, Schwarz F, Madi A, Weisshaar N, Mieg A, Hering M, Zettl F, Yan X, Mohr K, Ten Bosch N, Li Z, Poschet G, Rodewald HR, Papavasiliou N, Wang X, Gao P, Cui G. Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos. Sci Immunol 2024; 9:eadg8817. [PMID: 38640251 DOI: 10.1126/sciimmunol.adg8817] [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: 01/27/2023] [Accepted: 03/15/2024] [Indexed: 04/21/2024]
Abstract
CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences Treg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1-dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits antitumor immunity.
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Affiliation(s)
- Sicong Ma
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230601, China
| | - Roger Sandhoff
- Lipid Pathobiochemistry Group (A411), 69120 Heidelberg, Germany
| | - Xiu Luo
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Fuwei Shang
- Cellular Immunology (D110), German Cancer Research Center, 69120 Heidelberg, Germany
- Faculty of Medicine, Heidelberg University, Heidelberg, Germany
| | - Qiaozhen Shi
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Zhaolong Li
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Jingxia Wu
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230601, China
| | - Yanan Ming
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230601, China
| | - Frank Schwarz
- Core Facility Antibodies (W170), German Cancer Research Center, 69120 Heidelberg, Germany
| | - Alaa Madi
- Immune Diversity (D150), German Cancer Research Center, 69120 Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Nina Weisshaar
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- T Cell Metabolism (D192), German Cancer Research Center, 69120 Heidelberg, Germany
| | - Alessa Mieg
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- T Cell Metabolism (D192), German Cancer Research Center, 69120 Heidelberg, Germany
| | - Marvin Hering
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- T Cell Metabolism (D192), German Cancer Research Center, 69120 Heidelberg, Germany
| | - Ferdinand Zettl
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- T Cell Metabolism (D192), German Cancer Research Center, 69120 Heidelberg, Germany
| | - Xin Yan
- Immune Diversity (D150), German Cancer Research Center, 69120 Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Kerstin Mohr
- T Cell Metabolism (D192), German Cancer Research Center, 69120 Heidelberg, Germany
| | - Nora Ten Bosch
- T Cell Metabolism (D192), German Cancer Research Center, 69120 Heidelberg, Germany
| | - Zhe Li
- Division of Pathogenesis of Virus Associated Tumors (F100), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Gernot Poschet
- Metabolomics Core Technology Platform, Centre for Organismal Studies (COS), Heidelberg University, 69120 Heidelberg, Germany
| | - Hans-Reimer Rodewald
- Cellular Immunology (D110), German Cancer Research Center, 69120 Heidelberg, Germany
| | - Nina Papavasiliou
- Immune Diversity (D150), German Cancer Research Center, 69120 Heidelberg, Germany
| | - Xi Wang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Pu Gao
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Guoliang Cui
- Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230601, China
- T Cell Metabolism (D192), German Cancer Research Center, 69120 Heidelberg, Germany
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13
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Mbonye U, Karn J. The cell biology of HIV-1 latency and rebound. Retrovirology 2024; 21:6. [PMID: 38580979 PMCID: PMC10996279 DOI: 10.1186/s12977-024-00639-w] [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] [Indexed: 04/07/2024] Open
Abstract
Transcriptionally latent forms of replication-competent proviruses, present primarily in a small subset of memory CD4+ T cells, pose the primary barrier to a cure for HIV-1 infection because they are the source of the viral rebound that almost inevitably follows the interruption of antiretroviral therapy. Over the last 30 years, many of the factors essential for initiating HIV-1 transcription have been identified in studies performed using transformed cell lines, such as the Jurkat T-cell model. However, as highlighted in this review, several poorly understood mechanisms still need to be elucidated, including the molecular basis for promoter-proximal pausing of the transcribing complex and the detailed mechanism of the delivery of P-TEFb from 7SK snRNP. Furthermore, the central paradox of HIV-1 transcription remains unsolved: how are the initial rounds of transcription achieved in the absence of Tat? A critical limitation of the transformed cell models is that they do not recapitulate the transitions between active effector cells and quiescent memory T cells. Therefore, investigation of the molecular mechanisms of HIV-1 latency reversal and LRA efficacy in a proper physiological context requires the utilization of primary cell models. Recent mechanistic studies of HIV-1 transcription using latently infected cells recovered from donors and ex vivo cellular models of viral latency have demonstrated that the primary blocks to HIV-1 transcription in memory CD4+ T cells are restrictive epigenetic features at the proviral promoter, the cytoplasmic sequestration of key transcription initiation factors such as NFAT and NF-κB, and the vanishingly low expression of the cellular transcription elongation factor P-TEFb. One of the foremost schemes to eliminate the residual reservoir is to deliberately reactivate latent HIV-1 proviruses to enable clearance of persisting latently infected cells-the "Shock and Kill" strategy. For "Shock and Kill" to become efficient, effective, non-toxic latency-reversing agents (LRAs) must be discovered. Since multiple restrictions limit viral reactivation in primary cells, understanding the T-cell signaling mechanisms that are essential for stimulating P-TEFb biogenesis, initiation factor activation, and reversing the proviral epigenetic restrictions have become a prerequisite for the development of more effective LRAs.
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Affiliation(s)
- Uri Mbonye
- Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
| | - Jonathan Karn
- Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
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14
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Chaudhry MZ, Borkner L, Kulkarni U, Berberich-Siebelt F, Cicin-Sain L. NFAT signaling is indispensable for persistent memory responses of MCMV-specific CD8+ T cells. PLoS Pathog 2024; 20:e1012025. [PMID: 38346075 PMCID: PMC10890734 DOI: 10.1371/journal.ppat.1012025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 02/23/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Cytomegalovirus (CMV) induces a unique T cell response, where antigen-specific populations do not contract, but rather inflate during viral latency. It has been proposed that subclinical episodes of virus reactivation feed the inflation of CMV-specific memory cells by intermittently engaging T cell receptors (TCRs), but evidence of TCR engagement has remained lacking. Nuclear factor of activated T cells (NFAT) is a family of transcription factors, where NFATc1 and NFATc2 signal downstream of TCR in mature T lymphocytes. We show selective impacts of NFATc1 and/or NFATc2 genetic ablations on the long-term inflation of MCMV-specific CD8+ T cell responses despite largely maintained responses to acute infection. NFATc1 ablation elicited robust phenotypes in isolation, but the strongest effects were observed when both NFAT genes were missing. CMV control was impaired only when both NFATs were deleted in CD8+ T cells used in adoptive immunotherapy of immunodeficient mice. Transcriptome analyses revealed that T cell intrinsic NFAT is not necessary for CD8+ T cell priming, but rather for their maturation towards effector-memory and in particular the effector cells, which dominate the pool of inflationary cells.
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Affiliation(s)
- M. Zeeshan Chaudhry
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Lisa Borkner
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Upasana Kulkarni
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | | | - Luka Cicin-Sain
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Centre for Individualized Infection Medicine, a joint venture of Helmholtz Centre for Infection Research and Medical School Hannover, Hannover, Germany
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15
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Zhang P, Huang C, Liu H, Zhang M, Liu L, Zhai Y, Zhang J, Yang J, Yang J. The mechanism of the NFAT transcription factor family involved in oxidative stress response. J Cardiol 2024; 83:30-36. [PMID: 37149283 DOI: 10.1016/j.jjcc.2023.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 04/20/2023] [Accepted: 04/28/2023] [Indexed: 05/08/2023]
Abstract
As a transcriptional activator widely expressed in various tissues, nuclear factor of activated T cells (NFAT) is involved in the regulation of the immune system, the development of the heart and brain systems, and classically mediating pathological processes such as cardiac hypertrophy. Oxidative stress is an imbalance of intracellular redox status, characterized by excessive generation of reactive oxygen species, accompanied by mitochondrial dysfunction, calcium overload, and subsequent lipid peroxidation, inflammation, and apoptosis. Oxidative stress occurs during various pathological processes, such as chronic hypoxia, vascular smooth muscle cell phenotype switching, ischemia-reperfusion, and cardiac remodeling. Calcium overload leads to an increase in intracellular calcium concentration, while NFAT can be activated through calcium-calcineurin, which is also the main regulatory mode of NFAT factors. This review focuses on the effects of NFAT transcription factors on reactive oxygen species production, calcium overload, mitochondrial dysfunction, redox reactions, lipid peroxidation, inflammation, and apoptosis in response to oxidative stress. We hope to provide a reference for the functions and characteristics of NFAT involved in various stages of oxidative stress as well as related potential targets.
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Affiliation(s)
- Peiyue Zhang
- Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China; Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, China
| | - Cuiyuan Huang
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, China
| | - Haiyin Liu
- Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China; Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, China
| | - Mengting Zhang
- Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China; Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, China
| | - Li Liu
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, China
| | - Yuhong Zhai
- Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China; Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, China
| | - Jing Zhang
- Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, China; HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, China
| | - Jian Yang
- Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China; Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, China.
| | - Jun Yang
- Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, China; Institute of Cardiovascular Diseases, China Three Gorges University, Yichang, China.
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16
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Sun M, Lv F, Qin C, Du D, Li W, Liu S. The Potential Mechanism of Liujunzi Decoction in the Treatment of Breast Cancer based on Network Pharmacology and Molecular Docking Technology. Curr Pharm Des 2024; 30:702-726. [PMID: 38415453 DOI: 10.2174/0113816128289900240219104854] [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: 10/28/2023] [Revised: 01/18/2024] [Accepted: 02/06/2024] [Indexed: 02/29/2024]
Abstract
BACKGROUND Liujunzi Decoction (LJZD) is a potential clinical treatment for Breast Cancer (BC), but the active ingredients and mechanisms underlying its effectiveness remain unclear. OBJECTIVE The study aimed to investigate the target gene of LJZD compatibility and the possible mechanism of action in the treatment of breast cancer by using network pharmacology and molecular docking. METHODS Based on TCMSP, ETCM, and BATMAN database searching and screening to obtain the ingredients of LJZD, the related targets were obtained. Breast cancer-related targets were collected through GEO, Geencards, OMIM, and other databases, and drug-disease Venn diagrams were drawn by R. The PPI network map was constructed by using Cytoscape. The intersecting targets were imported into the STRING database, and the core targets were analyzed and screened. The intersected targets were analyzed by the DAVID database for GO and KEGG enrichment. AutoDock Vina and Gromacs were used for molecular docking and simulation of the core targets and active ingredients. RESULTS 126 active ingredients of LJZD were obtained; 241 targets related to breast cancer were sought after screening, and 180 intersection targets were identified through Venn diagram analysis. The core targets were FOS and ESR1. KEGG enrichment analysis mainly involved PI3K/Akt, MAPK, and other signaling pathways. CONCLUSION This study has explored the possible targets and signaling pathways of LJZD in treating breast cancer through network pharmacology and bioinformatics analysis. Molecular docking and simulation have further validated the potential mechanism of action of LJZD in breast cancer treatment, providing essential experimental data for future studies.
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Affiliation(s)
- Mei Sun
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Feng Lv
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Chunmeng Qin
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Dan Du
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Wenjun Li
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Songqing Liu
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
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17
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de Boer CG, Taipale J. Hold out the genome: a roadmap to solving the cis-regulatory code. Nature 2024; 625:41-50. [PMID: 38093018 DOI: 10.1038/s41586-023-06661-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 09/20/2023] [Indexed: 01/05/2024]
Abstract
Gene expression is regulated by transcription factors that work together to read cis-regulatory DNA sequences. The 'cis-regulatory code' - how cells interpret DNA sequences to determine when, where and how much genes should be expressed - has proven to be exceedingly complex. Recently, advances in the scale and resolution of functional genomics assays and machine learning have enabled substantial progress towards deciphering this code. However, the cis-regulatory code will probably never be solved if models are trained only on genomic sequences; regions of homology can easily lead to overestimation of predictive performance, and our genome is too short and has insufficient sequence diversity to learn all relevant parameters. Fortunately, randomly synthesized DNA sequences enable testing a far larger sequence space than exists in our genomes, and designed DNA sequences enable targeted queries to maximally improve the models. As the same biochemical principles are used to interpret DNA regardless of its source, models trained on these synthetic data can predict genomic activity, often better than genome-trained models. Here we provide an outlook on the field, and propose a roadmap towards solving the cis-regulatory code by a combination of machine learning and massively parallel assays using synthetic DNA.
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Affiliation(s)
- Carl G de Boer
- School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Jussi Taipale
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
- Department of Biochemistry, University of Cambridge, Cambridge, UK.
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18
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Wither MJ, White WL, Pendyala S, Leanza PJ, Fowler DM, Kueh HY. Antigen perception in T cells by long-term Erk and NFAT signaling dynamics. Proc Natl Acad Sci U S A 2023; 120:e2308366120. [PMID: 38113261 PMCID: PMC10756264 DOI: 10.1073/pnas.2308366120] [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: 05/29/2023] [Accepted: 10/20/2023] [Indexed: 12/21/2023] Open
Abstract
Immune system threat detection hinges on T cells' ability to perceive varying peptide-major histocompatibility complex (pMHC) antigens. As the Erk and NFAT pathways link T cell receptor engagement to gene regulation, their signaling dynamics may convey information about pMHC inputs. To test this idea, we developed a dual reporter mouse strain and a quantitative imaging assay that, together, enable simultaneous monitoring of Erk and NFAT dynamics in live T cells over day-long timescales as they respond to varying pMHC inputs. Both pathways initially activate uniformly across various pMHC inputs but diverge only over longer (9+ h) timescales, enabling independent encoding of pMHC affinity and dose. These late signaling dynamics are decoded via multiple temporal and combinatorial mechanisms to generate pMHC-specific transcriptional responses. Our findings underscore the importance of long timescale signaling dynamics in antigen perception and establish a framework for understanding T cell responses under diverse contexts.
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Affiliation(s)
- Matthew J. Wither
- University of Washington, Department of Bioengineering, Seattle, WA98195
| | - William L. White
- University of Washington, Department of Bioengineering, Seattle, WA98195
| | - Sriram Pendyala
- University of Washington, Department of Genome Sciences, Seattle, WA98195
| | - Paul J. Leanza
- University of Washington, Department of Bioengineering, Seattle, WA98195
| | - Douglas M. Fowler
- University of Washington, Department of Genome Sciences, Seattle, WA98195
| | - Hao Yuan Kueh
- University of Washington, Department of Bioengineering, Seattle, WA98195
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA98109
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19
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Zhang A, Lau NA, Wong A, Brown LG, Coleman IM, De Sarkar N, Li D, DeLucia DC, Labrecque MP, Nguyen HM, Conner JL, Dumpit RF, True LD, Lin DW, Corey E, Alumkal JJ, Nelson PS, Morrissey C, Lee JK. Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers. CANCER RESEARCH COMMUNICATIONS 2023; 3:2358-2374. [PMID: 37823778 PMCID: PMC10658857 DOI: 10.1158/2767-9764.crc-23-0250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/28/2023] [Accepted: 10/02/2023] [Indexed: 10/13/2023]
Abstract
Castration-resistant prostate cancer (CRPC) consists of multiple phenotypic subtypes including androgen receptor (AR)-active prostate cancer (ARPC) and neuroendocrine prostate cancer (NEPC). Tumor cells with these phenotypes can coexist between metastases within a patient and within an individual tumor. Treatments that are effective across CRPC subtypes are currently lacking. Histone deacetylation is crucial for the regulation of chromatin structure and maintenance of cancer cell state and activation of the PI3K/AKT/mTOR signaling cascade is a tumor growth-promoting pathway. We therefore investigated combined targeting of histone deacetylase (HDAC) and PI3K using a rationally designed dual inhibitor, fimepinostat, in CRPC subtypes in vitro and in vivo. Dual HDAC1/2 and PI3K/AKT pathway inhibition by fimepinostat led to robust tumor growth inhibition in both ARPC and NEPC models including cell line- and patient-derived xenografts. HDAC1/2 inhibition combined with PI3K/AKT inhibition was more effective than targeting each pathway alone, producing growth inhibitory effects through cell-cycle inhibition and apoptosis. Molecular profiling revealed on-target effects of combined HDAC1/2 and PI3K/AKT inhibition independent of tumor phenotype. Fimepinostat therapy was also associated with the suppression of lineage transcription factors including AR in ARPC and Achaete-scute homolog 1 (ASCL1) in NEPC. Together, these results indicate that fimepinostat represents a novel therapeutic that may be effective against both ARPC and NEPC through CRPC subtype-dependent and -independent mechanisms. SIGNIFICANCE CRPC is a heterogeneous disease constituting multiple phenotypic subtypes that often co-occur within tumors or across metastases in patients. Existing targeted therapies for CRPC do not take this into account. Here we show that fimepinostat, a dual HDAC1/2 and PI3K/AKT inhibitor investigated clinically in other cancer types but not prostate cancer, may overcome this heterogeneity by effectively inhibiting both ARPC and NEPC subtypes of CRPC.
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Affiliation(s)
- Ailin Zhang
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Nathan A. Lau
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Alicia Wong
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Lisha G. Brown
- Department of Urology, University of Washington School of Medicine, Seattle, Washington
| | - Ilsa M. Coleman
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Navonil De Sarkar
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington
- Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Dapei Li
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington
| | - Diana C. DeLucia
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Mark P. Labrecque
- Department of Urology, University of Washington School of Medicine, Seattle, Washington
| | - Holly M. Nguyen
- Department of Urology, University of Washington School of Medicine, Seattle, Washington
| | - Jennifer L. Conner
- Department of Urology, University of Washington School of Medicine, Seattle, Washington
| | - Ruth F. Dumpit
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Lawrence D. True
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington
| | - Daniel W. Lin
- Department of Urology, University of Washington School of Medicine, Seattle, Washington
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Eva Corey
- Department of Urology, University of Washington School of Medicine, Seattle, Washington
| | - Joshi J. Alumkal
- Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - Peter S. Nelson
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Colm Morrissey
- Department of Urology, University of Washington School of Medicine, Seattle, Washington
| | - John K. Lee
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, Washington
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20
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Schleussner N, Cauchy P, Franke V, Giefing M, Fornes O, Vankadari N, Assi SA, Costanza M, Weniger MA, Akalin A, Anagnostopoulos I, Bukur T, Casarotto MG, Damm F, Daumke O, Edginton-White B, Gebhardt JCM, Grau M, Grunwald S, Hansmann ML, Hartmann S, Huber L, Kärgel E, Lusatis S, Noerenberg D, Obier N, Pannicke U, Fischer A, Reisser A, Rosenwald A, Schwarz K, Sundararaj S, Weilemann A, Winkler W, Xu W, Lenz G, Rajewsky K, Wasserman WW, Cockerill PN, Scheidereit C, Siebert R, Küppers R, Grosschedl R, Janz M, Bonifer C, Mathas S. Transcriptional reprogramming by mutated IRF4 in lymphoma. Nat Commun 2023; 14:6947. [PMID: 37935654 PMCID: PMC10630337 DOI: 10.1038/s41467-023-41954-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 09/20/2023] [Indexed: 11/09/2023] Open
Abstract
Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.
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Affiliation(s)
- Nikolai Schleussner
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas, 13125, Berlin, Germany
- Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117, Berlin, Germany
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité and MDC, Berlin, Germany
| | - Pierre Cauchy
- Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
- University Medical Center Freiburg, 79106, Freiburg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Vedran Franke
- Bioinformatics and Omics Data Science Platform, Berlin Institute for Medical Systems Biology, Max-Delbrück-Center, Berlin, Germany
| | - Maciej Giefing
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, 60-479, Poland
- Institute of Human Genetics, Christian-Albrechts-University Kiel, 24105, Kiel, Germany
| | - Oriol Fornes
- Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Naveen Vankadari
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, 3000, Australia
| | - Salam A Assi
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Mariantonia Costanza
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas, 13125, Berlin, Germany
- Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117, Berlin, Germany
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité and MDC, Berlin, Germany
| | - Marc A Weniger
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, 45122, Essen, Germany
| | - Altuna Akalin
- Bioinformatics and Omics Data Science Platform, Berlin Institute for Medical Systems Biology, Max-Delbrück-Center, Berlin, Germany
| | - Ioannis Anagnostopoulos
- Institute of Pathology, Universität Würzburg and Comprehensive Cancer Centre Mainfranken (CCCMF), Würzburg, Germany
| | - Thomas Bukur
- TRON gGmbH - Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Germany
| | - Marco G Casarotto
- Research School of Biology, The Australian National University, Canberra, ACT, Australia
| | - Frederik Damm
- Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117, Berlin, Germany
| | - Oliver Daumke
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Structural Biology, 13125, Berlin, Germany
| | - Benjamin Edginton-White
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | | | - Michael Grau
- Department of Physics, University of Marburg, 35052, Marburg, Germany
- Medical Department A for Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Stephan Grunwald
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Structural Biology, 13125, Berlin, Germany
| | - Martin-Leo Hansmann
- Frankfurt Institute of Advanced Studies, Frankfurt am Main, Germany
- Institute for Pharmacology and Toxicology, Goethe University, Frankfurt am Main, Germany
| | - Sylvia Hartmann
- Dr. Senckenberg Institute of Pathology, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Lionel Huber
- Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
| | - Eva Kärgel
- Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | - Simone Lusatis
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas, 13125, Berlin, Germany
- Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117, Berlin, Germany
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité and MDC, Berlin, Germany
| | - Daniel Noerenberg
- Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117, Berlin, Germany
| | - Nadine Obier
- Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Ulrich Pannicke
- Institute for Transfusion Medicine, University of Ulm, Ulm, Germany
| | - Anja Fischer
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany
| | - Anja Reisser
- Department of Physics, Institute of Biophysics, Ulm University, Ulm, Germany
| | - Andreas Rosenwald
- Institute of Pathology, Universität Würzburg and Comprehensive Cancer Centre Mainfranken (CCCMF), Würzburg, Germany
| | - Klaus Schwarz
- Institute for Transfusion Medicine, University of Ulm, Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg-Hessen, Ulm, Germany
| | - Srinivasan Sundararaj
- Research School of Biology, The Australian National University, Canberra, ACT, Australia
| | - Andre Weilemann
- Medical Department A for Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Wiebke Winkler
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas, 13125, Berlin, Germany
- Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117, Berlin, Germany
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité and MDC, Berlin, Germany
| | - Wendan Xu
- Medical Department A for Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Georg Lenz
- Medical Department A for Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany
| | - Klaus Rajewsky
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Immune Regulation and Cancer, 13125, Berlin, Germany
| | - Wyeth W Wasserman
- Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Peter N Cockerill
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Claus Scheidereit
- Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
| | - Reiner Siebert
- Institute of Human Genetics, Christian-Albrechts-University Kiel, 24105, Kiel, Germany
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany
| | - Ralf Küppers
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, 45122, Essen, Germany
| | - Rudolf Grosschedl
- Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
| | - Martin Janz
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas, 13125, Berlin, Germany
- Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117, Berlin, Germany
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité and MDC, Berlin, Germany
| | - Constanze Bonifer
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Stephan Mathas
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas, 13125, Berlin, Germany.
- Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117, Berlin, Germany.
- Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité and MDC, Berlin, Germany.
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
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21
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Fu Y, Wang J, Liu C, Liao K, Gao X, Tang R, Fan B, Hong Y, Xiao N, Xiao C, Liu WH. Glycogen synthase kinase 3 controls T-cell exhaustion by regulating NFAT activation. Cell Mol Immunol 2023; 20:1127-1139. [PMID: 37553428 PMCID: PMC10541428 DOI: 10.1038/s41423-023-01075-0] [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: 03/10/2023] [Accepted: 07/26/2023] [Indexed: 08/10/2023] Open
Abstract
Cellular immunity mediated by CD8+ T cells plays an indispensable role in bacterial and viral clearance and cancers. However, persistent antigen stimulation of CD8+ T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors. Numerous studies have shown that glycogen synthase kinase 3 (GSK3) controls the function and development of immune cells, but whether GSK3 affects CD8+ T cells is not clearly elucidated. Here, we demonstrate that mice with deletion of Gsk3α and Gsk3β in activated CD8+ T cells (DKO) exhibited decreased CTL differentiation and effector function during acute and chronic viral infection. In addition, DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+ T cells. Strikingly, anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice. Mechanistically, GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT, thereby in turn dampening NFAT-mediated exhaustion-related gene expression, including TOX/TOX2 and PD-1. Thus, we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.
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Affiliation(s)
- Yubing Fu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Science, Xiamen University, Xiamen, 361102, Fujian, China.
| | - Jinjia Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Science, Xiamen University, Xiamen, 361102, Fujian, China
| | - Chenfeng Liu
- Department of Cell Biology, School of Life Science, Anhui Medical University, Hefei, 230031, Anhui, China
| | - Kunyu Liao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Science, Xiamen University, Xiamen, 361102, Fujian, China
| | - Xianjun Gao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Science, Xiamen University, Xiamen, 361102, Fujian, China
| | - Ronghan Tang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Science, Xiamen University, Xiamen, 361102, Fujian, China
| | - Binbin Fan
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Science, Xiamen University, Xiamen, 361102, Fujian, China
| | - Yazhen Hong
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Science, Xiamen University, Xiamen, 361102, Fujian, China
| | - Nengming Xiao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Science, Xiamen University, Xiamen, 361102, Fujian, China
| | - Changchun Xiao
- Sanofi Institute for Biomedical Research, Suzhou, Jiangsu, 215123, China
| | - Wen-Hsien Liu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Science, Xiamen University, Xiamen, 361102, Fujian, China.
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22
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Kaye J. Integrating T Cell Activation Signals to Regulate Gene Expression through Cyclosporin-Sensitive NFAT. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:323-324. [PMID: 37987776 DOI: 10.4049/jimmunol.2300224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
This Pillars of Immunology article is a commentary on three pivotal articles: “Nuclear factor of activated T cells contains Fos and Jun,” an article written by J. Jain, P. G. McCaffrey, V. E. Valge-Archer, and A. Rao, and published in Nature, in 1992, https://www.nature.com/articles/356801a0; “The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun,” written by J. Jain, P. G. McCaffrey, Z. Miner, T. K. Kerppola, J. N. Lambert, G. L. Verdine, T. Curran, and A. Rao, and published in Nature, in 1993, https://www.nature.com/articles/365352a0; and “Isolation of the cyclosporin-sensitive T cell transcription factor NFATp,” written by P. G. McCaffrey, C. Luo, T. K. Kerppola, J. Jain, T. M. Badalian, A. M. Ho, E. Burgeon, W. S. Lane, J. N. Lambert, T. Curran, et al., and published in Science, in 1993, https://www.science.org/doi/10.1126/science.8235597.
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Affiliation(s)
- Jonathan Kaye
- Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA
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23
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Wither MJ, White WL, Pendyala S, Leanza PJ, Fowler D, Kueh HY. Antigen perception in T cells by long-term Erk and NFAT signaling dynamics. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.01.543260. [PMID: 37333368 PMCID: PMC10274683 DOI: 10.1101/2023.06.01.543260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Immune system threat detection hinges on T cells' ability to perceive varying peptide major-histocompatibility complex (pMHC) antigens. As the Erk and NFAT pathways link T cell receptor engagement to gene regulation, their signaling dynamics may convey information about pMHC inputs. To test this idea, we developed a dual reporter mouse strain and a quantitative imaging assay that, together, enable simultaneous monitoring of Erk and NFAT dynamics in live T cells over day-long timescales as they respond to varying pMHC inputs. Both pathways initially activate uniformly across various pMHC inputs, but diverge only over longer (9+ hrs) timescales, enabling independent encoding of pMHC affinity and dose. These late signaling dynamics are decoded via multiple temporal and combinatorial mechanisms to generate pMHC-specific transcriptional responses. Our findings underscore the importance of long timescale signaling dynamics in antigen perception, and establish a framework for understanding T cell responses under diverse contexts. SIGNIFICANCE STATEMENT To counter diverse pathogens, T cells mount distinct responses to varying peptide-major histocompatibility complex ligands (pMHCs). They perceive the affinity of pMHCs for the T cell receptor (TCR), which reflects its foreignness, as well as pMHC abundance. By tracking signaling responses in single living cells to different pMHCs, we find that T cells can independently perceive pMHC affinity vs dose, and encode this information through the dynamics of Erk and NFAT signaling pathways downstream of the TCR. These dynamics are jointly decoded by gene regulatory mechanisms to produce pMHC-specific activation responses. Our work reveals how T cells can elicit tailored functional responses to diverse threats and how dysregulation of these responses may lead to immune pathologies.
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24
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Jung E, Ou S, Ahn SS, Yeo H, Lee YH, Shin SY. The JNK-EGR1 signaling axis promotes TNF-α-induced endothelial differentiation of human mesenchymal stem cells via VEGFR2 expression. Cell Death Differ 2023; 30:356-368. [PMID: 36371601 PMCID: PMC9950069 DOI: 10.1038/s41418-022-01088-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 10/24/2022] [Accepted: 11/04/2022] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) can differentiate into endothelial cells; however, the mechanisms underlying this process in the tumor microenvironment (TME) remain elusive. This study shows that tumor necrosis factor alpha (TNF-α), a key cytokine present in the TME, promotes the endothelial differentiation of MSCs by inducing vascular endothelial growth factor receptor 2 (VEGFR2) gene expression. EGR1 is a member of the zinc-finger transcription factor family induced by TNF-α. Our findings indicate that EGR1 directly binds to the VEGFR2 promoter and transactivates VEGFR2 expression. We also demonstrate that EGR1 forms a complex with c-JUN activated by c-JUN N-terminal kinase (JNK) to promote VEGFR2 transcription and endothelial differentiation in MSCs in response to TNF-α stimulation. The shRNA-mediated silencing of EGR1 or c-JUN abrogates TNF-α-induced VEGFR2 transcription and the endothelial differentiation of MSCs. To further evaluated the role of EGR1 in the endothelial differentiation of BM-MSCs, we used a syngenic tumor implantation model. 4T1 mouse mammary tumor cells were injected subcutaneously into BALB/c mice with primary mBM-MSCs isolated from wild-type (Egr1+/+) or Egr1-null (Egr1-/-) mice. CD31-positive cells were predominantly observed at the border of the tumor in the 4T1 plus wild-type MSC group, while staining less in the 4T1 alone or 4T1 plus Egr1-null MSC group. Collectively, these findings demonstrate that the JNK-EGR1 signaling axis plays a crucial role in the TNF-α-induced endothelial differentiation of MSCs in the TME, which could be a potential therapeutic target for solid tumors vasculatures.
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Affiliation(s)
- Euitaek Jung
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea
| | - Sukjin Ou
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea
| | - Sung Shin Ahn
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea
| | - Hyunjin Yeo
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea
| | - Young Han Lee
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea
| | - Soon Young Shin
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea.
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25
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Mbonye U, Kizito F, Karn J. New insights into transcription elongation control of HIV-1 latency and rebound. Trends Immunol 2023; 44:60-71. [PMID: 36503686 PMCID: PMC11932764 DOI: 10.1016/j.it.2022.11.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/07/2022] [Accepted: 11/09/2022] [Indexed: 12/13/2022]
Abstract
Antiretroviral therapy reduces circulating HIV-1 to undetectable amounts but does not eliminate the virus due to the persistence of a stable reservoir of latently infected cells. The reservoir is maintained both by proliferation of latently infected cells and by reseeding from reactivated cells. A major challenge for the field is to find safe and effective methods to eliminate this source of rebounding HIV-1. Studies on the molecular mechanisms leading to HIV-1 latency and reactivation are being transformed using latency models in primary and patient CD4+ T cells. These studies have revealed the central role played by the biogenesis of the transcription elongation factor P-TEFb (Positive Transcription Elongation Factor b) and its recruitment to proviral HIV-1, for the maintenance of viral latency and the control of viral reactivation.
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Affiliation(s)
- Uri Mbonye
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, USA
| | - Fredrick Kizito
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, USA
| | - Jonathan Karn
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH, USA.
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26
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Sharma AL, Shaffer D, Netting D, Tyagi M. Cocaine sensitizes the CD4 + T cells for HIV infection by co-stimulating NFAT and AP-1. iScience 2022; 25:105651. [PMID: 36483012 PMCID: PMC9722482 DOI: 10.1016/j.isci.2022.105651] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 10/28/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
The productive infection of HIV, which generates new viral progeny, depends on the activation status of the cell. In this study, we found cocaine exposure sensitizes partially active CD4+ T cells and makes them poised for productive HIV infection. We discovered that cocaine treatment enhances the metabolic state of the cells by co-stimulating several transcription factors, mainly NFAT and AP-1, the two transcription factors, which specifically play a crucial role in enhancing both HIV and the overall cellular gene expression in T cells. We found that cocaine-induced AP-1 works in tandem with NFAT to boost HIV transcription. The enhanced HIV transcription upon cocaine exposure was further confirmed through higher phosphorylation of the crucial serine residues at the carboxyl-terminal domain (CTD) of RNA polymerase II. The insights gained from this study could aid in developing highly specialized therapeutics combating the deleterious effects of cocaine on the cocaine-using HIV population.
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Affiliation(s)
| | - Dylan Shaffer
- Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA
| | - Daniel Netting
- Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA
| | - Mudit Tyagi
- Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA
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27
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Zhao Y, Vartak SV, Conte A, Wang X, Garcia DA, Stevens E, Kyoung Jung S, Kieffer-Kwon KR, Vian L, Stodola T, Moris F, Chopp L, Preite S, Schwartzberg PL, Kulinski JM, Olivera A, Harly C, Bhandoola A, Heuston EF, Bodine DM, Urrutia R, Upadhyaya A, Weirauch MT, Hager G, Casellas R. "Stripe" transcription factors provide accessibility to co-binding partners in mammalian genomes. Mol Cell 2022; 82:3398-3411.e11. [PMID: 35863348 PMCID: PMC9481673 DOI: 10.1016/j.molcel.2022.06.029] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 04/06/2022] [Accepted: 06/22/2022] [Indexed: 10/17/2022]
Abstract
Regulatory elements activate promoters by recruiting transcription factors (TFs) to specific motifs. Notably, TF-DNA interactions often depend on cooperativity with colocalized partners, suggesting an underlying cis-regulatory syntax. To explore TF cooperativity in mammals, we analyze ∼500 mouse and human primary cells by combining an atlas of TF motifs, footprints, ChIP-seq, transcriptomes, and accessibility. We uncover two TF groups that colocalize with most expressed factors, forming stripes in hierarchical clustering maps. The first group includes lineage-determining factors that occupy DNA elements broadly, consistent with their key role in tissue-specific transcription. The second one, dubbed universal stripe factors (USFs), comprises ∼30 SP, KLF, EGR, and ZBTB family members that recognize overlapping GC-rich sequences in all tissues analyzed. Knockouts and single-molecule tracking reveal that USFs impart accessibility to colocalized partners and increase their residence time. Mammalian cells have thus evolved a TF superfamily with overlapping DNA binding that facilitate chromatin accessibility.
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Affiliation(s)
- Yongbing Zhao
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA.
| | - Supriya V Vartak
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | - Andrea Conte
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | - Xiang Wang
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | - David A Garcia
- Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD 20893, USA; Department of Physics, University of Maryland, College Park, MD 20742, USA
| | - Evan Stevens
- Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | - Seol Kyoung Jung
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | | | - Laura Vian
- Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA
| | - Timothy Stodola
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Francisco Moris
- EntreChem S.L., Vivero Ciencias de la Salud, 33011 Oviedo, Spain
| | - Laura Chopp
- Laboratory of Immune Cell Biology, NCI, NIH, Bethesda, MD 20892, USA
| | - Silvia Preite
- Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD 20892, USA
| | | | - Joseph M Kulinski
- Mast cell Biology Section, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20892, USA
| | - Ana Olivera
- Mast cell Biology Section, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20892, USA
| | - Christelle Harly
- Laboratory of Genome Integrity, NCI, NIH, Bethesda, MD 20892, USA
| | | | | | - David M Bodine
- Genetics and Molecular Biology Branch, NHGRI, NIH, Bethesda, MD 20892, USA
| | - Raul Urrutia
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Arpita Upadhyaya
- Department of Physics, University of Maryland, College Park, MD 20742, USA
| | - Matthew T Weirauch
- Divisions of Biomedical Informatics and Developmental Biology, Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - Gordon Hager
- Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD 20893, USA
| | - Rafael Casellas
- The NIH Regulome Project, National Institutes of Health, Bethesda, MD 20892, USA; Lymphocyte Nuclear Biology, NIAMS-NCI, NIH, Bethesda, MD 20892, USA.
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Large-scale prediction of key dynamic interacting proteins in multiple cancers. Int J Biol Macromol 2022; 220:1124-1132. [PMID: 36027989 DOI: 10.1016/j.ijbiomac.2022.08.125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 08/15/2022] [Accepted: 08/17/2022] [Indexed: 11/21/2022]
Abstract
Tracking cancer dynamic protein-protein interactions (PPIs) and deciphering their pathogenesis remain a challenge. We presented a dynamic PPIs' hypothesis: permanent and transient interactions might achieve dynamic switchings from normal cells to malignancy, which could cause maintenance functions to be interrupted and transient functions to be sustained. Based on the hypothesis, we first predicted >1400 key cancer genes (KCG) by applying PPI-express we proposed to 18 cancer gene expression datasets. We then further screened out key dynamic interactions (KDI) of cancer based on KCG and transient and permanent interactions under both conditions. Two prominent functional characteristics, "Cell cycle-related" and "Immune-related", were presented for KCG, suggesting that these might be their general characteristics. We found that, compared to permanent to transient KDI pairs (P2T) in the network, transient to permanent (T2P) have significantly higher edge betweenness (EB), and P2T pairs tending to locate intra-functional modules may play roles in maintaining normal biological functions, while T2P KDI pairs tending to locate inter-modules may play roles in biological signal transduction. It was consistent with our hypothesis. Also, we analyzed network characteristics of KDI pairs and their functions. Our findings of KDI may serve to understand and explain a few hallmarks of cancer.
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29
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Liang X, Brooks MJ, Swaroop A. Developmental genome-wide occupancy analysis of bZIP transcription factor NRL uncovers the role of c-Jun in early differentiation of rod photoreceptors in the mammalian retina. Hum Mol Genet 2022; 31:3914-3933. [PMID: 35776116 DOI: 10.1093/hmg/ddac143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 06/15/2022] [Accepted: 06/21/2022] [Indexed: 11/12/2022] Open
Abstract
The basic motif-leucine zipper (bZIP) transcription factor NRL determines rod photoreceptor cell fate during retinal development, and its loss leads to cone-only retina in mice. NRL works synergistically with homeodomain protein CRX and other regulatory factors to control the transcription of most genes associated with rod morphogenesis and functional maturation, which span over a period of several weeks in the mammalian retina. We predicted that NRL gradually establishes rod cell identity and function by temporal and dynamic regulation of stage-specific transcriptional targets. Therefore, we mapped the genomic occupancy of NRL at four stages of mouse photoreceptor differentiation by CUT&RUN analysis. Dynamics of NRL-binding revealed concordance with the corresponding changes in transcriptome of the developing rods. Notably, we identified c-Jun proto-oncogene as one of the targets of NRL, which could bind to specific cis-elements in the c-Jun promoter and modulate its activity in HEK293 cells. Coimmunoprecipitation studies showed association of NRL with c-Jun, also a bZIP protein, in transfected cells as well as in developing mouse retina. Additionally, shRNA-mediated knockdown of c-Jun in the mouse retina in vivo resulted in altered expression of almost 1000 genes, with reduced expression of phototransduction genes and many direct targets of NRL in rod photoreceptors. We propose that c-Jun-NRL heterodimers prime the NRL-directed transcriptional program in neonatal rod photoreceptors before high NRL expression suppresses c-Jun at later stages. Our study highlights a broader cooperation among cell-type restricted and widely expressed bZIP proteins, such as c-Jun, in specific spatiotemporal contexts during cellular differentiation.
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Affiliation(s)
- Xulong Liang
- Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, 6 Center Drive, MSC0610, Bethesda, MD 20892, USA
| | - Matthew J Brooks
- Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, 6 Center Drive, MSC0610, Bethesda, MD 20892, USA
| | - Anand Swaroop
- Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, 6 Center Drive, MSC0610, Bethesda, MD 20892, USA
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30
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Cenci A, Macchia I, La Sorsa V, Sbarigia C, Di Donna V, Pietraforte D. Mechanisms of Action of Ozone Therapy in Emerging Viral Diseases: Immunomodulatory Effects and Therapeutic Advantages With Reference to SARS-CoV-2. Front Microbiol 2022; 13:871645. [PMID: 35531273 PMCID: PMC9069003 DOI: 10.3389/fmicb.2022.871645] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 03/07/2022] [Indexed: 12/24/2022] Open
Abstract
Medical oxygen-ozone (O2-O3) is a successful therapeutic approach accounting on the assessed beneficial action of ozone in the range 30–45 μg/ml (expanded range 10–80 μg/ml according to different protocols), as in this dosage range ozone is able to trigger a cellular hormetic response via the modulating activity of reactive oxygen species (ROS), as signaling molecules. The ozone-dependent ROS-mediated fatty acid oxidation leads to the formation of lipid ozonization products (LOPs), which act as signal transducers by triggering ROS signaling and therefore mitohormetic processes. These processes ultimately activate survival mechanisms at a cellular level, such as the Nrf2/Keap1/ARE system activation, the AMPK/FOXO/mTOR/Sir1 pathway and the Nrf2/NF-kB cross talk. Furthermore, indirectly, via these pathways, LOPs trigger the HIF-1α pathway, the HO-1 signaling and the NO/iNOS biochemical machinery. Ozone-driven shift of cytokine activation pathways, from pro-inflammatory to anti-inflammatory immediately afterwards, also exert direct immunoregulatory effects on regulatory T lymphocytes as well as on the intestinal microbiota, which in turn can affect immune response thus influencing the progression of the disease. In this review, we will describe the biological and biochemical mechanisms of action of ozone therapy with the aim of evaluating both positive and critical aspects of ozone use as a therapeutic adjuvant in the light of emerging viral infections, such as SARS-CoV-2 and microbiome-associated disorders related to SARS-CoV-2.
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Affiliation(s)
- Alessandra Cenci
- Core Facilities, Italian National Institute of Health, Rome, Italy
- *Correspondence: Alessandra Cenci,
| | - Iole Macchia
- Department of Oncology and Molecular Medicine, Italian National Institute of Health, Rome, Italy
| | - Valentina La Sorsa
- Research Coordination and Support Service, Italian National Institute of Health, Rome, Italy
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31
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Huber EM, Hortschansky P, Scheven MT, Misslinger M, Haas H, Brakhage AA, Groll M. Structural insights into cooperative DNA recognition by the CCAAT-binding complex and its bZIP transcription factor HapX. Structure 2022; 30:934-946.e4. [PMID: 35472306 DOI: 10.1016/j.str.2022.04.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/21/2022] [Accepted: 03/31/2022] [Indexed: 11/25/2022]
Abstract
The heterotrimeric CCAAT-binding complex (CBC) is a fundamental eukaryotic transcription factor recognizing the CCAAT box. In certain fungi, like Aspergilli, the CBC cooperates with the basic leucine zipper HapX to control iron metabolism. HapX functionally depends on the CBC, and the stable interaction of both requires DNA. To study this cooperative effect, X-ray structures of the CBC-HapX-DNA complex were determined. Downstream of the CCAAT box, occupied by the CBC, a HapX dimer binds to the major groove. The leash-like N terminus of the distal HapX subunit contacts the CBC, and via a flexible polyproline type II helix mediates minor groove interactions that stimulate sequence promiscuity. In vitro and in vivo mutagenesis suggest that the structural and functional plasticity of HapX results from local asymmetry and its ability to target major and minor grooves simultaneously. The latter feature may also apply to related transcription factors such as yeast Hap4 and distinct Yap family members.
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Affiliation(s)
- Eva M Huber
- Chair of Biochemistry, Center for Protein Assemblies, Technical University of Munich, Ernst-Otto-Fischer-Straße 8, 85748 Garching, Germany
| | - Peter Hortschansky
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (Leibniz-HKI), Adolf-Reichwein-Straße 23, 07745 Jena, Germany
| | - Mareike T Scheven
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (Leibniz-HKI), Adolf-Reichwein-Straße 23, 07745 Jena, Germany
| | - Matthias Misslinger
- Institute of Molecular Biology, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Hubertus Haas
- Institute of Molecular Biology, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Axel A Brakhage
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (Leibniz-HKI), Adolf-Reichwein-Straße 23, 07745 Jena, Germany; Institute for Microbiology, Friedrich Schiller University Jena, Neugasse 25, 07743 Jena, Germany.
| | - Michael Groll
- Chair of Biochemistry, Center for Protein Assemblies, Technical University of Munich, Ernst-Otto-Fischer-Straße 8, 85748 Garching, Germany.
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TCR-induced FOXP3 expression by CD8 + T cells impairs their anti-tumor activity. Cancer Lett 2022; 528:45-58. [PMID: 34973390 DOI: 10.1016/j.canlet.2021.12.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/09/2021] [Accepted: 12/25/2021] [Indexed: 11/23/2022]
Abstract
Adoptive cell transfer therapy using CD8+ T lymphocytes showed promising results eradicating metastatic malignancies. However, several regulatory mechanisms limit its efficacy. We studied the role of the expression of the transcription factor FOXP3 on CD8+ T cell function and anti-tumor immunity. Here we show that suboptimal T cell receptor stimulation of CD8+ T cells upregulates FOXP3 in vitro. Similarly, CD8 T cells transferred into tumor-bearing mice upregulate FOXP3 in vivo. Cell-intrinsic loss of FOXP3 by CD8+ T cells resulted in improved functionality after TCR stimulation and better antitumor responses in vivo. Inhibition of the FOXP3/NFAT interaction likewise improved CD8+ T cell functionality. Transcriptomic analysis of cells after TCR stimulation revealed an enrichment of genes implicated in the response to IFN-γ, IFN-α, inflammatory response, IL-6/JAK/STAT, G2M checkpoint and IL-2/STAT signaling in FOXP3-deficient CD8+ T cells with respect to FOXP3-wt CD8+ T cells. Our results suggest that transient expression of FOXP3 by CD8+ T cells in the tumor microenvironment restrains their anti-tumor activity, with clear implications for improving T cell responses during immunotherapy.
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Behrens G, Heissmeyer V. Cooperation of RNA-Binding Proteins – a Focus on Roquin Function in T Cells. Front Immunol 2022; 13:839762. [PMID: 35251035 PMCID: PMC8894612 DOI: 10.3389/fimmu.2022.839762] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/31/2022] [Indexed: 12/18/2022] Open
Abstract
Post-transcriptional gene regulation by RNA-binding proteins (RBPs) is important in the prevention of inflammatory and autoimmune diseases. With respect to T cell activation and differentiation, the RBPs Roquin-1/2 and Regnase-1 play pivotal roles by inducing degradation and/or translational silencing of target mRNAs. These targets encode important proinflammatory mediators and thus Roquin and Regnase-1 functions dampen cellular programs that can lead to inflammation and autoimmune disease. Recent findings demonstrate direct physical interaction of both RBPs. Here, we propose that cooperativity of trans-acting factors may be more generally used to reinforce the regulatory impact on selected targets and promote specific cell fate decisions. We develop this concept for Roquin and Regnase-1 function in resting and activated T cells and discuss the involvement in autoimmunity as well as how the therapeutic potential can be used in anti-tumor therapies.
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Affiliation(s)
- Gesine Behrens
- Institute for Immunology, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität in Munich, Planegg-Martinsried, Germany
| | - Vigo Heissmeyer
- Institute for Immunology, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität in Munich, Planegg-Martinsried, Germany
- Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, Munich, Germany
- *Correspondence: Vigo Heissmeyer,
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34
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Robinson EL, Drawnel FM, Mehdi S, Archer CR, Liu W, Okkenhaug H, Alkass K, Aronsen JM, Nagaraju CK, Sjaastad I, Sipido KR, Bergmann O, Arthur JSC, Wang X, Roderick HL. MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy. Cells 2022; 11:cells11040604. [PMID: 35203255 PMCID: PMC8870627 DOI: 10.3390/cells11040604] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/26/2022] [Accepted: 02/04/2022] [Indexed: 12/17/2022] Open
Abstract
Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 (AP-1) complex factors is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the mitogen and stress-activated protein kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights into the role of MAPK pathways in signalling to the epigenome and regulation of gene expression during cardiac hypertrophy.
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Affiliation(s)
- Emma L. Robinson
- Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, B-3000 Leuven, Belgium; (S.M.); (C.K.N.); (K.R.S.)
- Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, The Netherlands
- Correspondence: (E.L.R.); (H.L.R.)
| | - Faye M. Drawnel
- Epigenetics and Signalling Programmes, Babraham Institute, Cambridge CB22 3AT, UK; (F.M.D.); (C.R.A.); (H.O.)
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
| | - Saher Mehdi
- Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, B-3000 Leuven, Belgium; (S.M.); (C.K.N.); (K.R.S.)
| | - Caroline R. Archer
- Epigenetics and Signalling Programmes, Babraham Institute, Cambridge CB22 3AT, UK; (F.M.D.); (C.R.A.); (H.O.)
| | - Wei Liu
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK; (W.L.); (X.W.)
| | - Hanneke Okkenhaug
- Epigenetics and Signalling Programmes, Babraham Institute, Cambridge CB22 3AT, UK; (F.M.D.); (C.R.A.); (H.O.)
| | - Kanar Alkass
- Department of Oncology and Pathology, Karolinska Institute, SE-17177 Stockholm, Sweden;
| | - Jan Magnus Aronsen
- Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, 0450 Oslo, Norway; (J.M.A.); (I.S.)
- Bjørknes College, Oslo University, 0456 Oslo, Norway
| | - Chandan K. Nagaraju
- Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, B-3000 Leuven, Belgium; (S.M.); (C.K.N.); (K.R.S.)
| | - Ivar Sjaastad
- Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, 0450 Oslo, Norway; (J.M.A.); (I.S.)
- KG Jebsen Center for Cardiac Research, University of Oslo, 0450 Oslo, Norway
| | - Karin R. Sipido
- Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, B-3000 Leuven, Belgium; (S.M.); (C.K.N.); (K.R.S.)
| | - Olaf Bergmann
- Cell and Molecular Biology, Biomedicum, Karolinska Institutet, SE-17177 Stockholm, Sweden;
| | - J. Simon C. Arthur
- Division of Immunology and Cell Signalling, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK;
| | - Xin Wang
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK; (W.L.); (X.W.)
| | - H. Llewelyn Roderick
- Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, B-3000 Leuven, Belgium; (S.M.); (C.K.N.); (K.R.S.)
- KG Jebsen Center for Cardiac Research, University of Oslo, 0450 Oslo, Norway
- Correspondence: (E.L.R.); (H.L.R.)
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Bernardini A, Lorenzo M, Chaves-Sanjuan A, Swuec P, Pigni M, Saad D, Konarev PV, Graewert MA, Valentini E, Svergun DI, Nardini M, Mantovani R, Gnesutta N. The USR domain of USF1 mediates NF-Y interactions and cooperative DNA binding. Int J Biol Macromol 2021; 193:401-413. [PMID: 34673109 DOI: 10.1016/j.ijbiomac.2021.10.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 10/20/2022]
Abstract
The trimeric CCAAT-binding NF-Y is a "pioneer" Transcription Factor -TF- known to cooperate with neighboring TFs to regulate gene expression. Genome-wide analyses detected a precise stereo-alignment -10/12 bp- of CCAAT with E-box elements and corresponding colocalization of NF-Y with basic-Helix-Loop-Helix (bHLH) TFs. We dissected here NF-Y interactions with USF1 and MAX. USF1, but not MAX, cooperates in DNA binding with NF-Y. NF-Y and USF1 synergize to activate target promoters. Reconstruction of complexes by structural means shows independent DNA binding of MAX, whereas USF1 has extended contacts with NF-Y, involving the USR, a USF-specific amino acid sequence stretch required for trans-activation. The USR is an intrinsically disordered domain and adopts different conformations based on E-box-CCAAT distances. Deletion of the USR abolishes cooperative DNA binding with NF-Y. Our data indicate that the functionality of certain unstructured domains involves adapting to small variation in stereo-alignments of the multimeric TFs sites.
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Affiliation(s)
- Andrea Bernardini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano 20133, Italy
| | - Mariangela Lorenzo
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano 20133, Italy
| | | | - Paolo Swuec
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano 20133, Italy
| | - Matteo Pigni
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano 20133, Italy
| | - Dana Saad
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano 20133, Italy
| | - Petr V Konarev
- A.V. Shubnikov Institute of Crystallography, Federal Scientific Research Centre "Crystallography and Photonics" of Russian Academy of Science, Moscow 119333, Russian Federation
| | | | - Erica Valentini
- European Molecular Biology Laboratory, Hamburg Unit, Hamburg 22607, Germany
| | - Dmitri I Svergun
- European Molecular Biology Laboratory, Hamburg Unit, Hamburg 22607, Germany
| | - Marco Nardini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano 20133, Italy
| | - Roberto Mantovani
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano 20133, Italy.
| | - Nerina Gnesutta
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano 20133, Italy.
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Simonett SP, Shin S, Herring JA, Bacher R, Smith LA, Dong C, Rabaglia ME, Stapleton DS, Schueler KL, Choi J, Bernstein MN, Turkewitz DR, Perez-Cervantes C, Spaeth J, Stein R, Tessem JS, Kendziorski C, Keleş S, Moskowitz IP, Keller MP, Attie AD. Identification of direct transcriptional targets of NFATC2 that promote β cell proliferation. J Clin Invest 2021; 131:e144833. [PMID: 34491912 PMCID: PMC8553569 DOI: 10.1172/jci144833] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 09/02/2021] [Indexed: 12/13/2022] Open
Abstract
The transcription factor NFATC2 induces β cell proliferation in mouse and human islets. However, the genomic targets that mediate these effects have not been identified. We expressed active forms of Nfatc2 and Nfatc1 in human islets. By integrating changes in gene expression with genomic binding sites for NFATC2, we identified approximately 2200 transcriptional targets of NFATC2. Genes induced by NFATC2 were enriched for transcripts that regulate the cell cycle and for DNA motifs associated with the transcription factor FOXP. Islets from an endocrine-specific Foxp1, Foxp2, and Foxp4 triple-knockout mouse were less responsive to NFATC2-induced β cell proliferation, suggesting the FOXP family works to regulate β cell proliferation in concert with NFATC2. NFATC2 induced β cell proliferation in both mouse and human islets, whereas NFATC1 did so only in human islets. Exploiting this species difference, we identified approximately 250 direct transcriptional targets of NFAT in human islets. This gene set enriches for cell cycle-associated transcripts and includes Nr4a1. Deletion of Nr4a1 reduced the capacity of NFATC2 to induce β cell proliferation, suggesting that much of the effect of NFATC2 occurs through its induction of Nr4a1. Integration of noncoding RNA expression, chromatin accessibility, and NFATC2 binding sites enabled us to identify NFATC2-dependent enhancer loci that mediate β cell proliferation.
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Affiliation(s)
- Shane P. Simonett
- Biochemistry Department, University of Wisconsin–Madison, Madison, Wisconsin, USA
| | - Sunyoung Shin
- Department of Mathematical Sciences, University of Texas at Dallas, Richardson, Texas, USA
| | - Jacob A. Herring
- Nutrition, Dietetics and Food Science Department, Brigham Young University, Provo, Utah, USA
| | - Rhonda Bacher
- Department of Biostatistics, University of Florida, Gainesville, Florida, USA
| | - Linsin A. Smith
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, Illinois, USA
| | - Chenyang Dong
- Department of Biostatistics and Medical Informatics, University of Wisconsin–Madison, Madison, Wisconsin, USA
| | - Mary E. Rabaglia
- Biochemistry Department, University of Wisconsin–Madison, Madison, Wisconsin, USA
| | - Donnie S. Stapleton
- Biochemistry Department, University of Wisconsin–Madison, Madison, Wisconsin, USA
| | - Kathryn L. Schueler
- Biochemistry Department, University of Wisconsin–Madison, Madison, Wisconsin, USA
| | - Jeea Choi
- Department of Biostatistics and Medical Informatics, University of Wisconsin–Madison, Madison, Wisconsin, USA
| | | | - Daniel R. Turkewitz
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Carlos Perez-Cervantes
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, Illinois, USA
| | - Jason Spaeth
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Roland Stein
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Jeffery S. Tessem
- Nutrition, Dietetics and Food Science Department, Brigham Young University, Provo, Utah, USA
| | - Christina Kendziorski
- Department of Biostatistics and Medical Informatics, University of Wisconsin–Madison, Madison, Wisconsin, USA
| | - Sündüz Keleş
- Department of Biostatistics and Medical Informatics, University of Wisconsin–Madison, Madison, Wisconsin, USA
| | - Ivan P. Moskowitz
- Departments of Pediatrics, Pathology, and Human Genetics, University of Chicago, Chicago, Illinois, USA
| | - Mark P. Keller
- Biochemistry Department, University of Wisconsin–Madison, Madison, Wisconsin, USA
| | - Alan D. Attie
- Biochemistry Department, University of Wisconsin–Madison, Madison, Wisconsin, USA
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Ludwig LM, Hawley KM, Banks DB, Thomas-Toth AT, Blazar BR, McNerney ME, Leverson JD, LaBelle JL. Venetoclax imparts distinct cell death sensitivity and adaptivity patterns in T cells. Cell Death Dis 2021; 12:1005. [PMID: 34707089 PMCID: PMC8551340 DOI: 10.1038/s41419-021-04285-4] [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: 04/12/2021] [Revised: 09/17/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022]
Abstract
BH3 mimetics are increasingly used as anti-cancer therapeutics either alone or in conjunction with other chemotherapies. However, mounting evidence has also demonstrated that BH3 mimetics modulate varied amounts of apoptotic signaling in healthy immune populations. In order to maximize their clinical potential, it will be essential to understand how BH3 mimetics affect discrete immune populations and to determine how BH3 mimetic pressure causes immune system adaptation. Here we focus on the BCL-2 specific inhibitor venetoclax (ABT-199) and its effects following short-term and long-term BCL-2 blockade on T cell subsets. Seven day "short-term" ex vivo and in vivo BCL-2 inhibition led to divergent cell death sensitivity patterns in CD8+ T cells, CD4+ T cells, and Tregs resulting in shifting of global T cell populations towards a more memory T cell state with increased expression of BCL-2, BCL-XL, and MCL-1. However, twenty-eight day "long-term" BCL-2 blockade following T cell-depleted bone marrow transplantation did not lead to changes in the global T cell landscape. Despite the lack of changes in T cell proportions, animals treated with venetoclax developed CD8+ and CD4+ T cells with high levels of BCL-2 and were more resistant to apoptotic stimuli following expansion post-transplant. Further, we demonstrate through RNA profiling that T cells adapt while under BCL-2 blockade post-transplant and develop a more activated genotype. Taken together, these data emphasize the importance of evaluating how BH3 mimetics affect the immune system in different treatment modalities and disease contexts and suggest that venetoclax should be further explored as an immunomodulatory compound.
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Affiliation(s)
- Lindsey M. Ludwig
- grid.170205.10000 0004 1936 7822Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, IL USA
| | - Katrina M. Hawley
- grid.170205.10000 0004 1936 7822Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, IL USA
| | - David B. Banks
- grid.170205.10000 0004 1936 7822Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, IL USA ,grid.170205.10000 0004 1936 7822Medical Scientist Training Program, University of Chicago, Chicago, IL USA
| | - Anika T. Thomas-Toth
- grid.170205.10000 0004 1936 7822Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, IL USA
| | - Bruce R. Blazar
- grid.17635.360000000419368657Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN USA
| | - Megan E. McNerney
- grid.170205.10000 0004 1936 7822Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, IL USA ,grid.170205.10000 0004 1936 7822Department of Pathology, University of Chicago, Chicago, IL USA
| | - Joel D. Leverson
- grid.431072.30000 0004 0572 4227AbbVie Inc., North Chicago, IL USA
| | - James L. LaBelle
- grid.170205.10000 0004 1936 7822Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, IL USA
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Chronic LCMV Infection Is Fortified with Versatile Tactics to Suppress Host T Cell Immunity and Establish Viral Persistence. Viruses 2021; 13:v13101951. [PMID: 34696381 PMCID: PMC8537583 DOI: 10.3390/v13101951] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/15/2021] [Accepted: 09/22/2021] [Indexed: 12/19/2022] Open
Abstract
Ever since the immune regulatory strains of lymphocytic choriomeningitis virus (LCMV), such as Clone 13, were isolated, LCMV infection of mice has served as a valuable model for the mechanistic study of viral immune suppression and virus persistence. The exhaustion of virus-specific T cells was demonstrated during LCMV infection, and the underlying mechanisms have been extensively investigated using LCMV infection in mouse models. In particular, the mechanism for gradual CD8+ T cell exhaustion at molecular and transcriptional levels has been investigated. These studies revealed crucial roles for inhibitory receptors, surface markers, regulatory cytokines, and transcription factors, including PD-1, PSGL-1, CXCR5, and TOX in the regulation of T cells. However, the action mode for CD4+ T cell suppression is largely unknown. Recently, sphingosine kinase 2 was proven to specifically repress CD4+ T cell proliferation and lead to LCMV persistence. As CD4+ T cell regulation was also known to be important for viral persistence, research to uncover the mechanism for CD4+ T cell repression could help us better understand how viruses launch and prolong their persistence. This review summarizes discoveries derived from the study of LCMV in regard to the mechanisms for T cell suppression and approaches for the termination of viral persistence with special emphasis on CD8+ T cells.
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Abstract
Acute myeloid leukaemia (AML) is a haematological cancer with poor outcomes due to a lack of efficacious targeted therapies. The Nuclear Factor of Activated T Cells (NFAT) family of transcription factors is well characterised as a regulator of the cell cycle and differentiation in the myeloid lineage. Recent evidence has demonstrated that NFAT family members may have roles in regulating AML leukemogenesis and resistance to targeted therapy in myeloid leukaemia. Furthermore, gene expression data from patient samples show that some NFATs are more highly expressed in poorly differentiated AML and after disease relapse, implying that the NFAT family may have roles in specific types of AML. This review outlines the evidence for the role of NFAT in healthy myeloid tissue and explores how NFAT might regulate AML pathogenesis, highlighting the potential to target specific NFAT proteins therapeutically in AML.
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Duan X, Lv M, Liu A, Pang Y, Li Q, Su P, Gou M. Identification and evolution of transcription factors RHR gene family (NFAT and RBPJ) involving lamprey (Lethenteron reissneri) innate immunity. Mol Immunol 2021; 138:38-47. [PMID: 34332184 DOI: 10.1016/j.molimm.2021.07.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/15/2021] [Accepted: 07/16/2021] [Indexed: 10/20/2022]
Abstract
Nuclear factor of activated T cells (NFAT) and recombination signal binding protein (RBP) belong to the family of Rel homology region (RHR) transcription factors which regulate the expression of genes involved in different aspects of the immune response. To gain insights into the evolution and characterisation of RHR genes in lampreys, a jawless vertebrate, four RHR genes, including nuclear factor of activated T cells (NFAT) and recombination signal binding protein for immunoglobulin kappa J region (RBPJ), have been identified and cloned from the lamprey (Lethenteron reissneri) database. Evolutionary relationships of NFAT and RBPJ genes among different species were determined through molecular phylogenetic analysis. Motif, genetic structure, and tertiary structure analyses showed that NFATs and RBPJ are conserved and contain RHD and IPT domains. Moreover, synteny analysis showed that the neighbourhood genes of Lr-NFATs and Lr-RBPJ have undergone significant changes compared to jawed vertebrates. Real-time quantitative results demonstrated that the RHR gene family plays a significant role in immune defence. This study provides a new understanding of the origin and evolution of the RHR gene family in different species.
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Affiliation(s)
- Xuyuan Duan
- College of Life Science, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Menggang Lv
- College of Life Science, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Aijia Liu
- College of Life Science, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Yue Pang
- College of Life Science, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Qingwei Li
- College of Life Science, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China
| | - Peng Su
- College of Life Science, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China.
| | - Meng Gou
- College of Life Science, Liaoning Normal University, Dalian, 116081, China; Lamprey Research Center, Liaoning Normal University, Dalian, 116081, China; Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, 116034, China.
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Bevington SL, Ng STH, Britton GJ, Keane P, Wraith DC, Cockerill PN. Chromatin Priming Renders T Cell Tolerance-Associated Genes Sensitive to Activation below the Signaling Threshold for Immune Response Genes. Cell Rep 2021; 31:107748. [PMID: 32521273 PMCID: PMC7296351 DOI: 10.1016/j.celrep.2020.107748] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 02/20/2020] [Accepted: 05/18/2020] [Indexed: 12/13/2022] Open
Abstract
Immunological homeostasis in T cells is maintained by a tightly regulated signaling and transcriptional network. Full engagement of effector T cells occurs only when signaling exceeds a critical threshold that enables induction of immune response genes carrying an epigenetic memory of prior activation. Here we investigate the underlying mechanisms causing the suppression of normal immune responses when T cells are rendered anergic by tolerance induction. By performing an integrated analysis of signaling, epigenetic modifications, and gene expression, we demonstrate that immunological tolerance is established when both signaling to and chromatin priming of immune response genes are weakened. In parallel, chromatin priming of immune-repressive genes becomes boosted, rendering them sensitive to low levels of signaling below the threshold needed to activate immune response genes. Our study reveals how repeated exposure to antigens causes an altered epigenetic state leading to T cell anergy and tolerance, representing a basis for treating auto-immune diseases.
Activation of immune response genes is suppressed in tolerant T cells Epigenetic priming of repressive genes is boosted when tolerance is established Inhibitory receptor genes have a lower threshold of activation in tolerant cells Induction of tolerance by peptides points toward a therapy for multiple sclerosis
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Affiliation(s)
- Sarah L Bevington
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Sky T H Ng
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Graham J Britton
- Precision Immunology Institute and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Peter Keane
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - David C Wraith
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
| | - Peter N Cockerill
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
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The TLR-2/TonEBP signaling pathway regulates 29-kDa fibronectin fragment-dependent expression of matrix metalloproteinases. Sci Rep 2021; 11:8891. [PMID: 33903620 PMCID: PMC8076285 DOI: 10.1038/s41598-021-87813-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 04/05/2021] [Indexed: 02/06/2023] Open
Abstract
Tonicity-responsive enhancer-binding protein (TonEBP; nuclear factor of activated T cells 5) is a transcription factor that responds to changes in osmolality. However, recent studies have shown that it also modulates immune responses under inflammatory conditions independently of hyperosmolality. Fibronectin fragments (FN-fs), which are abundant in the synovial fluid of patients with osteoarthritis (OA), induce expression of matrix metalloproteinases (MMPs) via the toll-like receptor-2 (TLR-2) signaling pathway. In this study we examined whether TonEBP is involved in 29-kDa FN-f-induced expression of MMPs. The expression of TonEBP was significantly higher in human osteoarthritis compared with normal cartilage samples. 29-kDa FN-f affected the expression of MMPs 1, 3, and 13 via TonEBP, and expression and nuclear accumulation of TonEBP were induced by activation of the phospholipase C/NF-κB/MAPK signaling pathway and, in particular, modulated by TLR-2. In addition, 29-kDa FN-f induced the expression of osmoregulatory genes, including Tau-T, SMIT, and AR, as well as voltage-dependent calcium channels via the TonEBP/TLR-2 signaling pathway. These results show that 29-kDa FN-f upregulates MMPs in chondrocytes via the TLR-2/TonEBP signaling pathway.
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Ray S, Tillo D, Durell SR, Khund-Sayeed S, Vinson C. REL Domain of NFATc2 Binding to Five Types of DNA Using Protein Binding Microarrays. ACS OMEGA 2021; 6:4147-4154. [PMID: 33644537 PMCID: PMC7906578 DOI: 10.1021/acsomega.0c04069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 12/25/2020] [Indexed: 06/12/2023]
Abstract
NFATc2 is a DNA binding protein in the Rel family transcription factors, which binds a CGGAA motif better when both cytosines in the CG dinucleotide are methylated. Using protein binding microarrays (PBMs), we examined the DNA binding of NFATc2 to three additional types of DNA: single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with either 5-methylcytosine (5mC, M) or 5-hydroxymethylcytosine (5hmC, H) in one strand and a cytosine in the second strand. ATTTCCAC, the complement of the core GGAA motif, is better bound as ssDNA compared to dsDNA. dsDNA containing the 5-mer CGGAA with either 5mC or 5hmC in one DNA strand is bound stronger than CGGAA. In contrast, the reverse complement TTCCG is bound weaker when it contains 5mC. Analysis of the available NFATc2:dsDNA complexes rationalizes these PBM data.
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Affiliation(s)
- Sreejana Ray
- Laboratory
of Metabolism, National Cancer Institute,
National Institutes of Health, 37 Convent Drive, Building 37, Room 5000, Bethesda, Maryland 20892, United States
| | - Desiree Tillo
- Laboratory
of Metabolism, National Cancer Institute,
National Institutes of Health, 37 Convent Drive, Building 37, Room 5000, Bethesda, Maryland 20892, United States
| | - Stewart R. Durell
- Laboratory
of Cell Biology, National Cancer Institute,
National Institutes of Health, 37 Convent Drive, Building 37, Room 5000, Bethesda, Maryland 20892, United States
| | - Syed Khund-Sayeed
- Laboratory
of Metabolism, National Cancer Institute,
National Institutes of Health, 37 Convent Drive, Building 37, Room 5000, Bethesda, Maryland 20892, United States
| | - Charles Vinson
- Laboratory
of Metabolism, National Cancer Institute,
National Institutes of Health, 37 Convent Drive, Building 37, Room 5000, Bethesda, Maryland 20892, United States
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44
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Rao A. Scientific divagations: from signaling and transcription to chromatin changes in T cells. Nat Immunol 2021; 21:1473-1476. [PMID: 33173218 DOI: 10.1038/s41590-020-00823-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Anjana Rao
- Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA.
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Kim DO, Byun JE, Kim WS, Kim MJ, Choi JH, Kim H, Choi E, Kim TD, Yoon SR, Noh JY, Park YJ, Lee J, Cho HJ, Lee HG, Min SH, Choi I, Jung H. TXNIP Regulates Natural Killer Cell-Mediated Innate Immunity by Inhibiting IFN-γ Production during Bacterial Infection. Int J Mol Sci 2020; 21:ijms21249499. [PMID: 33327533 PMCID: PMC7765025 DOI: 10.3390/ijms21249499] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
The function of natural killer (NK) cell-derived interferon-γ (IFN-γ) expands to remove pathogens by increasing the ability of innate immune cells. Here, we identified the critical role of thioredoxin-interacting protein (TXNIP) in the production of IFN-γ in NK cells during bacterial infection. TXNIP inhibited the production of IFN-γ and the activation of transforming growth factor β-activated kinase 1 (TAK1) activity in primary mouse and human NK cells. TXNIP directly interacted with TAK1 and inhibited TAK1 activity by interfering with the complex formation between TAK1 and TAK1 binding protein 1 (TAB1). Txnip−/− (KO) NK cells enhanced the activation of macrophages by inducing IFN-γ production during Pam3CSK4 stimulation or Staphylococcus aureus (S. aureus) infection and contributed to expedite the bacterial clearance. Our findings suggest that NK cell-derived IFN-γ is critical for host defense and that TXNIP plays an important role as an inhibitor of NK cell-mediated macrophage activation by inhibiting the production of IFN-γ during bacterial infection.
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Affiliation(s)
- Dong Oh Kim
- Department of Innovative Toxicology Research, Korea Institute of Toxicology, Yuseong-gu, Daejeon 34114, Korea;
| | - Jae-Eun Byun
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 28644, Korea
| | - Won Sam Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Mi Jeong Kim
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Korea;
| | - Jung Ha Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Hanna Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Eunji Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Tae-Don Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
| | - Suk Ran Yoon
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
| | - Ji-Yoon Noh
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Young-Jun Park
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (Y.-J.P.); (J.L.)
| | - Jungwoon Lee
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (Y.-J.P.); (J.L.)
| | - Hee Jun Cho
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
| | - Hee Gu Lee
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Biomolecular Science, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
| | - Sang-Hyun Min
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Chumbokro Dong-gu, Daegu 41061, Korea;
| | - Inpyo Choi
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
- Correspondence: (I.C.); (H.J.)
| | - Haiyoung Jung
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Korea; (J.-E.B.); (W.S.K.); (J.H.C.); (H.K.); (E.C.); (T.-D.K.); (S.R.Y.); (J.-Y.N.); (H.J.C.); (H.G.L.)
- Department of Functional Genomics, Korea University of Science and Technology (UST), Yuseong-gu, Daejeon 34113, Korea
- Correspondence: (I.C.); (H.J.)
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Papavassiliou AG, Musti AM. The Multifaceted Output of c-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion. Cells 2020; 9:2470. [PMID: 33202877 PMCID: PMC7697663 DOI: 10.3390/cells9112470] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/07/2020] [Accepted: 11/11/2020] [Indexed: 12/19/2022] Open
Abstract
c-Jun is a major component of the dimeric transcription factor activator protein-1 (AP-1), a paradigm for transcriptional response to extracellular signaling, whose components are basic-Leucine Zipper (bZIP) transcription factors of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families. Extracellular signals regulate c-Jun/AP-1 activity at multiple levels, including transcriptional and posttranscriptional regulation of c-Jun expression and transactivity, in turn, establishing the magnitude and the duration of c-Jun/AP-1 activation. Another important level of c-Jun/AP-1 regulation is due to the capability of Jun family members to bind DNA as a heterodimer with every other member of the AP-1 family, and to interact with other classes of transcription factors, thereby acquiring the potential to integrate diverse extrinsic and intrinsic signals into combinatorial regulation of gene expression. Here, we review how these features of c-Jun/AP-1 regulation underlie the multifaceted output of c-Jun biological activity, eliciting quite distinct cellular responses, such as neoplastic transformation, differentiation and apoptosis, in different cell types. In particular, we focus on the current understanding of the role of c-Jun/AP-1 in the response of CD8 T cells to acute infection and cancer. We highlight the transcriptional and epigenetic regulatory mechanisms through which c-Jun/AP-1 participates in the productive immune response of CD8 T cells, and how its downregulation may contribute to the dysfunctional state of tumor infiltrating CD8 T cells. Additionally, we discuss recent insights pointing at c-Jun as a suitable target for immunotherapy-based combination approaches to reinvigorate anti-tumor immune functions.
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Affiliation(s)
- Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Anna Maria Musti
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
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Hörberg J, Reymer A. Specifically bound BZIP transcription factors modulate DNA supercoiling transitions. Sci Rep 2020; 10:18795. [PMID: 33139763 PMCID: PMC7606469 DOI: 10.1038/s41598-020-75711-4] [Citation(s) in RCA: 14] [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: 05/17/2020] [Accepted: 10/18/2020] [Indexed: 01/01/2023] Open
Abstract
Torsional stress on DNA, introduced by molecular motors, constitutes an important regulatory mechanism of transcriptional control. Torsional stress can modulate specific binding of transcription factors to DNA and introduce local conformational changes that facilitate the opening of promoters and nucleosome remodelling. Using all-atom microsecond scale molecular dynamics simulations together with a torsional restraint that controls the total twist of a DNA fragment, we address the impact of torsional stress on DNA complexation with a human BZIP transcription factor, MafB. We gradually over- and underwind DNA alone and in complex with MafB by 0.5° per dinucleotide step, starting from the relaxed state to a maximum of 5° per dinucleotide step, monitoring the evolution of the protein-DNA contacts at different degrees of torsional strain. Our computations show that MafB changes the DNA sequence-specific response to torsional stress. The dinucleotide steps that are susceptible to absorbing most of the torsional stress become more torsionally rigid, as they are involved in protein-DNA contacts. Also, the protein undergoes substantial conformational changes to follow the stress-induced DNA deformation, but mostly maintains the specific contacts with DNA. This results in a significant asymmetric increase of free energy of DNA twisting transitions, relative to free DNA, where overtwisting is more energetically unfavourable. Our data suggest that specifically bound BZIP factors could act as torsional stress insulators, modulating the propagation of torsional stress along the chromatin fibre, which might promote cooperative binding of collaborative DNA-binding factors.
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Affiliation(s)
- Johanna Hörberg
- Department of Chemistry and Molecular Biology, University of Gothenburg, 40530, Gothenburg, Sweden
| | - Anna Reymer
- Department of Chemistry and Molecular Biology, University of Gothenburg, 40530, Gothenburg, Sweden.
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48
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Verdon DJ, Mulazzani M, Jenkins MR. Cellular and Molecular Mechanisms of CD8 + T Cell Differentiation, Dysfunction and Exhaustion. Int J Mol Sci 2020; 21:ijms21197357. [PMID: 33027962 PMCID: PMC7582856 DOI: 10.3390/ijms21197357] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/01/2020] [Accepted: 10/02/2020] [Indexed: 02/07/2023] Open
Abstract
T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically “exhausted” in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.
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Affiliation(s)
- Daniel J. Verdon
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; (D.J.V.); (M.M.)
| | - Matthias Mulazzani
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; (D.J.V.); (M.M.)
| | - Misty R. Jenkins
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; (D.J.V.); (M.M.)
- Department of Medical Biology, The University of Melbourne, Parkville, VIC 3052, Australia
- Institute of Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
- Correspondence:
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49
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p63 uses a switch-like mechanism to set the threshold for induction of apoptosis. Nat Chem Biol 2020; 16:1078-1086. [DOI: 10.1038/s41589-020-0600-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 06/25/2020] [Indexed: 12/19/2022]
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50
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Yukawa M, Jagannathan S, Vallabh S, Kartashov AV, Chen X, Weirauch MT, Barski A. AP-1 activity induced by co-stimulation is required for chromatin opening during T cell activation. J Exp Med 2020; 217:jem.20182009. [PMID: 31653690 PMCID: PMC7037242 DOI: 10.1084/jem.20182009] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/06/2019] [Accepted: 09/23/2019] [Indexed: 12/24/2022] Open
Abstract
Activation of T cells is dependent on the organized and timely opening and closing of chromatin. Herein, we identify AP-1 as the transcription factor that directs most of this remodeling. Chromatin accessibility profiling showed quick opening of closed chromatin in naive T cells within 5 h of activation. These newly opened regions were strongly enriched for the AP-1 motif, and indeed, ChIP-seq demonstrated AP-1 binding at >70% of them. Broad inhibition of AP-1 activity prevented chromatin opening at AP-1 sites and reduced the expression of nearby genes. Similarly, induction of anergy in the absence of co-stimulation during activation was associated with reduced induction of AP-1 and a failure of proper chromatin remodeling. The translational relevance of these findings was highlighted by the substantial overlap of AP-1-dependent elements with risk loci for multiple immune diseases, including multiple sclerosis, inflammatory bowel disease, and allergic disease. Our findings define AP-1 as the key link between T cell activation and chromatin remodeling.
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Affiliation(s)
- Masashi Yukawa
- Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Sajjeev Jagannathan
- Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Sushmitha Vallabh
- Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Andrey V Kartashov
- Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Xiaoting Chen
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Matthew T Weirauch
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.,Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.,Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Artem Barski
- Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.,Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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