Autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes and lupus, etc., affect approximately 50 million Americans. The immune responses of self-reactive T lymphocytes play critical roles in autoimmune diseases. Therefore, identification of novel molecules that regulate T cell immune functions are important for a better understanding of the mechanisms underlying the disease development and for seeking novel therapies. During the current finding period, we have discovered that the type III histone deacetylase Sirt1 as a critical suppressor to T cell immunity and macrophage activation by suppressing the transcription factors AP-1, indicating Sirt1 as a potential therapeutic target for autoimmune and inflammatory diseases. In fact, we further demonstrated that the Sirt1 activator resveratrol prevents/treats type 1 diabetes in mice. Our preliminary study of the current competitive renewal application demonstrates that the deacetylase Sirt1 and the acetyltransferase GCN5 oppositely regulate T cell activation. Genetic deletion of GCN5 gene inhibits T cell immune responses in mice, identifying GCN5 as a critical positive regulator for T cell immunity. Interestingly, treatment of mice with GCN5 specific inhibitor attenuated autoimmune disease development. Therefore, based on the above preliminary findings, we propose that the histone deacetylase Sirt1 is a negative regulator and the acetyltransferase GCN5 is a positive regulator for T cell immunity, and that the Sirt1 activator and GCN5 inhibitor have great therapeutic potentials in treatment of autoimmune diseases. This project is to address this hypothesis using the state-of-art approaches of both immunological and molecular studies. Results from this proposed study discover novel molecular mechanisms behind Sirt1 and GCN5 in T cell activation and autoimmunity, providing rationales for the uses of Sirt1 deacetylase activators and GCN5 acetyltransferase inhibitors in treating/preventing autoimmune diseases.

Public Health Relevance

This study identifies the histone deacetylase Sirt1 as a negative regulator and the acetyltransferase GCN5 as a positive regulator for T cell immune response. Therefore, Sirt1 activators and GCN5 inhibitors have great therapeutic potentials in the treatment of autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079056-06
Application #
8601163
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Peyman, John A
Project Start
2008-09-25
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$386,250
Indirect Cost
$136,250
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Gao, Beixue; Kong, Qingfei; Zhang, Yana et al. (2017) The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation. J Immunol 198:3927-3938
Hou, Xia; Yang, Zhao; Zhang, Kezhong et al. (2017) SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6. Biochem Biophys Res Commun 494:446-451
Wang, Yajun; Yun, Chawon; Gao, Beixue et al. (2017) The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation. Cell Rep 20:600-612
Kong, Sinyi; Yang, Yi; Xu, Yuanming et al. (2016) Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas. Proc Natl Acad Sci U S A 113:10394-9
Principe, Daniel R; DeCant, Brian; MascariƱas, Emman et al. (2016) TGF? Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. Cancer Res 76:2525-39
Haque, Mohammad; Song, Jianyong; Fino, Kristin et al. (2016) Stem cell-derived tissue-associated regulatory T cells ameliorate the development of autoimmunity. Sci Rep 6:20588
Haque, Mohammad; Song, Jianyong; Fino, Kristin et al. (2016) C-Myc regulation by costimulatory signals modulates the generation of CD8+ memory T cells during viral infection. Open Biol 6:150208
Xu, Yuanming; Zhao, Fang; Qiu, Quan et al. (2016) The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity. Nat Commun 7:12073
Huang, Qi-Quan; Perlman, Harris; Birkett, Robert et al. (2015) CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis. Nat Commun 6:7086
Melo-Cardenas, Johanna; Kong, Sinyi; Fang, Deyu (2015) A Hrd way for MHC-II expression. Oncotarget 6:21767-8

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