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 #
2R01AI079056-05A1
Application #
8503339
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
2013-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$121,024
Indirect Cost
$42,691
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Yang, Yi; Kong, Sinyi; Zhang, Yana et al. (2018) The endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice. J Biol Chem 293:12934-12944
Wei, Juncheng; Chen, Lu; Li, Fei et al. (2018) HRD1-ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination. EMBO J 37:
Melo-Cardenas, Johanna; Xu, Yuanming; Wei, Juncheng et al. (2018) USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism. Blood 132:423-434
Wang, Wenhui; Li, Fei; Xu, Yuanming et al. (2018) JAK1-mediated Sirt1 phosphorylation functions as a negative feedback of the JAK1-STAT3 pathway. J Biol Chem 293:11067-11075
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
Gao, Beixue; Kong, Qingfei; Zhang, Yana et al. (2017) The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation. J Immunol 198:3927-3938
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

Showing the most recent 10 out of 40 publications