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 currentcompetitive 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
High Priority, Short Term Project Award (R56)
Project #
2R56AI079056-05
Application #
8482769
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Peyman, John A
Project Start
2008-09-25
Project End
2012-12-31
Budget Start
2012-09-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
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
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
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
Li, Fei; Gao, Beixue; Dong, Hongxin et al. (2015) Icariin induces synoviolin expression through NFE2L1 to protect neurons from ER stress-induced apoptosis. PLoS One 10:e0119955
Kong, Sinyi; Dong, Hongxin; Song, Jianxun et al. (2015) Deleted in Breast Cancer 1 Suppresses B Cell Activation through RelB and Is Regulated by IKK? Phosphorylation. J Immunol 195:3685-93
Yang, Heeyoung; Qiu, Quan; Gao, Beixue et al. (2014) Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation. J Exp Med 211:2467-79
Kong, Sinyi; Thiruppathi, Muthusamy; Qiu, Quan et al. (2014) DBC1 is a suppressor of B cell activation by negatively regulating alternative NF-?B transcriptional activity. J Immunol 193:5515-24
Wu, Tongde; Zhao, Fei; Gao, Beixue et al. (2014) Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes Dev 28:708-22

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