Reciprocal Regulation Of Rorγt Acetylation And Function By P300 And HDAC1

IL-17 producing T helper 17(Th17) cells have been described as a separate CD4+T helper cell subset distinct from Th1, Th2 and regulatory T(Treg) cells. IL-17 plays an important inflammatory role by inducing production of proinflammatory cytokines and chemokines, including IL-6 and CXCL8. Because IL-17 is a potent proinflammatory cytokine, Th17 cells have been associated with the development of autoimmune diseases and inflammatory diseases such as systemic lupus erythematous(SLE), rheumatoid arthritis(RA), multiple sclerosis(MS), inflammatory bowel disease(IBD), psoriasis and Hashimoto’s Thyroiditis(HT) and so on.Retinoid-related orphan receptor gammat(RORγt) is a key transcription factor involved in Th17 cells, which and RORα in conjunction with other essential transcription factors such as the signal transducer and activator of transcription 3(STAT3), the aryl hydrocarbon receptor(Ahr), interferon regulatory factor 4(IRF4), the Runt-related transcription factor 1(Runx1), B-cell-activating transcription factor(BATF) drive Th17 cell differentiation. In addition, transforming growth factor-β(TGF-β), IL-23 and proin?ammatory cytokines(IL-1β and IL-6) are all essential for human Th17 cell differentiation and the expression of IL-17 A, IL-17 F, IL-23 receptor(IL-23R) and RORγt.Protein acetyltransferases and deacetylases regulating the balance between acetylation and deacetylation of transcriptional factors, thereby, affecting expression of the involved genes. Histone acetyltransferase regulate histone and non-histone proteins. Acetylation of these transcription factors can modulate their transcriptional activity by altering their stability, subcellular localization and/or DNA-binding activity. In addition,Ubiquitination modification play an important role in protein degradation, location, metabolism and function also, who participate in cell proliferaton, differentiation, apoptosis, signal transduction, transcriptional control, DNA repair and immune response.RORγt regulation of expression, post-translational states and activity direct immune activity of Th17 cells. How RORγt itself is regulated remains unclear. Here, we report that RORγt is acetylated in Th17 cells and RORγt acetylation is significantly enhanced in the presence of HDAC inhibitors by immunoprecpitation. p300 interacts with RORγt in Th17 cells by coimmunoprecipitation, and p300 acetylates RORγt mainly at lysine 81 of RORγt. p300 could stabilize RORγt protein level, and knockdown of p300 downregulates RORγt protein and RORγt-mediated gene expression in Th17 cells such as IL-17 A, IL-17 F, IL-21 and IL-23 R. In addition, p300 ubiquitinate RORγt by K63 linked-ubiquitination and mainly at lysine 258 of RORγt. More interestingly, the deacetylase HDAC1 can also interact with RORγt and reduce its acetylation level. p300 upregulates RORγt-mediated IL-17 transcription in a dose dependent manner, which is inhibited by HDAC1.Here, we demonstrate that RORγt is acetylated,and that this acetylation is reciprocally regulated by the histone acetyltransferase p300 and the histone deacetylase HDAC1, which suggests that p300 and HDAC1 may be novel targets for the treatment of RORγt-mediated autoimmune diseases.