Sumoylation of ROR?t regulates TH17 differentiation and thymocyte development.

ABSTRACT: ROR?t controls the differentiation of TH17 cells, which are mediators of autoimmune conditions such as experimental autoimmune encephalomyelitis (EAE). ROR?t also regulates thymocyte development and lymph node genesis. Here we show that the function of ROR?t is regulated by its sumoylation. Loss of Sumo3, but not Sumo1, dampens TH17 differentiation and delays the progression of thymic CD8+ immature single-positive cells (ISPs). ROR?t is SUMO3-modified by E3 ligase PIAS4 at lysine 31 (K31), and the mutation of K31 to arginine in mice prevents ROR?t sumoylation, leading to impaired TH17 differentiation, resistance to TH17-mediated EAE, accumulation of thymic ISPs, and a lack of Peyer's patches. Mechanistically, sumoylation of ROR?t-K31 recruits histone acetyltransferase KAT2A, which stabilizes the binding of SRC1 to enhance ROR?t transcription factor activity. This study thus demonstrates that sumoylation is a critical mechanism for regulating ROR?t function, and reveals new drug targets for preventing TH17-mediated autoimmunity.

SUBMITTER: He Z 

PROVIDER: S-EPMC6242824 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other