Sumoylation of ROR gamma t regulates T(H)17 differentiation and thymocyte development

ROR gamma t controls the differentiation of T(H)17 cells, which are mediators of autoimmune conditions such as experimental autoimmune encephalomyelitis (EAE). ROR gamma t also regulates thymocyte development and lymph node genesis. Here we show that the function of ROR gamma t is regulated by its sumoylation. Loss of Sumo3, but not Sumo1, dampens T(H)17 differentiation and delays the progression of thymic CD8+ immature single-positive cells (ISPs).ROR gamma t is SUMO3-modified by E3 ligase PIAS4 at lysine 31 (K31), and the mutation of K31 to arginine in mice prevents ROR gamma tsumoylation, leading to impaired T(H)17 differentiation, resistance to T(H)17-mediated EAE, accumulation of thymic ISPs, and a lack of Peyer's patches. Mechan-istically, sumoylation of ROR gamma t-K31 recruits histone acetyltransferase KAT2A, which stabilizes the binding of SRC1 to enhance ROR gamma t transcription factor activity. This study thus demonstrates that sumoylation is a critical mechanism for regulating ROR gamma t function, and reveals new drug targets for preventing T(H)17-mediated autoimmunity.