Sumoylation of RORgt controls TH17 differentiation and thymocyte development

Here we reveal sumoylation as a novel mechanism to regulate RORgt function. Loss of Sumo3, but not Sumo1, dampens TH17 differentiation and delays the progression of thymic immature CD8+ cells (ISP), both of which are dependent on RORgt. RORgt is indeed SUMO3-modified at lysine 31 (K31), and mutation of K31 to arginine (RORgtK31R) to prevent sumoylation impairs RORgt-dependent function as mice harboring such mutation display defective TH17 differentiation, resistance to TH17-mediated EAE, accumulation of thymic ISP and lack of Peyer’s Patches. Mechanically, RORgt-K31 sumoylation stabilizes the binding of steroid coactivator SRC1 through facilitating the recruitment of histone acetyltransferase KAT2A. Lastly, E3 ligasePIAS4 binds and sumoylates RORgt at K31, and regulates RORgt-dependent TH17 differentiation and progression of thymic ISP. This study thus demonstrates sumoylation as a novel regulatory mechanism for controlling RORgt function, and reveal new drug targets for preventing TH17-mediated autoimmunity