Abstract
RORγt controls the differentiation of TH17 cells, which are mediators of autoimmune conditions such as experimental autoimmune encephalomyelitis (EAE). RORγt also regulates thymocyte development and lymph node genesis. Here we show that the function of RORγt 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). RORγt is SUMO3-modified by E3 ligase PIAS4 at lysine 31 (K31), and the mutation of K31 to arginine in mice prevents RORγt 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 RORγt-K31 recruits histone acetyltransferase KAT2A, which stabilizes the binding of SRC1 to enhance RORγt transcription factor activity. This study thus demonstrates that sumoylation is a critical mechanism for regulating RORγt function, and reveals new drug targets for preventing TH17-mediated autoimmunity.
Highlights
RORγt controls the differentiation of TH17 cells, which are mediators of autoimmune conditions such as experimental autoimmune encephalomyelitis (EAE)
To the deletion of Sumo[3] shown here, the deletion of RORγt in mice resulted in more immature single-positive cells (ISPs) and reduced TH17 differentiation[33], which suggested that RORγt may be SUMO3-modified
We found in the literature a report that KAT2A, a histone acetyltransferase, is able to synergize with steroid receptor coactivator 1 (SRC1) to bind to nuclear receptors[40]
Summary
RORγt controls the differentiation of TH17 cells, which are mediators of autoimmune conditions such as experimental autoimmune encephalomyelitis (EAE). RORγt is SUMO3-modified by E3 ligase PIAS4 at lysine 31 (K31), and the mutation of K31 to arginine in mice prevents RORγt sumoylation, leading to impaired TH17 differentiation, resistance to TH17-mediated EAE, accumulation of thymic ISPs, and a lack of Peyer’s patches. This study demonstrates that sumoylation is a critical mechanism for regulating RORγt function, and reveals new drug targets for preventing TH17-mediated autoimmunity. Because RORγt is required for the generation of pathogenic TH17 cells responsible for autoimmunity, it is an attractive target for the development of drugs to control TH17mediated immunological disorders[19,20]. The very carboxyl terminal of the ligand-binding domain is an activation function 2 (AF2) motif responsible for recruiting steroid receptor coactivator 1 (SRC1) to nuclear receptors, which is required for RORγt-mediated transactivation of genes essential for TH17 differentiation[23,24,25]. The post-translational mechanisms that regulate RORγt function have long been neglected
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