Abstract
Dysregulated ROR-γt-mediated IL-17 transcription is central to the pathogenesis of several inflammatory disorders, yet the molecular mechanisms that govern the transcription factor activity of ROR-γt in the regulation of IL-17 are not fully defined. Here we show that SUMO-conjugating enzyme Ubc9 interacts with a conserved GKAE motif in ROR-γt to induce SUMOylation of ROR-γt and suppress IL-17 expression. Th17 cells expressing SUMOylation-defective ROR-γt are highly colitogenic upon transfer to Rag1–/– mice. Mechanistically, SUMOylation of ROR-γt facilitates the binding of HDAC2 to the IL-17 promoter and represses IL-17 transcription. Mice with conditional deletion of HDAC2 in CD4+ T cells have elevated IL-17 expression and severe colitis. The identification of the Ubc9/ROR-γt/HDAC2 axis that governs IL-17 expression may open new venues for the development of therapeutic measures for inflammatory disorders.
Highlights
Dysregulated ROR-γt-mediated IL-17 transcription is central to the pathogenesis of several inflammatory disorders, yet the molecular mechanisms that govern the transcription factor activity of ROR-γt in the regulation of IL-17 are not fully defined
We demonstrate that the T cells expressing SUMOylation-defective ROR-γt are highly colitogenic upon transfer to Rag1–/– mice
Given the central role of colonic lamina propria lymphocytes in gut homeostasis and inflammation, we isolated cLPLs from C57BL/6 (WT) mice followed by lysis and ROR-γt immunoprecipitation using a validated anti–ROR-γt antibody
Summary
Dysregulated ROR-γt-mediated IL-17 transcription is central to the pathogenesis of several inflammatory disorders, yet the molecular mechanisms that govern the transcription factor activity of ROR-γt in the regulation of IL-17 are not fully defined. We show that SUMOconjugating enzyme Ubc[9] interacts with a conserved GKAE motif in ROR-γt to induce SUMOylation of ROR-γt and suppress IL-17 expression. Th17 cells expressing SUMOylationdefective ROR-γt are highly colitogenic upon transfer to Rag1–/– mice. Intracellular localization, interaction with partners, and activity of target proteins, SUMOylation affects several biological processes including the cell cycle, DNA repair, chromatin dynamics, gene transcription, and inflammation[9,10,11]. We demonstrate that the T cells expressing SUMOylation-defective ROR-γt are highly colitogenic upon transfer to Rag1–/– mice. We uncover a mechanism by which IL-17 expression is regulated, which could be exploited therapeutically in inflammatory diseases
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