SUMOylation of ROR-?t inhibits IL-17 expression and inflammation via HDAC2.

ABSTRACT: Dysregulated ROR-?t-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-?t 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-?t to induce SUMOylation of ROR-?t and suppress IL-17 expression. Th17 cells expressing SUMOylation-defective ROR-?t are highly colitogenic upon transfer to Rag1-/- mice. Mechanistically, SUMOylation of ROR-?t 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-?t/HDAC2 axis that governs IL-17 expression may open new venues for the development of therapeutic measures for inflammatory disorders.

SUBMITTER: Singh AK 

PROVIDER: S-EPMC6207785 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature