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

Nature communications (2018-10-31)
Amir Kumar Singh, Prashant Khare, Abeer Obaid, Kevin P Conlon, Venkatesha Basrur, Ronald A DePinho, K Venuprasad
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.

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Sigma-Aldrich
Resazurin sodium salt, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Resazurin sodium salt, certified by the Biological Stain Commission