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

Amir Kumar Singh, Prashant Khare, Abeer Obaid, Kevin P. Conlon, Venkatesha Basrur, Ronald A. DePinho and K. Venuprasad ()
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Amir Kumar Singh: Baylor Scott & White Research Institute
Prashant Khare: Baylor Scott & White Research Institute
Abeer Obaid: Baylor Scott & White Research Institute
Kevin P. Conlon: University of Michigan
Venkatesha Basrur: University of Michigan
Ronald A. DePinho: The University of Texas MD Anderson Cancer Center
K. Venuprasad: Baylor Scott & White Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06924-5

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