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, K. Venuprasad

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Article number4515
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Singh, A. K., Khare, P., Obaid, A., Conlon, K. P., Basrur, V., DePinho, R. A., & Venuprasad, K. (2018). SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2. Nature communications, 9(1), [4515]. https://doi.org/10.1038/s41467-018-06924-5