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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Amir Kumar Singh & Prashant Khare & Abeer Obaid & Kevin P. Conlon & Venkatesha Basrur & Ronald A. DePinho & K. Venuprasad, 2018. "SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06924-5
    DOI: 10.1038/s41467-018-06924-5
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