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

Nat Commun. 2018 Oct 30;9(1):4515. doi: 10.1038/s41467-018-06924-5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / metabolism
  • Histone Deacetylase 2 / immunology
  • Histone Deacetylase 2 / metabolism*
  • Homeodomain Proteins / genetics
  • Inflammation
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism*
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
  • Sumoylation / immunology*
  • Th17 Cells / immunology*
  • Ubiquitin-Conjugating Enzymes / metabolism*


  • Homeodomain Proteins
  • Il17a protein, mouse
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RAG-1 protein
  • Ubiquitin-Conjugating Enzymes
  • Hdac2 protein, mouse
  • Histone Deacetylase 2
  • ubiquitin-conjugating enzyme UBC9