Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-γt ubiquitination

Nat Immunol. 2016 Aug;17(8):997-1004. doi: 10.1038/ni.3488. Epub 2016 Jun 20.


Dysregulated expression of interleukin 17 (IL-17) in the colonic mucosa is associated with colonic inflammation and cancer. However, the cell-intrinsic molecular mechanisms by which IL-17 expression is regulated remain unclear. We found that deficiency in the ubiquitin ligase Itch led to spontaneous colitis and increased susceptibility to colon cancer. Itch deficiency in the TH17 subset of helper T cells, innate lymphoid cells and γδ T cells resulted in the production of elevated amounts of IL-17 in the colonic mucosa. Mechanistically, Itch bound to the transcription factor ROR-γt and targeted ROR-γt for ubiquitination. Inhibition or genetic inactivation of ROR-γt attenuated IL-17 expression and reduced spontaneous colonic inflammation in Itch(-/-) mice. Thus, we have identified a previously unknown role for Itch in regulating IL-17-mediated colonic inflammation and carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Colitis / immunology*
  • Colon / pathology*
  • Colorectal Neoplasms / immunology*
  • Dextran Sulfate
  • Humans
  • Interleukin-17 / immunology
  • Intestinal Mucosa / immunology*
  • Lymphocytes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism*
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Th17 Cells / physiology*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination


  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Antigen, T-Cell, gamma-delta
  • Dextran Sulfate
  • Itch protein, mouse
  • Ubiquitin-Protein Ligases