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

Mahesh Kathania, Prashant Khare, Minghui Zeng, Brandi Cantarel, Haiying Zhang, Hideki Ueno, K. Venuprasad

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

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 T H 17 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.

Original languageEnglish (US)
Pages (from-to)997-1004
Number of pages8
JournalNature Immunology
Volume17
Issue number8
DOIs
StatePublished - Jul 19 2016

ASJC Scopus subject areas

  • Immunology

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