Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-γt ubiquitination.
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.
Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, Texas, USA.
Mahesh
M
Kathania
Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, Texas, USA.
Prashant
P
Khare
Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, Texas, USA.
Minghui
M
Zeng
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Brandi
B
Cantarel
Department of Pathology, Baylor University Medical Center, Dallas, Texas, USA.
Haiying
H
Zhang
Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Hideki
0000-0002-7128-3816
H
Ueno
Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, Texas, USA.
K
K
Venuprasad
D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology*; D003106:Colon / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000276:immunology*; D016264:Dextran Sulfate; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D058504:Th17 Cells / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016692:Receptors, Antigen, T-Cell, gamma-delta; D016264:Dextran Sulfate; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases