Abstract
Intestinal fibrosis is a major complication in inflammatory bowel diseases, but the regulatory mechanism that inhibits fibrosis remains unclear. Here we demonstrate that Itch-/-myofibroblasts express increased amounts of profibrotic collagen type I and α-SMA in response to IL-17. Mechanistically, we demonstrate that Itch directly binds to HIC-5 and targets it for K63-linked ubiquitination to inhibit IL-17-driven intestinal fibrosis. Reconstitution of Itch-/- myofibroblasts with wild-type Itch but not the Itch-C830A mutant normalized the expression of profibrotic genes. Similarly, shRNA-mediated inhibition of HIC-5 normalized the expression of profibrotic gene expression. Thus, we have uncovered a novel mechanism by which Itch negatively regulates intestinal fibrosis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Actins / genetics
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Actins / metabolism
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Animals
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Collagen Type I / genetics
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Collagen Type I / metabolism
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Colon / pathology*
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Fibrosis
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HEK293 Cells
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Humans
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Inflammatory Bowel Diseases / immunology*
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Interleukin-17 / metabolism*
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Intestines / immunology
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Intestines / pathology*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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LIM Domain Proteins / genetics
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LIM Domain Proteins / metabolism*
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Mice
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Mice, Knockout
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Mutation / genetics
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Myofibroblasts / physiology*
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RNA, Small Interfering / genetics
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination
Substances
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Actins
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Collagen Type I
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Interleukin-17
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Intracellular Signaling Peptides and Proteins
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LIM Domain Proteins
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RNA, Small Interfering
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Repressor Proteins
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TGFB1I1 protein, human
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alpha-smooth muscle actin, mouse
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ITCH protein, human
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Ubiquitin-Protein Ligases