The E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1.

TitleThe E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1.
Publication TypeJournal Article
Year of Publication2015
AuthorsTheivanthiran B, Kathania M, Zeng M, Anguiano E, Basrur V, Vandergriff T, Pascual V, Wei W-Z, Massoumi R, Venuprasad K
JournalSci Signal
Date Published2015 Feb 24
KeywordsAdaptor Proteins, Signal Transducing, Animals, Cytokines, Dermatitis, MAP Kinase Signaling System, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 14, Phosphorylation, Skin, Ubiquitin-Protein Ligases, Ubiquitination

Deficiency in the E3 ubiquitin ligase Itch causes a skin-scratching phenotype in mice. We found that there was increased phosphorylation and activation of the mitogen-activated protein kinase p38α in spontaneous and experimentally induced skin lesions of Itch-deficient (Itch-/-) mice. Itch bound directly to the TGF-β-activated kinase 1-binding protein 1 (Tab1) through a conserved PPXY motif and inhibited the activation of p38α. Knockdown of Tab1 by short hairpin RNA attenuated the prolonged p38α phosphorylation exhibited by Itch-/- cells. Similarly, reconstitution of Itch-/- cells with wild-type Itch, but not the ligase-deficient Itch-C830A mutant, inhibited the phosphorylation and activation of p38α. Compared to the skin of wild-type mice, the skin of Itch-/- mice contained increased amounts of the mRNAs of proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1β, IL-11, and IL-19. Inhibition of p38 or blocking the interaction between p38α and Tab1 with a cell-permeable peptide substantially attenuated skin inflammation in Itch-/- mice. These findings provide insight into how Itch-mediated regulatory mechanisms prevent chronic skin inflammation, which could be exploited therapeutically.

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Alternate JournalSci Signal
PubMed ID25714464

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