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    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. Copyright © 2015, American Association for the Advancement of Science.

    Citation

    Balamayooran Theivanthiran, Mahesh Kathania, Minghui Zeng, Esperanza Anguiano, Venkatesha Basrur, Travis Vandergriff, Virginia Pascual, Wei-Zen Wei, Ramin Massoumi, K Venuprasad. The E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1. Science signaling. 2015 Feb 24;8(365):ra22

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    PMID: 25714464

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