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

Balamayooran Theivanthiran, Mahesh Kathania, Minghui Zeng, Esperanza Anguiano, Venkatesha Basrur, Travis Vandergriff, Virginia Pascual, Wei Zen Wei, Ramin Massoumi, K. Venuprasad

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18 Scopus citations

Abstract

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 p38a. Knockdown of Tab1 by short hairpin RNA attenuated the prolonged p38a 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.

Original languageEnglish (US)
Article numberra22
JournalScience Signaling
Volume8
Issue number365
DOIs
StatePublished - Feb 24 2015

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Theivanthiran, B., Kathania, M., Zeng, M., Anguiano, E., Basrur, V., Vandergriff, T., Pascual, V., Wei, W. Z., Massoumi, R., & Venuprasad, K. (2015). The E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1. Science Signaling, 8(365), [ra22]. https://doi.org/10.1126/scisignal.2005903