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

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 p38 alpha in spontaneous and experimentally induced skin lesions of Itch-deficient (Itch(-/-)) mice. Itch bound directly to the TGF-beta-activated kinase 1-binding protein 1 (Tab1) through a conserved PPXY motif and inhibited the activation of p38 alpha. Knockdown of Tab1 by short hairpin RNA attenuated the prolonged p38 alpha 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 p38 alpha. 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-1 beta, IL-11, and IL-19. Inhibition of p38 or blocking the interaction between p38 alpha 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.