| First Author | Theivanthiran B | Year | 2015 |
| Journal | Sci Signal | Volume | 8 |
| Issue | 365 | Pages | ra22 |
| PubMed ID | 25714464 | Mgi Jnum | J:243854 |
| Mgi Id | MGI:5912633 | Doi | 10.1126/scisignal.2005903 |
| Citation | Theivanthiran B, et al. (2015) The E3 ubiquitin ligase Itch inhibits p38alpha signaling and skin inflammation through the ubiquitylation of Tab1. Sci Signal 8(365):ra22 |
| abstractText | 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 p38alpha 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 p38alpha. Knockdown of Tab1 by short hairpin RNA attenuated the prolonged p38alpha 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 p38alpha. 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-1beta, IL-11, and IL-19. Inhibition of p38 or blocking the interaction between p38alpha 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. |
