The E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1.
Författare
Summary, in English
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.
Avdelning/ar
- Avdelningen för translationell cancerforskning
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publiceringsår
2015
Språk
Engelska
Sidor
22-22
Publikation/Tidskrift/Serie
Science Signaling
Volym
8
Issue
365
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
American Association for the Advancement of Science (AAAS)
Ämne
- Biochemistry and Molecular Biology
Status
Published
ISBN/ISSN/Övrigt
- ISSN: 1937-9145