TY - JOUR
T1 - The E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1
AU - Theivanthiran, Balamayooran
AU - Kathania, Mahesh
AU - Zeng, Minghui
AU - Anguiano, Esperanza
AU - Basrur, Venkatesha
AU - Vandergriff, Travis
AU - Pascual, Virginia
AU - Wei, Wei Zen
AU - Massoumi, Ramin
AU - Venuprasad, K.
N1 - Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2015/2/24
Y1 - 2015/2/24
N2 - 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.
AB - 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.
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U2 - 10.1126/scisignal.2005903
DO - 10.1126/scisignal.2005903
M3 - Article
C2 - 25714464
AN - SCOPUS:84923645267
SN - 1945-0877
VL - 8
JO - Science signaling
JF - Science signaling
IS - 365
M1 - ra22
ER -