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

Theivanthiran, Balamayooran ; Kathania, Mahesh ; Zeng, Minghui ; Anguiano, Esperanza ; Basrur, Venkatesha ; Vandergriff, Travis ; Pascual, Virginia ; Wei, Wei-Zen ; Massoumi, Ramin LU and Venuprasad, K (2015) In Science Signaling 8(365). p.22-22
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 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... (More)
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. (Less)
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; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Signaling
volume
8
issue
365
pages
22 - 22
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:25714464
  • wos:000349851300003
  • scopus:84923645267
  • pmid:25714464
ISSN
1937-9145
DOI
10.1126/scisignal.2005903
language
English
LU publication?
yes
id
e38808e9-c66c-4877-a509-0ba48835427d (old id 5142699)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25714464?dopt=Abstract
date added to LUP
2016-04-01 10:41:13
date last changed
2022-02-17 20:21:46
@article{e38808e9-c66c-4877-a509-0ba48835427d,
  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 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.}},
  author       = {{Theivanthiran, Balamayooran and Kathania, Mahesh and Zeng, Minghui and Anguiano, Esperanza and Basrur, Venkatesha and Vandergriff, Travis and Pascual, Virginia and Wei, Wei-Zen and Massoumi, Ramin and Venuprasad, K}},
  issn         = {{1937-9145}},
  language     = {{eng}},
  number       = {{365}},
  pages        = {{22--22}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Signaling}},
  title        = {{The E3 ubiquitin ligase Itch inhibits p38α signaling and skin inflammation through the ubiquitylation of Tab1.}},
  url          = {{http://dx.doi.org/10.1126/scisignal.2005903}},
  doi          = {{10.1126/scisignal.2005903}},
  volume       = {{8}},
  year         = {{2015}},
}