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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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author
organization
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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
ISSN
1937-9145
DOI
10.1126/scisignal.2005903
language
English
LU publication?
yes
id
e38808e9-c66c-4877-a509-0ba48835427d (old id 5142699)
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http://www.ncbi.nlm.nih.gov/pubmed/25714464?dopt=Abstract
date added to LUP
2015-03-10 22:11:48
date last changed
2017-09-03 03:21:23
@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},
  volume       = {8},
  year         = {2015},
}