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The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation

Ahmed, Neesar; Zeng, Minghui; Sinha, Indrajit; Polin, Lisa; Wei, Wei-Zen; Rathinam, Chozhavendan; Flavell, Richard; Massoumi, Ramin LU and Venuprasad, K. (2011) In Nature Immunology 12(12). p.1-1176
Abstract
Chronic inflammation has been strongly associated with tumor progression, but the underlying mechanisms remain elusive. Here we demonstrate that E3 ligase Itch and deubiquitinase Cyld formed a complex via interaction through 'WW-PPXY' motifs. The Itch-Cyld complex sequentially cleaved Lys63-linked ubiquitin chains and catalyzed Lys48-linked ubiquitination on the kinase Tak1 to terminate inflammatory signaling via tumor necrosis factor. Reconstitution of wild-type Cyld but not the mutant Cyld(Y485A), which cannot associate with Itch, blocked sustained Tak1 activation and proinflammatory cytokine production by Cyld(-/-) bone marrow-derived macrophages. Deficiency in Itch or Cyld led to chronic production of tumor-promoting cytokines by... (More)
Chronic inflammation has been strongly associated with tumor progression, but the underlying mechanisms remain elusive. Here we demonstrate that E3 ligase Itch and deubiquitinase Cyld formed a complex via interaction through 'WW-PPXY' motifs. The Itch-Cyld complex sequentially cleaved Lys63-linked ubiquitin chains and catalyzed Lys48-linked ubiquitination on the kinase Tak1 to terminate inflammatory signaling via tumor necrosis factor. Reconstitution of wild-type Cyld but not the mutant Cyld(Y485A), which cannot associate with Itch, blocked sustained Tak1 activation and proinflammatory cytokine production by Cyld(-/-) bone marrow-derived macrophages. Deficiency in Itch or Cyld led to chronic production of tumor-promoting cytokines by tumor-associated macrophages and aggressive growth of lung carcinoma. Thus, we have identified an Itch-Cyld-mediated regulatory mechanism in innate inflammatory cells. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Immunology
volume
12
issue
12
pages
1 - 1176
publisher
Nature Publishing Group
external identifiers
  • wos:000297202700012
  • scopus:81255177676
ISSN
1529-2908
DOI
10.1038/ni.2157
language
English
LU publication?
yes
id
d49214eb-3280-42c7-965a-3ac00ee187e1 (old id 2252651)
date added to LUP
2012-01-02 08:14:29
date last changed
2017-11-19 03:43:51
@article{d49214eb-3280-42c7-965a-3ac00ee187e1,
  abstract     = {Chronic inflammation has been strongly associated with tumor progression, but the underlying mechanisms remain elusive. Here we demonstrate that E3 ligase Itch and deubiquitinase Cyld formed a complex via interaction through 'WW-PPXY' motifs. The Itch-Cyld complex sequentially cleaved Lys63-linked ubiquitin chains and catalyzed Lys48-linked ubiquitination on the kinase Tak1 to terminate inflammatory signaling via tumor necrosis factor. Reconstitution of wild-type Cyld but not the mutant Cyld(Y485A), which cannot associate with Itch, blocked sustained Tak1 activation and proinflammatory cytokine production by Cyld(-/-) bone marrow-derived macrophages. Deficiency in Itch or Cyld led to chronic production of tumor-promoting cytokines by tumor-associated macrophages and aggressive growth of lung carcinoma. Thus, we have identified an Itch-Cyld-mediated regulatory mechanism in innate inflammatory cells.},
  author       = {Ahmed, Neesar and Zeng, Minghui and Sinha, Indrajit and Polin, Lisa and Wei, Wei-Zen and Rathinam, Chozhavendan and Flavell, Richard and Massoumi, Ramin and Venuprasad, K.},
  issn         = {1529-2908},
  language     = {eng},
  number       = {12},
  pages        = {1--1176},
  publisher    = {Nature Publishing Group},
  series       = {Nature Immunology},
  title        = {The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation},
  url          = {http://dx.doi.org/10.1038/ni.2157},
  volume       = {12},
  year         = {2011},
}