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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
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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
  • pmid:22057290
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
2016-04-01 13:10:28
date last changed
2022-05-07 07:55:30
@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}},
  doi          = {{10.1038/ni.2157}},
  volume       = {{12}},
  year         = {{2011}},
}