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Nat Immunol. 2011 Nov 6;12(12):1176-83. doi: 10.1038/ni.2157.

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

Author information

1
Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan, USA.

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.

PMID:
22057290
PMCID:
PMC3219826
DOI:
10.1038/ni.2157
[Indexed for MEDLINE]
Free PMC Article

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