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

N Ahmed, M Zeng, I Sinha, L Polin, WZ Wei… - Nature …, 2011 - nature.com
N Ahmed, M Zeng, I Sinha, L Polin, WZ Wei, C Rathinam, R Flavell, R Massoumi…
Nature immunology, 2011nature.com
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 …
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.
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