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The E3 ligase Itch and deubiquitinase Cyld co-operatively regulate Tak1 and inflammation

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 form a complex via the interaction through ‘WW-PPXY’ motifs. The Itch-Cyld complex sequentially cleaved K63-linked u...

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Autores principales: Ahmed, Neesar, Zeng, Minghui, Sinha, Indrajit, Polin, Lisa, Wei, Wei-Zen, Rathinam, Chozhavendan, Flavell, Richard, Massoumi, Ramin, Venuprasad, K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219826/
https://www.ncbi.nlm.nih.gov/pubmed/22057290
http://dx.doi.org/10.1038/ni.2157
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author Ahmed, Neesar
Zeng, Minghui
Sinha, Indrajit
Polin, Lisa
Wei, Wei-Zen
Rathinam, Chozhavendan
Flavell, Richard
Massoumi, Ramin
Venuprasad, K
author_facet Ahmed, Neesar
Zeng, Minghui
Sinha, Indrajit
Polin, Lisa
Wei, Wei-Zen
Rathinam, Chozhavendan
Flavell, Richard
Massoumi, Ramin
Venuprasad, K
author_sort Ahmed, Neesar
collection PubMed
description 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 form a complex via the interaction through ‘WW-PPXY’ motifs. The Itch-Cyld complex sequentially cleaved K63-linked ubiquitin chains and catalyzed K48-linked ubiquitination on the kinase Tak1 to terminate inflammatory tumor necrosis factor signaling. Reconstitution of wild-type Cyld but not mutant Cyld(Y485A), which cannot associate with Itch, blocked the sustained Tak1 activation and proinflammatory cytokine production by Cyld(−/−) bone marrow-derived macrophages. Itch or Cyld deficiency resulted in chronic production of tumor-promoting cytokines by the tumor-associated macrophages and aggressive growth of lung carcinoma. Thus, we have uncovered an Itch-Cyld mediated regulatory mechanism in innate inflammatory cells.
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spelling pubmed-32198262012-06-01 The E3 ligase Itch and deubiquitinase Cyld co-operatively regulate Tak1 and inflammation Ahmed, Neesar Zeng, Minghui Sinha, Indrajit Polin, Lisa Wei, Wei-Zen Rathinam, Chozhavendan Flavell, Richard Massoumi, Ramin Venuprasad, K Nat Immunol Article 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 form a complex via the interaction through ‘WW-PPXY’ motifs. The Itch-Cyld complex sequentially cleaved K63-linked ubiquitin chains and catalyzed K48-linked ubiquitination on the kinase Tak1 to terminate inflammatory tumor necrosis factor signaling. Reconstitution of wild-type Cyld but not mutant Cyld(Y485A), which cannot associate with Itch, blocked the sustained Tak1 activation and proinflammatory cytokine production by Cyld(−/−) bone marrow-derived macrophages. Itch or Cyld deficiency resulted in chronic production of tumor-promoting cytokines by the tumor-associated macrophages and aggressive growth of lung carcinoma. Thus, we have uncovered an Itch-Cyld mediated regulatory mechanism in innate inflammatory cells. 2011-11-06 /pmc/articles/PMC3219826/ /pubmed/22057290 http://dx.doi.org/10.1038/ni.2157 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Ahmed, Neesar
Zeng, Minghui
Sinha, Indrajit
Polin, Lisa
Wei, Wei-Zen
Rathinam, Chozhavendan
Flavell, Richard
Massoumi, Ramin
Venuprasad, K
The E3 ligase Itch and deubiquitinase Cyld co-operatively regulate Tak1 and inflammation
title The E3 ligase Itch and deubiquitinase Cyld co-operatively regulate Tak1 and inflammation
title_full The E3 ligase Itch and deubiquitinase Cyld co-operatively regulate Tak1 and inflammation
title_fullStr The E3 ligase Itch and deubiquitinase Cyld co-operatively regulate Tak1 and inflammation
title_full_unstemmed The E3 ligase Itch and deubiquitinase Cyld co-operatively regulate Tak1 and inflammation
title_short The E3 ligase Itch and deubiquitinase Cyld co-operatively regulate Tak1 and inflammation
title_sort e3 ligase itch and deubiquitinase cyld co-operatively regulate tak1 and inflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219826/
https://www.ncbi.nlm.nih.gov/pubmed/22057290
http://dx.doi.org/10.1038/ni.2157
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