The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2252651
- author
- Ahmed, Neesar ; Zeng, Minghui ; Sinha, Indrajit ; Polin, Lisa ; Wei, Wei-Zen ; Rathinam, Chozhavendan ; Flavell, Richard ; Massoumi, Ramin LU and Venuprasad, K.
- organization
- publishing date
- 2011
- 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}}, }