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

Neesar Ahmed, Minghui Zeng, Indrajit Sinha, Lisa Polin, Wei Zen Wei, Chozhavendan Rathinam, Richard Flavell, Ramin Massoumi, K. Venuprasad

Research output: Contribution to journalArticle

80 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1176-1183
Number of pages8
JournalNature Immunology
Volume12
Issue number12
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

Fingerprint

Ubiquitin-Protein Ligases
Inflammation
Macrophages
Cytokines
Neoplasms
Ubiquitination
Ubiquitin
Phosphotransferases
Tumor Necrosis Factor-alpha
Carcinoma
Lung
Growth
Deubiquitinating Enzymes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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; Venuprasad, K.

In: Nature Immunology, Vol. 12, No. 12, 01.12.2011, p. 1176-1183.

Research output: Contribution to journalArticle

Ahmed, N, Zeng, M, Sinha, I, Polin, L, Wei, WZ, Rathinam, C, Flavell, R, Massoumi, R & Venuprasad, K 2011, 'The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation', Nature Immunology, vol. 12, no. 12, pp. 1176-1183. https://doi.org/10.1038/ni.2157
Ahmed N, Zeng M, Sinha I, Polin L, Wei WZ, Rathinam C et al. The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation. Nature Immunology. 2011 Dec 1;12(12):1176-1183. https://doi.org/10.1038/ni.2157
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 act together to regulate Tak1 and inflammation. In: Nature Immunology. 2011 ; Vol. 12, No. 12. pp. 1176-1183.
@article{3f00eefa7fc44cc79d6a764fb7882ce1,
title = "The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation",
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 = "Neesar Ahmed and Minghui Zeng and Indrajit Sinha and Lisa Polin and Wei, {Wei Zen} and Chozhavendan Rathinam and Richard Flavell and Ramin Massoumi and K. Venuprasad",
year = "2011",
month = "12",
day = "1",
doi = "10.1038/ni.2157",
language = "English (US)",
volume = "12",
pages = "1176--1183",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation

AU - Ahmed, Neesar

AU - Zeng, Minghui

AU - Sinha, Indrajit

AU - Polin, Lisa

AU - Wei, Wei Zen

AU - Rathinam, Chozhavendan

AU - Flavell, Richard

AU - Massoumi, Ramin

AU - Venuprasad, K.

PY - 2011/12/1

Y1 - 2011/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=81255177676&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81255177676&partnerID=8YFLogxK

U2 - 10.1038/ni.2157

DO - 10.1038/ni.2157

M3 - Article

C2 - 22057290

AN - SCOPUS:81255177676

VL - 12

SP - 1176

EP - 1183

JO - Nature Immunology

JF - Nature Immunology

SN - 1529-2908

IS - 12

ER -