Title

MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-kappa B signaling

Authors

Authors

J. A. Liang; Y. Saad; T. H. Lei; J. Wang; D. F. Qi; Q. L. Yang; P. E. Kolattukudy;M. G. Fu

Comments

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Abbreviated Journal Title

J. Exp. Med.

Keywords

TUMOR-NECROSIS-FACTOR; UBIQUITIN-CONJUGATING ENZYME; SUPPRESSOR CYLD; IMMUNE-RESPONSES; MESSENGER-RNA; CELL-DEATH; ACTIVATION; ISOPEPTIDASE; INFLAMMATION; DEGRADATION; Immunology; Medicine, Research & Experimental

Abstract

The intensity and duration of macrophage-mediated inflammatory responses are controlled by proteins that modulate inflammatory signaling pathways. MCPIP1 (monocyte chemotactic protein-induced protein 1), a recently identified CCCH Zn finger-containing protein, plays an essential role in controlling macrophage-mediated inflammatory responses. However, its mechanism of action is poorly understood. In this study, we show that MCPIP1 negatively regulates c-Jun N-terminal kinase (JNK) and NF-kappa B activity by removing ubiquitin moieties from proteins, including TRAF2, TRAF3, and TRAF6. MCPIP1-deficient mice spontaneously developed fatal inflammatory syndrome. Macrophages and splenocytes from MCPIP1(-/-) mice showed elevated expression of inflammatory gene expression, increased JNK and I. B kinase activation, and increased polyubiquitination of TNF receptor-associated factors. In vitro assays directly demonstrated the deubiquitinating activity of purified MCPIP1. Sequence analysis together with serial mutagenesis defined a deubiquitinating enzyme domain and a ubiquitin association domain in MCPIP1. Our results indicate that MCPIP1 is a critical modulator of inflammatory signaling.

Journal Title

Journal of Experimental Medicine

Volume

207

Issue/Number

13

Publication Date

1-1-2010

Document Type

Article

Language

English

First Page

2959

Last Page

2973

WOS Identifier

WOS:000285503000017

ISSN

0022-1007

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