期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 13, 页码 5115-5120出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1220271110
关键词
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资金
- Chinese Ministry of Science and Technology [2012CB910201, 2013CB530500]
- National Natural Science Foundation of China [31221061, 31170792, 31270932, 31000639]
- Academic Award for Excellent PhD Candidates
- Ministry of Education of China
Recognition of viral double-stranded RNA by Toll-like receptor 3 (TLR3) triggers activation of the transcription factors NF-kappa B and interferon regulated factor 3, leading to induction of type I interferons and proinflammatory cytokines. TIR-domain-containing adapter-inducing interferon-beta (TRIF) is an adapter protein required for TLR3-mediated signaling. Here we identified the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2) as a TRIF-associated protein by biochemical purification. WWP2 mediated K48-linked ubiquitination and degradation of TRIF upon TLR3 activation. Overexpression of WWP2 inhibited TLR3-mediated NF-kappa B and interferon regulated factor 3 activation, whereas knockdown of WWP2 had opposite effects. We generated Wwp2-deficient mice to further investigate the roles of Wwp2 in innate immune responses. Consistently, production of IFN-beta, CCL5, TNF alpha, and IL-6 in response to the TLR3 ligand poly(I:C) was elevated in Wwp2(-/-) macrophages and Wwp2-deficient mice exhibited increased susceptibility to poly(I:C)-induced death than the control littermates. Our findings suggest that WWP2 negatively regulates TLR3-mediated innate immune and inflammatory responses by targeting TRIF for ubiquitination and degradation.
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