期刊
JOURNAL OF VIROLOGY
卷 85, 期 17, 页码 8811-8818出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00447-11
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资金
- National Basic Research Program of China (973 Project) [2011CB504903]
- Chinese Ministry of Education [NCET-07-0506]
- Institute of Pathogen Biology, Chinese Academy of Medical Sciences [2009IPB112]
- U.S. National Institute of Allergy and Infectious Diseases [AI092230]
Enterovirus 71 (EV71) causes hand-foot-and-mouth disease and neurological complications in young children. Although the underlying mechanisms remain obscure, impaired or aberrant immunity is thought to play a role. In infected cells, EV71 suppresses type I interferon responses mediated by retinoid acid-inducible gene I (RIG-I). This involves the EV71 3C protein, which disrupts the formation of a functional RIG-I complex. In the present study, we report that EV71 inhibits the induction of innate immunity by Toll-like receptor 3 (TLR3) via a distinct mechanism. In HeLa cells stimulated with poly(I center dot C), EV71 inactivates interferon regulatory factor 3 and drastically suppresses interferon-stimulated gene expression. Notably, EV71 specifically down-regulates a TRIF, TIR domain-containing adaptor inducing beta interferon (IFN-beta). When expressed alone in mammalian cells, EV71 3C is capable of exhibiting these activities. EV71 3C associates with and induces TRIF cleavage in the presence of Z-VAD-FMK, a caspase inhibitor. TRIF cleavage depends on its amino acid pair Q312-S313, which resembles a proteolytic site of picornavirus 3C proteases. Further, site-specific 3C mutants with a defective protease activity bind TRIF but fail to mediate TRIF cleavage. Consequently, these 3C mutants are unable to inhibit NF-kappa B and IFN-beta promoter activation. TRIF cleavage mediated by EV71 may be a mechanism to impair type I IFN production in response to Toll-like receptor 3 (TLR3) activation.
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