Regulation of Signal Transduction by Enzymatically Inactive Antiviral RNA Helicase Proteins MDA5, RIG-I, and LGP2

被引:140
作者
Bamming, Darja [1 ]
Horvath, Curt M. [1 ,2 ,3 ]
机构
[1] Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA
[2] Northwestern Univ, Dept Med, Evanston, IL 60208 USA
[3] Evanston NW Healthcare, Dept Med, Evanston, IL 60208 USA
基金
美国国家卫生研究院;
关键词
HEPATITIS-C VIRUS; INDUCIBLE GENE-I; INNATE IMMUNITY; ADAPTER PROTEIN; ATPASE ACTIVITY; RESPONSES; RECOGNITION; DOMAIN; ACID; BETA;
D O I
10.1074/jbc.M807365200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Intracellular pattern recognition receptors MDA5, RIG-I, and LGP2 are essential components of the cellular response to virus infection and are homologous to the DEXH box subfamily of RNA helicases. However, the relevance of helicase activity in the regulation of interferon production remains elusive. To examine the importance of the helicase domain function for these signaling proteins, a series of mutations targeting conserved helicase sequence motifs were analyzed for enzymatic activity, RNA binding, interferon induction, and antiviral signaling. Results indicate that all targeted motifs are required for ATP hydrolysis, but a subset is involved in RNA binding. The enzymatically inactive mutants differed in their signaling ability. Notably, mutations to MDA5 motifs I, III, and VI and RIG-I motif III produced helicase proteins with constitutive antiviral activity, whereas mutations in RIG-I motif V retained ATP hydrolysis but failed to mediate signal transduction. These findings demonstrate that type I interferon production mediated by full-length MDA5 and RIG-I is independent of the helicase domain catalytic activity. In addition, neither enzymatic activity nor RNA binding was required for negative regulation of antiviral signaling by LGP2, supporting an RNA-independent interference mechanism.
引用
收藏
页码:9700 / 9712
页数:13
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