ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA

作者：Laessig Charlotte; Matheisl Sarah; Sparrer Konstantin M J; Mann Carina C de Oliveira; Moldt Manuela; Patel Jenish R; Goldeck Marion; Hartmann Gunther; Garcia Sastre Adolfo; Hornung Veit; Conzelmann Karl Klaus; Beckmann Roland; Hopfner Karl Peter

来源：eLife, 2015, 4: e10859.

DOI：10.7554/eLife.10859

The cytosolic antiviral innate immune sensor RIG-I distinguishes 5' tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) and increased interferon levels, suggesting misregulated signaling by RIG-I. Here we report that SMS mutations phenocopy a mutation that allows ATP binding but prevents hydrolysis. ATPase deficient RIG-I constitutively signals through endogenous RNA and co-purifies with self-RNA even from virus infected cells. Biochemical studies and cryo-electron microscopy identify a 60S ribosomal expansion segment as a dominant self-RNA that is stably bound by ATPase deficient RIG-I. ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5' triphosphate dsRNA. Our results indicate that ATP-hydrolysis prevents recognition of self-RNA and suggest that SMS mutations lead to unintentional signaling through prolonged RNA binding.

• 出版日期2015-11-26