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

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 und Hopfner, Karl-Peter (2015): ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA. In: eLife, Vol. 4, e10859

Abstract

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.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Biochemistry
• Subjects: 500 Science > 540 Chemistry
• ISSN: 2050-084X
• Language: English