
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 |
URN: | urn:nbn:de:bvb:19-epub-33966-0 |
ISSN: | 2050-084X |
Language: | English |
Item ID: | 33966 |
Date Deposited: | 15. Feb 2017, 16:02 |
Last Modified: | 04. Nov 2020, 13:11 |