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Elife. 2015 Nov 26;4. pii: e10859. doi: 10.7554/eLife.10859.

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

Author information

1
Gene Center, Department of Biochemistry, Ludwig Maximilian University of Munich, Munich, Germany.
2
Max von Pettenkofer-Institute, Gene Center, Ludwig Maximilian University of Munich, Munich, Germany.
3
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, United States.
4
Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, United States.
5
Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn, Germany.
6
Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, United States.
7
Institute of Molecular Medicine, University Hospital Bonn, University of Bonn, Bonn, Germany.
8
Center for Integrated Protein Science Munich, Munich, Germany.

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.

KEYWORDS:

ATPase domain; RIG-I; RLR; Singleton-Merten Syndrome; autoimmune response / disease; cell biology; human; immunology; innate immune system

PMID:
26609812
PMCID:
PMC4733034
DOI:
10.7554/eLife.10859
[Indexed for MEDLINE]
Free PMC Article

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