ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA
- Ludwig Maximilian University of Munich, Germany
- Harvard Medical School, United States
- Icahn School of Medicine at Mount Sinai, United States
- University of Bonn, 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.
Article and author information
Author details
Reviewing Editor
- Stephen C Kowalczykowski, University of California, Davis, United States
Version history
- Received: August 14, 2015
- Accepted: November 25, 2015
- Accepted Manuscript published: November 26, 2015 (version 1)
- Version of Record published: January 15, 2016 (version 2)
- Version of Record updated: March 2, 2016 (version 3)
Copyright
© 2015, Lässig et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA
eLife 4:e10859.
https://doi.org/10.7554/eLife.10859
Further reading
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- Biochemistry and Chemical Biology
- Immunology and Inflammation
Retinoic acid-inducible gene I (RIG-I) initiates a rapid innate immune response upon detection and binding to viral ribonucleic acid (RNA). This signal activation occurs only when pathogenic RNA is identified, despite the ability of RIG-I to bind endogenous RNA while surveying the cytoplasm. Here we show that ATP binding and hydrolysis by RIG-I play a key role in the identification of viral targets and the activation of signaling. Using biochemical and cell-based assays together with mutagenesis, we show that ATP binding, and not hydrolysis, is required for RIG-I signaling on viral RNA. However, we show that ATP hydrolysis does provide an important function by recycling RIG-I and promoting its dissociation from non-pathogenic RNA. This activity provides a valuable proof-reading mechanism that enhances specificity and prevents an antiviral response upon encounter with host RNA molecules.
