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

By Charlotte Lässig, Sarah Matheisl, K. Sparrer, C. C. de Oliveira Mann, Manuela Moldt, Jenish R. Patel, Marion Goldeck, G. Hartmann, A. García‐Sastre, V. Hornung and 3 more. 2015

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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. DOI: http://dx.doi.org/10.7554/eLife.10859.001

Subfields: Immunology, Molecular Biology

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Citations in the corpus

RIG-I uses an ATPase-powered translocation-throttling mechanism for kinetic proofreading of RNAs and oligomerization (2018, background): “Another model proposes that ATP hydrolysis offers this proofreading function (Lassig et al., 2015; Louber et al., 2015).”
Selective RNA targeting and regulated signaling by RIG-I is controlled by coordination of RNA and ATP binding (2016, background): “An example is the E373Q RIG-I variant, which was shown to undergo activation by cellular ribosomal RNA, suggesting a proof-reading defect that leads to autoimmunity (28,29).”