Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants.

Abstract

The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signaling state and to trigger an immune response. Previously, we showed that ATP hydrolysis removes RIG-I from lower-affinity self-RNAs (<xref ref-type="bibr" rid="bib19">Lässig et al., 2015</xref>), revealing how ATP turnover helps RIG-I distinguish viral from self-RNA and explaining why a mutation in a motif that slows down ATP hydrolysis causes the autoimmune disease Singleton-Merten syndrome (SMS). Here we show that a different, mechanistically unexplained SMS variant, C268F, which is localized in the ATP-binding P-loop, can signal independently of ATP but is still dependent on RNA. The structure of RIG-I C268F in complex with double-stranded RNA reveals that C268F helps induce a structural conformation in RIG-I that is similar to that induced by ATP. Our results uncover an unexpected mechanism to explain how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP.

• Authors: Charlotte Lässig, Katja Lammens, Jacob Lucián Gorenflos López, Sebastian Michalski, Olga Fettscher, Karl-Peter Hopfner
• Journal: eLife (Elife) Vol. 7 (07 26 2018) ISSN: 2050-084X [Electronic] England
• PMID: 30047865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018, Lässig et al.

Chemical References

• RNA, Double-Stranded
• RNA, Viral
• Receptors, Immunologic
• Adenosine Triphosphate
• Adenosine Triphosphatases
• DDX58 protein, human
• AAA Proteins
• DEAD Box Protein 58

Topics

• AAA Proteins (chemistry, genetics)
• Adenosine Triphosphatases (chemistry, genetics)
• Adenosine Triphosphate (chemistry, metabolism)
• Aortic Diseases (enzymology, genetics, pathology)
• Cytosol (virology)
• DEAD Box Protein 58 (chemistry, genetics)
• Dental Enamel Hypoplasia (enzymology, genetics, pathology)
• Humans
• Hydrolysis
• Immunity, Innate (genetics)
• Metacarpus (abnormalities, enzymology, pathology)
• Muscular Diseases (enzymology, genetics, pathology)
• Mutation
• Odontodysplasia (enzymology, genetics, pathology)
• Osteoporosis (enzymology, genetics, pathology)
• Protein Binding
• Protein Conformation
• RNA, Double-Stranded (chemistry, genetics)
• RNA, Viral (chemistry, genetics)
• Receptors, Immunologic
• Vascular Calcification (enzymology, genetics, pathology)