Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants
By Charlotte Lässig, K. Lammens, Jacob Lucián Gorenflos López, Sebastian Michalski, O. Fettscher, K. Hopfner. 2018
33 citations recorded by the source corpus.
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 (Lässig et al., 2015), 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.
Subfields: Epidemiology, Immunology, Rheumatology
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Citations in the corpus
- RNA binding activates RIG-I by releasing an autorepressed signaling domain (2019, background): “These observations led to the hypothesis that, following RNA binding, ATP binding promotes signaling by enhancing 2CARD ejection (18, 35).”