HDX-MS reveals dysregulated checkpoints that compromise discrimination against self RNA during RIG-I mediated autoimmunity
By Jie Zheng, Chen Wang, M. Chang, S. Devarkar, Brandon D Schweibenz, Gogce Crynen, Rubén D. Garcia-Ordoñez, B. Pascal, S. Novick, Smita S. Patel and 2 more. 2018
33 citations recorded by the source corpus.
Retinoic acid inducible gene-I (RIG-I) ensures immune surveillance of viral RNAs bearing a 5’-triphosphate (5’ppp) moiety. Mutations in RIG-I (C268F and E373A) lead to impaired ATPase activity, thereby driving hyperactive signaling associated with autoimmune diseases. Here we report, using hydrogen/deuterium exchange, mechanistic models for dysregulated RIG-I proofreading that ultimately result in the improper recognition of cellular RNAs bearing 7-methylguanosine and N1-2’-O-methylation (Cap1) on the 5’ end. Cap1-RNA compromises its ability to stabilize RIG-I helicase and blunts caspase activation and recruitment domains (CARD) partial opening by threefold. RIG-I H830A mutation restores Cap1-helicase engagement as well as CARDs partial opening event to a level comparable to that of 5’ppp. However, E373A RIG-I locks the receptor in an ATP-bound state, resulting in enhanced Cap1-helicase engagement and a sequential CARDs stimulation. C268F mutation renders a more tethered ring architecture and results in constitutive CARDs signaling in an ATP-independent manner. RIG-I is a critical receptor in the induction of innate immune responses, but mutations in RIG-I can be associated with hyperactive signalling and autoimmune disease. Here Zheng et al. apply HDX-MS approaches to reveal dysregulated checkpoints that result in recognition of self-derived RNA during RIG-I mediated autoimmunity.
Subfields: Immunology, Molecular Biology
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Citations in the corpus
- The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, positive): “The cryo-EM structures of RIG-I complexed with p2dsRNA and p3dsRNA are consistent with hydrogen deuterium exchange mass spectrometry (HDX-MS) data showing that HelTNT remains dynamic upon RIG-I binding viral dsRNA (Zheng et al., 2018).”
- RIG-I-like receptors: their regulation and roles in RNA sensing (2020, background): “The CTD has a pocket binding specifically to 5′-PPP or 5′-PP groups and also contacts the unmethylated 2′-O group of the first nucleotide 20, [35] [36] [37] .”