Abstract
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.
Highlights
Retinoic acid inducible gene-I (RIG-I) ensures immune surveillance of viral RNAs bearing a 5’triphosphate (5’ppp) moiety
The innate immune system provides the first barrier against invasion of RNA viruses, which are sensed by cytosolic retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including RIG-I and melanoma differentiation-associated protein 5 (MDA5)[1,2,3,4,5]
These observations suggest that cap and N1-2′-O-methylation (Cap1)-10l, as a self-RNA representative, behaves differently from pathogen-associated molecular patterns (PAMPs)-RNAs with respect to RNA discrimination by RIG-I and caspase activation and recruitment domains (CARD) activation
Summary
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. Cap1-RNA compromises its ability to stabilize RIG-I helicase and blunts caspase activation and recruitment domains (CARD) partial opening by threefold. The innate immune system provides the first barrier against invasion of RNA viruses, which are sensed by cytosolic retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including RIG-I and melanoma differentiation-associated protein 5 (MDA5)[1,2,3,4,5]. Wild-type (WT) RIG-I and MDA5 are pattern recognition receptors (PRRs) of an innate immune system that ensure immune surveillance of RNAs with pathogen-associated molecular patterns (PAMPs) 15,16.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
