HDX-MS reveals dysregulated checkpoints that compromise discrimination against self RNA during RIG-I mediated autoimmunity

Jie Zheng (), Chen Wang, Mi Ra Chang, Swapnil C. Devarkar, Brandon Schweibenz, Gogce C. Crynen, Ruben D. Garcia-Ordonez, Bruce D. Pascal, Scott J. Novick, Smita S. Patel, Joseph Marcotrigiano () and Patrick R. Griffin ()
Additional contact information
Jie Zheng: The Scripps Research Institute
Chen Wang: National Institutes of Health
Mi Ra Chang: The Scripps Research Institute
Swapnil C. Devarkar: Rutgers University
Brandon Schweibenz: Rutgers University
Gogce C. Crynen: The Scripps Research Institute
Ruben D. Garcia-Ordonez: The Scripps Research Institute
Bruce D. Pascal: The Scripps Research Institute
Scott J. Novick: The Scripps Research Institute
Smita S. Patel: Rutgers University
Joseph Marcotrigiano: National Institutes of Health
Patrick R. Griffin: The Scripps Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07780-z

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