Human RIG-I Antiviral Deficiency Caused by a Dominant-Negative Variant Trapped in a Signaling-Inactive State
Year: 2026
Type: preprint
Abstract: RIG-I is a cytosolic pattern-recognition receptor that detects viral RNA to initiate type I interferon responses. While gain-of-function helicase mutations cause human autoinflammatory disease, naturally occurring loss-of-function variants in conserved helicase motifs remain undescribed. Here, we identify a heterozygous G731R substitution in helicase motif VI in a patient with life-threatening COVID-19 pneumonia. Patient-derived immune cells exhibit severe defects in RIG-I-dependent antiviral signaling. Mechanistically, G731R is an intrinsic dominant-negative loss-of-function variant that retains high-affinity binding to viral RNA and ATP but lacks RNA-stimulated ATPase activity. Hydrogen-deuterium exchange mass spectrometry and stopped-flow kinetic analyses reveal that G731R fails to undergo the conformational transitions required for productive CARD exposure, trapping RIG-I in an RNA-bound, signaling-inactive CTD-mode intermediate that competitively inhibits wild-type RIG-I. In contrast, distinct substitutions at the same residue bidirectionally tune receptor activity, with bulky charged residues producing loss-of-function phenotypes and small hydrophobic residues producing gain-of-function phenotypes. Studies of this first naturally occurring dominant-negative RIG-I variant demonstrate that the conserved helicase motifs function as ATP-dependent conformational checkpoints that couple viral RNA recognition to productive antiviral signaling.
Source: Research Square
Authors: Smita Patel, Mihai Solotchi, Huie Jing, Emma Gebauer, Scott Novick, Bruce Pascal, Wesley Tung, Pranita Hanpude, Luigi Apollon, Talia Madura, Yu Zhang, Camille Alba, Basak Kayaoglu, Annalisa Saracino, Paola Laghetti, Anna Volpe, Imad Isehak, Elana Shaw, Lindsey Rosen, Colin Sweeney, Steven Holland, Andrea Lisco, Clifton Dalgard, Joseph Marcotrigiano, Patrick Griffin, Helen Su
Institutions: Rutgers, The State University of New Jersey, Rutgers New Jersey Medical School, National Institute of Allergy and Infectious Diseases, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, National Institutes of Health, Uniformed Services University of the Health Sciences, Azienda Universitaria Ospedaliera Consorziale - Policlinico Bari, University of Bari Aldo Moro
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7203758421