Endomembrane targeting of human OAS1 p46 augments antiviral activity

eLife

Karen Cerosaletti¹  Cate Speake¹  Jane H Buckner¹  Joseph Perez²  Saumendra N Sarkar²  Eric J Allenspach³  Joshua J Woodward⁴  Tien-Ying Hsiang⁵  Ram Savan⁵  Chiraag Balu⁵  Katharina Esser-Nobis⁵  Daniel B Stetson⁵  Justin A Roby⁵  Julian R Smith⁵  Johannes Schwerk⁵  Frank W Soveg⁵  Snehal Ozarkar⁵  Michael Gale⁵  Jonathan M Clingan⁵  Nandan S Gokhale⁵  Amy EL Stone⁶  Adriana Forero⁷  Alison M Kell⁸  Uma Malhotra⁹  Jennifer L Hyde^1,10  Vineet D Menachery^1,11  Eileen T McAnarney^1,11  Shivam A Zaver^1,12  Erola Pairo-Castineira^1,13  John Kenneth Baillie^1,14 

[1] Benaroya Research Institute at Virginia Mason, Seattle, United States;Cancer Virology Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, United States;Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, United States;Center for Innate Immunity and Immune Disease, University of Washington, Seattle, United States;Department of Microbiology, School of Medicine, University of Washington, Seattle, United States;Department of Immunology, School of Medicine, University of Washington, Seattle, United States;Center for Innate Immunity and Immune Disease, University of Washington, Seattle, United States;Department of Immunology, School of Medicine, University of Washington, Seattle, United States;Center for Innate Immunity and Immune Disease, University of Washington, Seattle, United States;Department of Basic Sciences, College of Osteopathic Medicine, Touro University Nevada, Henderson, United States;Department of Immunology, School of Medicine, University of Washington, Seattle, United States;Center for Innate Immunity and Immune Disease, University of Washington, Seattle, United States;Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, United States;Department of Immunology, School of Medicine, University of Washington, Seattle, United States;Center for Innate Immunity and Immune Disease, University of Washington, Seattle, United States;Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico, Albuquerque, United States;Department of Infectious Disease, Virginia Mason Medical Center, Seattle, United States;Department of Medicine, Section of Infectious Diseases, University of Washington, Seattle, United States;Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, United States;Department of Microbiology and Immunology, University of Texas Medical Center, Galveston, United States;Department of Microbiology, School of Medicine, University of Washington, Seattle, United States;Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom;Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom;MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom;

关键词: innate immunity;    interferon stimulated genes;    RNA virus;    COVID-19;    SARS-CoV-2;    Human;   

DOI  :  10.7554/eLife.71047

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity.

【 授权许可】

CC BY