title: Structures of arenaviral nucleoproteins with triphosphate dsRNA reveal a unique mechanism of immune suppression.
abstract: A hallmark of severe Lassa fever is the generalized immune suppression, the mechanism of which is poorly understood. Lassa virus (LASV) nucleoprotein (NP) is the only known 3'-5' exoribonuclease that can suppress type I interferon (IFN) production possibly by degrading immune-stimulatory RNAs. How this unique enzymatic activity of LASV NP recognizes and processes RNA substrates is unknown. We provide an atomic view of a catalytically active exoribonuclease domain of LASV NP (LASV NP-C) in the process of degrading a 5' triphosphate double-stranded (ds) RNA substrate, a typical pathogen-associated molecular pattern molecule, to induce type I IFN production. Additionally, we provide for the first time a high-resolution crystal structure of an active exoribonuclease domain of Tacaribe arenavirus (TCRV) NP. Coupled with the in vitro enzymatic and cell-based interferon suppression assays, these structural analyses strongly support a unified model of an exoribonuclease-dependent IFN suppression mechanism shared by all known arenaviruses. New knowledge learned from these studies should aid the development of therapeutics against pathogenic arenaviruses that can infect hundreds of thousands of individuals and kill thousands annually.
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom.
authors.forename: Xue
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, Twin Cities, St. Paul, Minnesota 55108.
authors.forename: Qinfeng
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Laboratory of Department of Surgery, the First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Wang
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom; Biomedical Sciences Research Complex, University of St. Andrews, St. Andrews KY16 9ST, United Kingdom.
authors.forename: Haohao
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, Twin Cities, St. Paul, Minnesota 55108. Electronic address: hly@umn.edu.
authors.forename: Hinh
authors.initials: H
authors.lastname: Ly
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, Twin Cities, St. Paul, Minnesota 55108. Electronic address: liangy@umn.edu.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom. Electronic address: c.dong@uea.ac.uk.
authors.forename: Changjiang
authors.initials: C
authors.lastname: Dong
mesh_terms: D006477:Arenaviruses, New World / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D018360:Crystallography, X-Ray; D005095:Exoribonucleases / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D007835:Lassa Fever / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007836:Lassa virus / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D009698:Nucleoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D009698:Nucleoproteins; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D014764:Viral Proteins; D005095:Exoribonucleases
keywords: 3′-5′ Exoribonuclease; Immune Evasion; Immunosuppression; Lassa Fever Virus; Nucleic Acid Enzymology; Protein Structure; Protein-nucleic Acid Interaction; Tacaribe Virus; Type I Interferons; Viral Protein