title: Identification of residues of SARS-CoV nsp1 that differentially affect inhibition of gene expression and antiviral signaling.
abstract: An epidemic of Severe Acute Respiratory Syndrome (SARS) led to the identification of an associated coronavirus, SARS-CoV. This virus evades the host innate immune response in part through the expression of its non-structural protein (nsp) 1, which inhibits both host gene expression and virus- and interferon (IFN)-dependent signaling. Thus, nsp1 is a promising target for drugs, as inhibition of nsp1 would make SARS-CoV more susceptible to the host antiviral defenses. To gain a better understanding of nsp1 mode of action, we generated and analyzed 38 mutants of the SARS-CoV nsp1, targeting 62 solvent exposed residues out of the 180 amino acid protein. From this work, we identified six classes of mutants that abolished, attenuated or increased nsp1 inhibition of host gene expression and/or antiviral signaling. Each class of mutants clustered on SARS-CoV nsp1 surface and suggested nsp1 interacts with distinct host factors to exert its inhibitory activities. Identification of the nsp1 residues critical for its activities and the pathways involved in these activities should help in the design of drugs targeting nsp1. Significantly, several point mutants increased the inhibitory activity of nsp1, suggesting that coronaviruses could evolve a greater ability to evade the host response through mutations of such residues.
authors: Infectious Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors: Andrew R
authors: AR
authors: Jauregui
authors: Dhruti
authors: D
authors: Savalia
authors: Virginia K
authors: VK
authors: Lowry
authors: Cara M
authors: CM
authors: Farrell
authors: Marc G
authors: MG
authors: Wathelet
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D057809:HEK293 Cells; D006801:Humans; D057131:Immune Evasion / Q000235:genetics*; D008156:Luciferases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D001616:beta-Galactosidase
chemical_list: D000596:Amino Acids; D017361:Viral Nonstructural Proteins; D049452:Green Fluorescent Proteins; D008156:Luciferases; C521592:Nsp1 protein, SARS coronavirus; D012324:RNA-Dependent RNA Polymerase; D001616:beta-Galactosidase
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