title: Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists.
abstract: The severe acute respiratory syndrome coronavirus (SARS-CoV) is highly pathogenic in humans, with a death rate near 10%. This high pathogenicity suggests that SARS-CoV has developed mechanisms to overcome the host innate immune response. It has now been determined that SARS-CoV open reading frame (ORF) 3b, ORF 6, and N proteins antagonize interferon, a key component of the innate immune response. All three proteins inhibit the expression of beta interferon (IFN-beta), and further examination revealed that these SARS-CoV proteins inhibit a key protein necessary for the expression of IFN-beta, IRF-3. N protein dramatically inhibited expression from an NF-kappaB-responsive promoter. All three proteins were able to inhibit expression from an interferon-stimulated response element (ISRE) promoter after infection with Sendai virus, while only ORF 3b and ORF 6 proteins were able to inhibit expression from the ISRE promoter after treatment with interferon. This indicates that N protein inhibits only the synthesis of interferon, while ORF 3b and ORF 6 proteins inhibit both interferon synthesis and signaling. ORF 6 protein, but not ORF 3b or N protein, inhibited nuclear translocation but not phosphorylation of STAT1. Thus, it appears that these three interferon antagonists of SARS-CoV inhibit the interferon response by different mechanisms.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Kopecky-Bromberg
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Sobrido
authors.forename: Matthew
authors.initials: M
authors.lastname: Frieman
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Baric
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D019590:Nucleocapsid Proteins / Q000235:genetics / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics / Q000502:physiology*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D019590:Nucleocapsid Proteins; D014764:Viral Proteins; D016899:Interferon-beta