TABLE 1.

Nomenclature and functional characteristics of SARS-CoV gene products and their interactions with host cells in disease pathogenesis

Gene nomenclature (no. of amino acid residues in product)Gene product and/or characteristic(s) (reference[s])Effect on cellular response of host (reference[s])
Orf1a/b
    nsp1 (180)Expression promoted degradation of host endogenous mRNAs, which may inhibit host protein synthesis and prevented endogenous IFN-β mRNA accumulation (167)Induce CCL5, CXCL10 (IP10), and CCL3 expression in human lung epithelial cells via activation of NF-κB; increases cellular RNA degradation, which might facilitate SARS-CoV replication or block immune responses (81, 192)
    nsp2 (638)Deletion attenuates viral growth and RNA synthesis (106)
    nsp3 (1,922)Papain-like protease 2; proteolytic processing of the viral polyprotein at 3 sites and participation in synthesis of subgenomic RNA segment (15, 121, 224)Putative catalytic triad (Cys1651-His1812-Asp1826) and zinc-binding site have deubiquitinating activity; this unexpected activity in addition to its papain-like protease suggests a novel viral strategy to modulate the host cell ubiquitination machinery to its advantage (15, 224, 279)
ADP-ribose 1-phosphatase; dephosphorylates Appr-1‴-p, a side product of cellular tRNA splicing, to ADP-ribose (271)
    nsp4 (500)Not known
    nsp5 (306)3C-like protease; proteolytic processing of the replicative polyprotein at 11 specific sites and forming key functional enzymes such as replicase and helicase (5, 394)Growth arrest and apoptosis via caspase-3 and caspase-9 activities demonstrated in SARS-CoV 3CLpro-expressing human promonocyte cells with increased activation of the nuclear factor-κB-dependent reporter (222)
    nsp6 (290)Not known
    nsp7 (83)Three-dimensional structure by nuclear magnetic resonance study found potential sites for protein-protein interactions (261)
    nsp8 (198)Putative RNA-dependent RNA polymerase; crystal structure of the hexadecameric nsp7-nsp8 possesses a central channel with dimensions and positive electrostatic properties favorable for nucleic acid binding; it is probably another unique RNA-dependent RNA polymerase for its large genome (158, 414)
    nsp9 (113)Three-dimensional crystal structure of a dimer which binds viral RNA and interacts with nsp8 (92, 316)
    nsp10 (139)Crystal structure suggests a nucleic acid binding function within a larger RNA binding protein complex for viral gene transcription and replication (166, 309)Interacts specifically with the NADH 4L subunit and cytochrome oxidase II with depolarization of inner mitochondrial membrane of transfected human embryo lung fibroblast and extensive cytopathic effect (210)
    nsp11 (13)Not known
    nsp12 (932)RNA-dependent RNA polymerase; replication and transcription to produce genome- and subgenome-sized RNAs of both polarities (158)
    nsp13 (601)Helicase (dNTPase and RNA 5′-triphosphatase activities) (95)
    nsp14 (527)3′→5′-exoribonuclease; this unusual 3′→5′-exoribonuclease activity supplements the endoribonuclease activity in the replication of the giant RNA genome (242)
    nsp15 (346)Uridylate-specific endoribonuclease; RNA endonuclease that is critically involved in the coronavirus replication cycle (284)
    nsp16 (298)Putative 2′-O-ribose methyltransferase (343)
Orf2 (1,255)Spike protein; binds to the host cell receptor ACE2 and other coreceptors, mediates viral entry into host cells as a type 1 viral fusion protein; required acidification of endosomes for efficient S-mediated viral entry; proteolytic cleavage by abundantly expressed infected cell membrane-associated factor Xa into S1 and S2; protease activation required for cell-cell fusion (159, 162, 206, 214, 227, 301, 334)293 T cells transfected with ACE2 can form multinucleated syncytia with cells expressing the spike; intraperitoneal injections of spike protein into mice reduced ACE2 expression in lungs and worsened acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway (181); recombinant baculovirus expressing different deletion and insertion fragments identified the functional region of S protein from amino acids 324-688, which can induce the release of IL-8 in lung cells (43); induces unfolded protein response in cultured cells as SARS-CoV with a substantial amt of S protein accumulation in the endoplasmic reticulum, which may modulate viral replication (30)
Orf3a (274)Forms potassium-sensitive ion channel, may promote virus budding and release (234)Overexpression in cell line may trigger apoptosis; its expression in A549 lung epithelial cells up-regulates mRNA and intracellular and secreted levels of all three subunits, alpha, beta, and gamma, of fibrinogen, which is also observed in SARS-CoV-infected Vero E6 cells; it is highly immunogenic and induces neutralizing antibodies (193, 321); 3a/X1 and 7a/X4 were capable of activating NF-κB and c-Jun N-terminal kinase and significantly enhanced IL-8 promoter activity in A549 cells; enhanced production of inflammatory chemokines that were known to be up-regulated in SARS-CoV infection (169)
Orf3b (154)Predominately localized to the nucleolus in different transfected cells (409)Vero E6 but not 293T cells transfected with a construct for expressing Orf3b underwent necrosis as early as 6 h after transfection but underwent simultaneous necrosis and apoptosis at later time points; Orf3b inhibits expression of IFN-β at synthesis and signaling (175, 178)
Orf4 (76)Envelope protein; synthetic peptides form ion channels in planar lipid bilayers, which are more permeable to monovalent cations than to monovalent anions; putatively involved in viral budding and release (359)Induced apoptosis in transfected Jurkat T cells especially in the absence of growth factors; a novel BH3-like region was located in the C-terminal cytosolic domain of SARS-CoV E protein can bind to Bcl-xL, whose overexpression can antagonize apoptosis; this may explain the consistent lymphopenia found in SARS patients (397)
Orf5 (221)Membrane protein; surface protein responsible for viral assembly and buddingM protein induced apoptosis in HEK293T cells, which could be suppressed by caspase inhibitors (29)
Orf6 (63)Novel membrane protein that accelerates replication and virulence of a recombinant mouse coronavirus expressing Orf6; an important virulence factor in vivo demonstrated in a mouse model (327)Inhibits both IFN synthesis and signaling; inhibited nuclear translocation but not phosphorylation of STAT1 (178); Orf6 is localized to the endoplasmic reticulum/Golgi membrane of infected cells; it binds and disrupts nuclear import complex formation by tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane; this retention of the complex at the endoplasmic reticulum/Golgi membrane leads to a loss of STAT1 transport into the nucleus despite viral RNA-induced IFN signaling; thus, it blocks the expression of STAT1-activated genes, which are essential for establishing an antiviral state (100)
Orf7a (122)Unique type I transmembrane protein; involved in viral assembly by interacting with M and E, which are essential for virus-like particle formation when coexpressed with S and N (97, 150, 245)Expression of Orf7a induces apoptosis via a caspase-3-dependent pathway and in cell lines derived from different organs including lung, kidney, and liver (179, 320, 408)
Orf7b (44)Not known
Orf8a (39)Not knownOrf8a was localized in mitochondria, and overexpression resulted in increases in mitochondrial transmembrane potential, reactive oxygen species production, caspase-3 activity, and cellular apoptosis; Orf8a enhances viral replication and induces apoptosis through a mitochondrion-dependent pathway (49)
Orf8b (84)May modulate viral replication; expression of E was down-regulated by Orf8b but not Orf8a or Orf8ab (172)
Orf9 (422)Nucleocapsid protein; binding and packaging of viral RNA in assembly of the virion (147)N antagonized IFN by inhibiting synthesis of IFN-β (130); NF-κB activation in Vero E6 cells expressing the N protein is dose dependent (220); N may cause inflammation of the lungs by activating COX-2 gene expression by binding directly to the promoter, resulting in inflammation through multiple COX-2 signaling cascades (393); induced apoptosis of COS-1 monkey kidney but not 293T cells in the absence of growth factors; induced actin reorganization in cells devoid of growth factors (315)
Orf9b (98)Crystal structure of Orf9b, an alternative ORF within the N gene, may be involved in membrane attachment and associates with intracellular vesicles, consistent with a role in assembly of the virion (241)