TABLE 2.
Nomenclature and putative functional characteristics of MERS-CoV gene products with analogy to SARS-CoVa
| Gene (no. of amino acid residues in product) | Gene product and/or putative functional domain(s) | Characteristics and/or effect on cellular response of host | References |
|---|---|---|---|
| ORF1a/b | |||
| nsp1 (193) | Unknown | May induce template-dependent endonucleolytic cleavage of host mRNA but not viral RNA and may interact with cyclophilins which may be blocked by cyclosporine | 16, 20–22, 251, 297, 298 |
| nsp2 (660) | Unknown | May interact with prohibitin 1 and 2, disrupts intracellular signaling | 16, 20–22, 251, 299 |
| nsp3 (1,887) | Papain-like protease | Structurally similar to the papain-like protease of SARS-CoV albeit with only 30% sequence identity, consisting of a right-hand-like architecture with palm, thumb, and fingers domains; specific conserved structural features include the ubiquitin-like domain, a catalytic triad consisting of C1594-H1761-D1776, and the ubiquitin-binding domain at the zinc finger; functions: proteolytic processing of the viral replicase polyprotein at 3 sites (nsp1-2, 2-3, and 3-4) to generate nsps that contribute to subgenomic RNA synthesis, deISGylating (ISG15-linked ISGylation) and deubiquitinating (K48- and K63-linked ubiquitination) activities, interferon antagonist (reduces induction of NF-κB, blocks phosphorylation and nuclear translocation of IRF3, and blocks upregulation of cytokines CCL5, interferon beta, and CXCL10 in HEK293T cells | 16, 20–22, 28, 171, 172, 251, 300–303 |
| ADP-ribose 1″-phosphatase | Putative dephosphorylation of Appr-1″-p, a side product of cellular tRNA splicing, to ADP-ribose | 16, 20–22, 251 | |
| Transmembrane domain | Uncertain function, but may be similar to other CoVs, including SARS-CoV, in anchoring the viral replication complex through recruitment of intracellular membranes to form a reticulovesicular network of CMs and DMVs interconnected via the outer membrane with the rough endoplasmic reticulum | 16, 20–22, 251, 304 | |
| nsp4 (507) | Transmembrane domain | Similar to nsp3 and may help to form part of the viral replication complex | 16, 20–22, 251, 304 |
| nsp5 (306) | Main, chymotrypsin-like, or 3C-like protease | Proteolytic processing of the replicative polyprotein at specific sites and forming key functional enzymes such as replicase and helicase | 16, 20, 22, 251 |
| nsp6 (292) | Transmembrane domain | Membrane-spanning integral component of the viral replication complex involved in DMV formation; substitutions may lead to resistance to the viral RNA synthesis inhibitor K22 | 16, 20–22, 251, 304 |
| nsp7 (83) | Unknown | In SARS-CoV, nsp7 and -8 are part of a unique multimeric RNA polymerase complex | 16, 20–22, 251, 305 |
| nsp8 (199) | Primase | 16, 20–22, 251 | |
| nsp9 (110) | Unknown | In SARS-CoV, nsp9 is an essential protein dimer with RNA/DNA binding activity | 16, 20–22, 252, 306 |
| nsp10 (140) | Unknown | In SARS-CoV, nsp10 is required for nsp16 to bind both m7GpppA-RNA substrate and S-adenosyl-l-methionine cofactor; nsp16 possesses the canonical scaffold of MTase and associates with nsp10 at 1:1 ratio | 16, 20–22, 252, 307 |
| nsp11 (14) | Unknown | Unknown | 16, 20–22, 251 |
| nsp12 (933) | RNA-dependent RNA polymerase | Replication and transcription to produce genome- and subgenome-size RNAs of both polarities | 16, 20–22, 251 |
| nsp13 (598) | Superfamily 1 helicase | Putative dNTPase and RNA 5′-triphosphatase activities | 16, 20–22, 251 |
| Zinc-binding domain | 16, 20–22, 251 | ||
| nsp14 (524) | 3′-to-5′ exonuclease | Putative endoribonuclease activity in the replication of the giant RNA genome | 16, 20–22, 251 |
| N7-methyltransferase | 16, 20–22, 251 | ||
| nsp15 (343) | Nidoviral endoribonuclease specific for U | Putative RNA endonuclease that is essential in the CoV replication cycle | 16, 20–22, 251 |
| nsp16 (303) | S-Adenosylmethionine-dependent ribose 2′-O-methyltransferase | In SARS-CoV, nsp16 is critical for capping of viral mRNA and prevents recognition by host sensor molecules | 16, 20–22, 251, 308 |
| ORF2 (1,353) | Spike (S) protein | A type I transmembrane glycoprotein displayed on viral membrane surface critical for receptor binding and membrane fusion | 16, 20–22, 251 |
| ORF3 (103) | Accessory protein 3 | Deletion of ORF3, -4, and -5 accessory cluster showed ∼1.5-log reduction in viral titer compared with recombinant MERS-CoV and resulted in enhanced expression of subgenomic gRNA2 encoding the S protein associated with an increased fusion phenotype; not essential for virus replication in Vero A66 and Huh-7 cells | 16, 20–22, 187, 251, 309 |
| ORF4a (109) | Accessory protein 4a | A dsRNA-binding protein with a dsRNA-binding domain (residues 3 to 83) that potently antagonizes host interferon response via inhibition of interferon production (interferon beta promoter activity, IRF-3/7 and NF-κB activation), ISRE promoter element signaling pathways, and/or suppression of PACT-induced activation of RIG-I and MDA5 in an RNA-dependent manner; not essential for virus replication in Vero A66 and Huh-7 cells | 16, 20–22, 24, 25, 251, 309 |
| ORF4b (246) | Accessory protein 4b | May have interferon antagonist activity; not essential for virus replication in Vero A66 and Huh-7 cells | 16, 20–22, 24–27, 251, 309 |
| ORF5 (224) | Accessory protein 5 | Interferon antagonist with no effect on interferon beta promoter activation; not essential for virus replication in Vero A66 and Huh-7 cells | 16, 20–22, 27, 187, 251, 309 |
| ORF6 (82) | Envelope (E) protein | Putative ion channel activity and is involved in viral budding and release; essential for efficient virus propagation in Vero A66 and Huh-7 cells | 16, 20–22, 251, 309 |
| ORF7 (219) | Membrane (M) protein | Surface protein that incorporates viral components into virions and interacts with N protein in infected cells; interferon antagonist | 16, 20–22, 24, 251 |
| ORF8a (413) | Nucleocapsid (N) protein | Interacts with C-terminal domain of M protein for binding and packaging of viral RNA in assembly of the virion | 16, 20–22, 251 |
| ORF8b (112) | Unknown | Unknown | 16, 20–22, 251 |
a
The putative functions of the accessory gene products of MERS-CoV and SARS-CoV may not directly correlate, as the accessory genes of these two viruses are not homologous. Abbreviations: CCL5, chemokine ligand 5; CM, convoluted membrane; CoV, coronavirus; CXCL10, chemokine (C-X-C motif) ligand 10; DMV, double membrane vesicle; dNTPase, deoxynucleoside triphosphatase; IRF3, interferon regulatory factor 3; ISG, interferon-stimulated gene; nsp, nonstructural protein.