ORF9c

ORF9c (formerly also called ORF14) is an open reading frame (ORF) in coronavirus genomes of the subgenus Sarbecovirus.[1] It is 73 codons long in the SARS-CoV-2 genome.[2] Although it is often included in lists of Sarbecovirus viral accessory protein genes, experimental and bioinformatics evidence suggests ORF9c may not be a functional protein-coding gene.[3]

Betacoronavirus uncharacterised protein 14
Identifiers
SymbolbCoV_Orf14
PfamPF17635
InterProIPR035113
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Nomenclature

There has been inconsistency in the nomenclature used for this gene in the scientific literature. In some work on SARS-CoV, it has been referred to as ORF14.[4] It has sometimes been referred to as ORF9b, while its longer upstream neighbor ORF9b was given the name ORF9a. The current recommended nomenclature refers to this gene as ORF9c, and the upstream gene as ORF9b.[2]

Expression and interactions

ORF9c is one of two overlapping genes fully contained within the open reading frame of the N gene encoding coronavirus nucleocapsid protein, the other being ORF9b. It is unclear if ORF9c is functionally expressed during SARS-CoV-2 infections; it is reportedly not translated under experimental conditions.[5] When experimentally overexpressed, the protein interacts with sigma receptors and with the NF-kB pathway.[1][6] The SARS-CoV protein forms self-interactions suggesting protein dimer or higher-order oligomer formation.[7]

Evolution

ORF9c has about 74% sequence identity between SARS-CoV and SARS-CoV-2.[1]

SARS-CoV-2 variants have been identified in which premature stop codons are introduced or where its start codon was lost, and the amino acid sequence is poorly conserved, supporting the hypothesis that it does not encode a functional protein.[3][6]

References
  1. Redondo, Natalia; Zaldívar-López, Sara; Garrido, Juan J.; Montoya, Maria (7 July 2021). "SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns". Frontiers in Immunology. 12: 708264. doi:10.3389/fimmu.2021.708264. PMC 8293742. PMID 34305949.
  2. Jungreis, Irwin; Nelson, Chase W.; Ardern, Zachary; Finkel, Yaara; Krogan, Nevan J.; Sato, Kei; Ziebuhr, John; Stern-Ginossar, Noam; Pavesi, Angelo; Firth, Andrew E.; Gorbalenya, Alexander E.; Kellis, Manolis (June 2021). "Conflicting and ambiguous names of overlapping ORFs in the SARS-CoV-2 genome: A homology-based resolution". Virology. 558: 145–151. doi:10.1016/j.virol.2021.02.013. PMC 7967279. PMID 33774510.
  3. Jungreis, Irwin; Sealfon, Rachel; Kellis, Manolis (December 2021). "SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes". Nature Communications. 12 (1): 2642. Bibcode:2021NatCo..12.2642J. doi:10.1038/s41467-021-22905-7. PMC 8113528. PMID 33976134.
  4. Marra, Marco A.; Jones, Steven J. M.; Astell, Caroline R.; Holt, Robert A.; Brooks-Wilson, Angela; Butterfield, Yaron S. N.; Khattra, Jaswinder; Asano, Jennifer K.; Barber, Sarah A.; Chan, Susanna Y.; Cloutier, Alison; Coughlin, Shaun M.; Freeman, Doug; Girn, Noreen; Griffith, Obi L.; Leach, Stephen R.; Mayo, Michael; McDonald, Helen; Montgomery, Stephen B.; Pandoh, Pawan K.; Petrescu, Anca S.; Robertson, A. Gordon; Schein, Jacqueline E.; Siddiqui, Asim; Smailus, Duane E.; Stott, Jeff M.; Yang, George S.; Plummer, Francis; Andonov, Anton; Artsob, Harvey; Bastien, Nathalie; Bernard, Kathy; Booth, Timothy F.; Bowness, Donnie; Czub, Martin; Drebot, Michael; Fernando, Lisa; Flick, Ramon; Garbutt, Michael; Gray, Michael; Grolla, Allen; Jones, Steven; Feldmann, Heinz; Meyers, Adrienne; Kabani, Amin; Li, Yan; Normand, Susan; Stroher, Ute; Tipples, Graham A.; Tyler, Shaun; Vogrig, Robert; Ward, Diane; Watson, Brynn; Brunham, Robert C.; Krajden, Mel; Petric, Martin; Skowronski, Danuta M.; Upton, Chris; Roper, Rachel L. (30 May 2003). "The Genome Sequence of the SARS-Associated Coronavirus". Science. 300 (5624): 1399–1404. Bibcode:2003Sci...300.1399M. doi:10.1126/science.1085953. PMID 12730501. S2CID 5491256.
  5. Finkel, Yaara; Mizrahi, Orel; Nachshon, Aharon; Weingarten-Gabbay, Shira; Morgenstern, David; Yahalom-Ronen, Yfat; Tamir, Hadas; Achdout, Hagit; Stein, Dana; Israeli, Ofir; Beth-Din, Adi; Melamed, Sharon; Weiss, Shay; Israely, Tomer; Paran, Nir; Schwartz, Michal; Stern-Ginossar, Noam (7 January 2021). "The coding capacity of SARS-CoV-2". Nature. 589 (7840): 125–130. Bibcode:2021Natur.589..125F. doi:10.1038/s41586-020-2739-1. PMID 32906143. S2CID 221624633.
  6. Gordon, David E.; et al. (16 July 2020). "A SARS-CoV-2 protein interaction map reveals targets for drug repurposing". Nature. 583 (7816): 459–468. Bibcode:2020Natur.583..459G. doi:10.1038/s41586-020-2286-9. PMC 7431030. PMID 32353859.
  7. von Brunn, Albrecht; Teepe, Carola; Simpson, Jeremy C.; Pepperkok, Rainer; Friedel, Caroline C.; Zimmer, Ralf; Roberts, Rhonda; Baric, Ralph; Haas, Jürgen (23 May 2007). "Analysis of Intraviral Protein-Protein Interactions of the SARS Coronavirus ORFeome". PLOS ONE. 2 (5): e459. Bibcode:2007PLoSO...2..459V. doi:10.1371/journal.pone.0000459. PMC 1868897. PMID 17520018.
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