ORF6

ORF6 is a gene that encodes a viral accessory protein in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It is not present in MERS-CoV. It is thought to reduce the immune system response to viral infection through interferon antagonism.[1][2][3]

Betacoronavirus NS6 protein
Identifiers
SymbolbCoV_NS6
PfamPF12133
InterProIPR022736
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Structure

The ORF6 protein is fairly small at 63 amino acid residues long in SARS-CoV[2] and 61 in SARS-CoV-2.[3] The ORF6 sequence is not well conserved and it has a relatively low sequence identity between the two viruses at about 66%.[4] It has an amphipathic N-terminal alpha helix that associates with the membrane, but is not a transmembrane protein. Its approximately 20-residue C-terminal tail is polar and extends into the cytosol, and contains signal sequences for protein trafficking.[1][2]

Expression and localization

Like the genes for other accessory proteins, the ORF6 gene is located near those encoding the structural proteins, at the 5' end of the coronavirus RNA genome. Along with ORF7a, ORF7b, and ORF8, ORF6 is located between the membrane (M) and nucleocapsid (N) genes.[1][2][3] It is localized to the endoplasmic reticulum and Golgi apparatus,[1][2][3] with studies in SARS-CoV-2 also indicating association with vesicles such as autophagosomes and lysosomes.[3]

Function

The primary function of the ORF6 protein is thought to be immunomodulation and interferon antagonism. It is not essential for viral replication, though its absence appears to reduce replication efficiency.[1][2]

Viral protein interactions

Studies in SARS-CoV suggest that the ORF6 protein exhibits protein-protein interactions with another viral accessory protein, ORF9b protein.[1][5] In SARS-CoV, but not in recombinant murine hepatitis virus, ORF6 protein has been detected in virus-like particles and mature virions, suggesting it can be a minor viral structural protein.[1][2]

Immune effects

The ORF6 protein from both SARS-CoV and SARS-CoV-2 is an interferon antagonist and thought to be involved in immune evasion. Several protein-protein interactions with host cell proteins have been described to mediate this effect. It has been reported to inhibit nuclear import of the STAT transcription factor, inhibiting interferon activation.[1][3] Studies of SARS-CoV report this may be mediated by binding of ORF6 protein to karyopherins.[1][4] In SARS-CoV-2, the ORF6 protein reportedly interacts with RAE1 and NUP98, blocking karyopherin interactions.[3][6]

References
  1. Liu, Ding Xiang; Fung, To Sing; Chong, Kelvin Kian-Long; Shukla, Aditi; Hilgenfeld, Rolf (September 2014). "Accessory proteins of SARS-CoV and other coronaviruses". Antiviral Research. 109: 97–109. doi:10.1016/j.antiviral.2014.06.013. PMC 7113789. PMID 24995382.
  2. McBride, Ruth; Fielding, Burtram (7 November 2012). "The Role of Severe Acute Respiratory Syndrome (SARS)-Coronavirus Accessory Proteins in Virus Pathogenesis". Viruses. 4 (11): 2902–2923. doi:10.3390/v4112902. PMC 3509677. PMID 23202509.
  3. 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.
  4. Suryawanshi, Rahul K.; Koganti, Raghuram; Agelidis, Alex; Patil, Chandrashekhar D.; Shukla, Deepak (March 2021). "Dysregulation of Cell Signaling by SARS-CoV-2". Trends in Microbiology. 29 (3): 224–237. doi:10.1016/j.tim.2020.12.007. PMC 7836829. PMID 33451855.
  5. Calvo, Enrique; DeDiego, Marta L.; García, Pilar; López, Juan A.; Pérez-Breña, Pilar; Falcón, Ana (October 2012). "Severe acute respiratory syndrome coronavirus accessory proteins 6 and 9b interact in vivo". Virus Research. 169 (1): 282–288. doi:10.1016/j.virusres.2012.07.012. PMC 7114373. PMID 22820404.
  6. Miorin, Lisa; Kehrer, Thomas; Sanchez-Aparicio, Maria Teresa; Zhang, Ke; Cohen, Phillip; Patel, Roosheel S.; Cupic, Anastasija; Makio, Tadashi; Mei, Menghan; Moreno, Elena; Danziger, Oded; White, Kris M.; Rathnasinghe, Raveen; Uccellini, Melissa; Gao, Shengyan; Aydillo, Teresa; Mena, Ignacio; Yin, Xin; Martin-Sancho, Laura; Krogan, Nevan J.; Chanda, Sumit K.; Schotsaert, Michael; Wozniak, Richard W.; Ren, Yi; Rosenberg, Brad R.; Fontoura, Beatriz M. A.; García-Sastre, Adolfo (10 November 2020). "SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling". Proceedings of the National Academy of Sciences. 117 (45): 28344–28354. doi:10.1073/pnas.2016650117. PMC 7668094. PMID 33097660.
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