Coronavirus gene encoding an accessory protein
Protein family
ORF6 is a gene that encodes a viral accessory protein in coronaviruses of the subgenus Sarbecovirus 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]
Structure
The ORF6 protein is fairly small at 63 amino acid residues long in SARS-CoV [ 2] SARS-CoV-2 .[ 3] conserved and it has a relatively low sequence identity between the two viruses at about 66%.[ 4] 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] localized to the endoplasmic reticulum and Golgi apparatus ,[ 1] [ 2] [ 3] 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] 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] karyopherins .[ 1] [ 4] RAE1 and NUP98 , blocking karyopherin interactions.[ 3] [ 6]
References
^ a b c d e f g h i Liu DX, Fung TS, Chong KK, Shukla A, Hilgenfeld R (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 . ^ a b c d e f g McBride R, Fielding BC (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 . ^ a b c d e f g Redondo N, Zaldívar-López S, Garrido JJ, Montoya M (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 . ^ a b Suryawanshi RK, Koganti R, Agelidis A, Patil CD, Shukla D (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 . ^ Calvo E, DeDiego ML, García P, López JA, Pérez-Breña P, Falcón A (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 . ^ Miorin L, Kehrer T, Sanchez-Aparicio MT, Zhang K, Cohen P, Patel RS, et al. (November 2020). "SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling" . Proceedings of the National Academy of Sciences of the United States of America . 117 (45): 28344– 28354. Bibcode :2020PNAS..11728344M . doi :10.1073/pnas.2016650117 PMC 7668094 PMID 33097660 .
