Description
SARS-CoV-2 Open Reading Frame 6 (ORF6) is one of the nine downstream accessory protein open reading frames of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 (1). SARS-CoV-2 ORF6 is 61 amino acids (aa) with a theoretical molecular weight of 7.2 kDa (2, 3). The amino acid sequence alignment of SARS-CoV and SARS-CoV-2's ORF7a has 68.9% sequence identity and 93.4% sequence similarity (3).
SARS-CoV-2 ORF6 is an ER/Golgi membrane protein that disrupts the formation of the nuclear import complex by binding karyopherin alpha 2 (KPNA2) and karyopherin beta 1 (KPNB1) (2, 4). More specifically, it was found that this disruption is mediated by ORF6's localization to the nuclear pore complex (NPC) where it binds Nup98-Rae1 to target the nuclear import pathway (5). This disruption further prevents the transport of signal transducer and activator of transcription 1 (STAT1) and ultimately blocks interferon (IFN) production and antiviral responses (2, 4, 5). It has been hypothesized that the pathology of COVID-19 is largely initiated by the SARS-CoV-2 proteins ORF6 and non-structural protein 1 (NSP1) which together inhibit STAT1 activity (4). The repression of STAT1 thereby instead promotes STAT3 activation and the upregulation of plasminogen activator inhibitor-1 (PAI-1), leading to a cascade of events that are key features of COVID-19 (4). These harmful events include thrombosis, production of cytokines and chemokines by macrophages, profibrotic changes, hypoxia, and eventual T-cell lymphopenia (4). These finding suggest that targeting STAT1 and STAT3 might be beneficial therapeutic strategies for treating COVID-19.
References
1. Michel, C. J., Mayenr, C., Poch, O., & Thompson, J. D. (2020). Characterization of accessory genes in coronavirus genomes. Virology journal. https://doi.org/10.1186/s12985-020-01402-1
2. UniProt (P0DTC6)
3. Yoshimoto F. K. (2020). The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19. The protein journal. https://doi.org/10.1007/s10930-020-09901-4
4. Matsuyama, T., Kubli, S. P., Yoshinaga, S. K., Pfeffer, K., & Mak, T. W. (2020). An aberrant STAT pathway is central to COVID-19. Cell death and differentiation, 1-17. Advance online publication. https://doi.org/10.1038/s41418-020-00633-7
5. Miorin, L., Kehrer, T., Sanchez-Aparicio, M. T., Zhang, K., Cohen, P., Patel, R. S., Cupic, A., Makio, T., Mei, M., Moreno, E., Danziger, O., White, K. M., Rathnasinghe, R., Uccellini, M., Gao, S., Aydillo, T., Mena, I., Yin, X., Martin-Sancho, L., Krogan, N. J., ... Garcia-Sastre, A. (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, 202016650. Advance online publication. https://doi.org/10.1073/pnas.2016650117
Bioinformatics
| Product By Gene ID |
43740572 |
| Alternate Names |
- 2019-nCoV ORF6 Protein
- 2019-nCoV ORF6
- Accessory Protein 6
- COVID-19 Non-structural protein 6
- COVID-19 ns6
- COVID-19 ORF6
- COVID-19 Protein X3
- Human coronavirus ORF6 Protein
- Non-structural protein 6
- NS6
- ORF6 protein
- SARS-CoV-2 Accessory Protein 6
- SARS-CoV-2 Non-structural protein 6
- SARS-CoV-2 ns6
- SARSCoV2 ORF6 Protein
- SARS-CoV-2 ORF6 Protein
- SARS-CoV-2 Protein X3
- SARS-CoV-2
- Severe Acute Respiratory Syndrome Coronavirus 2
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