8.B.42.  The Coronavirus Orf6 (CV-Orf6) Family (formerly TC# 9.B.380)

Proteins of this family are small (30 - 60 aas) and have a single TMS. They are exclusively from coronaviruses. Orf6 disrupts bidirectional nucleocytoplasmic transport by interacting with the host RAE1-NUP98 complex (Kato et al. 2021, Addetia et al. 2021). It also disrupts cell nuclear import complex formation by tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane (Xia et al. 2020). Retention of import factors at the ER/Golgi membrane leads to a loss of transport into the nucleus. It prevents STAT1 nuclear translocation in response to interferon signaling, thus blocking the expression of interferon stimulated genes that display multiple antiviral activities (Miorin et al. 2020). It suppresses IFN-beta production, possibly by blocking IRF3 nuclear translocation (Xia et al. 2020). SARS-CoV-2 ORF6 localization and interferon antagonism can be decoupled (Wong et al. 2022).



Addetia, A., N.A.P. Lieberman, Q. Phung, T.Y. Hsiang, H. Xie, P. Roychoudhury, L. Shrestha, M.A. Loprieno, M.L. Huang, M. Gale, Jr, K.R. Jerome, and A.L. Greninger. (2021). SARS-CoV-2 ORF6 Disrupts Bidirectional Nucleocytoplasmic Transport through Interactions with Rae1 and Nup98. mBio 12:.

Kato, K., D.K. Ikliptikawati, A. Kobayashi, H. Kondo, K. Lim, M. Hazawa, and R.W. Wong. (2021). Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex. Biochem. Biophys. Res. Commun. 536: 59-66.

Miorin, L., T. Kehrer, M.T. Sanchez-Aparicio, K. Zhang, P. Cohen, R.S. Patel, A. Cupic, T. Makio, M. Mei, E. Moreno, O. Danziger, K.M. White, R. Rathnasinghe, M. Uccellini, S. Gao, T. Aydillo, I. Mena, X. Yin, L. Martin-Sancho, N.J. Krogan, S.K. Chanda, M. Schotsaert, R.W. Wozniak, Y. Ren, B.R. Rosenberg, B.M.A. Fontoura, and A. GarcĂ­a-Sastre. (2020). SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling. Proc. Natl. Acad. Sci. USA 117: 28344-28354.

Wong, H.T., V. Cheung, and D.J. Salamango. (2022). Decoupling SARS-CoV-2 ORF6 localization and interferon antagonism. J Cell Sci. [Epub: Ahead of Print]

Xia, H., Z. Cao, X. Xie, X. Zhang, J.Y. Chen, H. Wang, V.D. Menachery, R. Rajsbaum, and P.Y. Shi. (2020). Evasion of Type I Interferon by SARS-CoV-2. Cell Rep 33: 108234.


TC#NameOrganismal TypeExample

ORF6 protein of 62 aas and 1 TMS.

ORF6 of bat coronavirus BM48-31


Orf6 of 61 aas and 1 TMS

Orf6 of severe acute respiratory syndrome coronavirus 2


Uncharacterized protein of 30 aas and 1 TMS.

UP of Bat SARS-like coronavirus YNLF_31C