SARS-CoV-2 6 binds NUP98:RAE1 within NPC

Stable Identifier
R-HSA-9708889
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
cytosol, nuclear envelope
ReviewStatus
5/5
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SARS-CoV-2 6 binds NUP98:RAE1 within NPC
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Accessory protein ORF6 (6) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) exhibited strong inhibition on type I interferon (IFN)-responsive promoter activation in human embryonic kidney 293 (HEK293) cells that were transfected with either IFN-stimulated response element (ISRE) luciferase reporter plasmid and viral protein 6 expressing plasmid (Li JY et al. 2020; Yuen CK et al. 2020; Xia H et al. 2020; Miorin L et al. 2020). Fluorescence microscopy revealed that the expression of viral 6 (ORF6) protein blocked translocation of interferon regulatory factor 3 (IRF3) to the cell nucleus in poly(I:C)-induced human alveolar basal epithelial A549 cells (Xia H et al. 2020) and in Sendai virus (SeV)-induced HEK293 cells (Lei X et a. 2020; Yuen CK et al. 2020). The overexpression of ORF6 also blocked the nuclear translocation of signal transducer and activator of transcription 1 (STAT1) and STAT2 in HEK293T cells and African green monkey kidney (Vero) cells (Xia H et al. 2020; Lei X et a. 2020; Miorin L et al. 2020). Upon activation, IRF3:IRF3, STAT1:STAT1 or STAT1:STAT2 dimers translocate into the nucleus by binding to the import receptor karyopherin (importin) alpha proteins such as KPNA1 which bind to nuclear localization signals (NLS) in cargo substrates. KPNA1 in turn interacts with karyopherin (importin) β‑1 (KPNB1), which mediates docking of NLS-containing cargo substrate bound to importin alpha subunit to the nuclear pore complex (NPC). SARS-CoV-2 6 (ORF6) was found to bind KPNA2 blocking IRF3 and STAT nuclear translocation (Xia H et al. 2020). In addition, viral ORF6 localized at NPC where it directly interacted with NUP98 and RAE1 in ORF6-expressing HEK293T cells (Miorin L et al. 2020; Addetia A et al. 2021; Kato K et al. 2021). Mass spectrometry-based proteomics further confirm the 6:NUP98:RAE1 complex formation (Gordon DE et al. 2020; Meyers JM et al. 2021). Orf6 binding to NUP98 is thought to impair docking of he NLS‑cargo:KPNA1:KPNB1 ternary complexes at the NPC (Miorin L et al. 2020). Similar findings were reported for SARS-CoV-1 ORF6 which inhibited IRF3-regulated interferon production (Kopecky-Bromberg SA et al. 2007) and antagonized STAT1 function (interferon signalling) by tethering the nuclear import factors KPNA2 and KPNB1 to the ER/Golgi membrane (Frieman M et al. 2007) or by impairing docking of cargo-receptor (karyopherin/importin) complex thus disrupting nuclear import (Miorin L et al. 2020).

In addition to blocking nuclear import of host proteins, targeting the NUP98:RAE complex by SARS-CoV-2 6 prevents host mRNA export through NPC (Addetia A et al. 2021; Kato K et al. 2021).

Literature References
PubMed ID Title Journal Year
33097660 SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling

Mena, I, Patel, RS, García-Sastre, A, Mei, M, Rosenberg, BR, Cupic, A, Makio, T, Martin-Sancho, L, Rathnasinghe, R, Sanchez-Aparicio, MT, Fontoura, BMA, Kehrer, T, Uccellini, M, Danziger, O, Chanda, SK, Schotsaert, M, White, KM, Krogan, NJ, Moreno, E, Yin, X, Miorin, L, Ren, Y, Zhang, K, Gao, S, Cohen, P, Aydillo, T, Wozniak, RW

Proc Natl Acad Sci U S A 2020
34597346 The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation

Miao, W, Reynolds, D, Guo, MG, Ferguson, I, Yang, YY, Donohue, L, Yang, X, Rao, DS, Wang, Y, Meyers, JM, Shanderson, RL, Khavari, PA, Ramanathan, M, Zhao, Y, Blish, C, Beck, A

PLoS Pathog 2021
33849972 SARS-CoV-2 ORF6 Disrupts Bidirectional Nucleocytoplasmic Transport through Interactions with Rae1 and Nup98

Huang, ML, Jerome, KR, Roychoudhury, P, Xie, H, Hsiang, TY, Lieberman, NAP, Shrestha, L, Phung, Q, Greninger, AL, Addetia, A, Loprieno, MA, Gale, M

mBio 2021
33360543 Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex

Hazawa, M, Lim, K, Kondo, H, Kobayashi, A, Ikliptikawati, DK, Wong, RW, Kato, K

Biochem Biophys Res Commun 2021
32353859 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Foussard, H, Beltrao, P, Koh, C, Vignuzzi, M, Peng, S, Subramanian, A, Richards, AL, Kuzuoglu-Ozturk, D, Bouhaddou, M, Melnyk, JE, Ruggero, D, Wang, HY, Venkataramanan, S, Tummino, TA, Meyer, B, O'Neal, MC, Wenzell, NA, Guo, JZ, Barrio-Hernandez, I, Huang, XP, Verba, KA, Chorba, JS, Emerman, M, Ideker, T, Lyu, J, Hernandez-Armenta, C, Fabius, JM, Obernier, K, Safari, M, Craik, CS, Dai, SA, Kim, M, Perica, T, Haas, P, Moreno, E, Zhang, Z, Cakir, M, Soucheray, M, Liu, Y, Cai, Y, Hüttenhain, R, Rosenthal, SB, Hiatt, J, Chang, JCJ, Ashworth, A, Calviello, L, Ott, M, Kortemme, T, Klippsten, S, Kaake, RM, Jang, GM, Broadhurst, DJ, Memon, D, Gordon, DE, Roth, TL, d'Enfert, C, Shi, Y, Floor, SN, Frankel, AD, Fujimori, DG, Trenker, R, Vallet, T, McGregor, MJ, Mukherjee, S, García-Sastre, A, Fletcher, SJ, Fraser, JS, Xu, J, Saltzberg, DJ, Sharp, PP, White, KM, Kirby, IT, Braberg, H, Schwartz, O, Lin, Y, Naing, ZZC, Shoichet, BK, Noack, J, Mac Kain, A, Polacco, BJ, Lou, K, Rosenberg, OS, Mathy, CJP, Bennett, MJ, Shen, W, Ganesan, SJ, Bohn, M, Savar, NS, Cavero, DA, Haas, K, Stroud, RM, Eckhardt, M, Li, Q, Young, JM, O'Meara, MJ, Miorin, L, Liboy-Lugo, J, Swaney, DL, Gross, JD, Pilla, KB, von Zastrow, M, Jacobson, M, Tutuncuoglu, B, Roesch, F, Shokat, KM, Rezelj, VV, Zhou, Y, Krogan, NJ, Roth, BL, Agard, DA, Ugur, FS, Sali, A, Malik, HS, Liu, X, Jura, N, Taunton, J, Verdin, E, Batra, J, Hubert, M, Rathore, U, Rakesh, R, Tran, QD, Shengjuler, D, Modak, M, Wankowicz, SA

Nature 2020
Participants
Input
Output
Participates
as an event of
Disease
Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
Authored
Shamovsky, V  (2021-10-27)
Reviewed
Messina, F  (2022-02-18)
Created
Shamovsky, V  (2020-12-03)
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