SARS-CoV-2 6 binds KPNA2

Stable Identifier
Reaction [binding]
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
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Accessory open reading frame protein 6 (ORF6 or 6) of severe acute respiratory syndrome coronavirus 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 luciferase reporter plasmid pIFN-β-luc and viral protein expressing plasmid (Li JY et al. 2020; Yuen CK et al. 2020; Xia H et al. 2020; Lei X et al. 2020). Fluorescence microscopy revealed that the overexpression 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 HEK293T cells (Lei X et al. 2020). Mutagenesis analysis showed that the C-terminus of SARS-CoV-2 6 (from a.a. 53 to 61) is responsible for its antagonistic activity (Lei X et al. 2020). Co-immunoprecipitation using HEK293 cells that were co-transfected with FLAG-tagged ORF6-expressing plasmid and HA-tagged karyopherin α 1–6 (KPNA1–6) plasmids showed that viral ORF6 selectively interacted with KPNA2 but not the other KPNAs, suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Xia H et al. 2020). Moreover, overexpression of viral ORF6 blocked STAT1 nuclear translocation in HEK293T cells (Lei X et al. 2020). Similar findings were reported for SARS-CoV-1 6 (ORF6) which inhibited IRFs-mediated IFN production (Kopecky-Bromberg SA et al. 2007) and antagonized STAT1 function (IFN signaling) by tethering the nuclear import factors KPNA2 and KPNB1 to the ER/Golgi membrane (Frieman M et al. 2007). These data suggest that SARS-CoV 6 antagonizes both production and signaling of type I IFNs by preventing nuclear translocation of transcription factors.

This Reactome event describes binding of SARS-CoV-2 6 to KPNA2.

Literature References
PubMed ID Title Journal Year
32979938 Evasion of Type I Interferon by SARS-CoV-2

Chen, JY, Rajsbaum, R, Zhang, X, Xia, H, Cao, Z, Wang, H, Menachery, VD, Shi, PY, Xie, X

Cell Rep 2020
Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
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