6:KPNA2 binds KPNB1

Stable Identifier
R-HSA-9706977
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Human SARS coronavirus
Compartment
ReviewStatus
5/5
Locations in the PathwayBrowser
General
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Severe acute respiratory syndrome coronavirus type 1 (SARS-CoV-1) encodes an accessory protein orf6 which inhibits the type I interferon signaling by blocking the nuclear import of signal transducer and activator of transcription 1 (STAT1) (Kopecky-Bromberg SA et al. 2007; Frieman M et al. 2007). Translocation of activated STAT1 to the nucleus is mediated by importin subunit α-5 (also known as karyopherin subunit α-1 or KPNA1) (McBride KM et al. 2002; Nardozzi J et al. 2010). KPNA1 recognizes and binds the unique nonclassical nuclear localization signal (NLS) sequence of STAT1, which is exposed only upon phosphorylation-induced dimerization of STAT1 (Nardozzi J et al. 2010; Fagerlund R et al. 2002; McBride KM et al. 2002). Like other members of the importin α family, NLS-cargo-bound KPNA1 recruits the receptor importin subunit β-1 (karyopherin subunit β-1 or KPNB1) via the N-terminal importin β binding (IBB) domain of KPNA1 (Cingolani G et al. 1999). The formed NLS-cargo:KPNA1:KPNB1 complex is targeted to the nuclear pore complex (NPC) and then passes through nuclear pores via the interaction of KPNB1 with phenylalanine-glycine repeats (FG- repeats) (Moroianu J et al. 1995; McBride KM et al. 2002; Otsuka S et al. 2008; Chook    YM & Süel KE. 2011). SARS-CoV-1 orf6 binds importin subunit α-1 (KPNA2), which also functions as an adapter protein for KPNB1 (Frieman M et al. 2007). Unlike KPNA1, KPNA2 is not involved in the translocation of activated STAT1 complexes into the nucleus (Frieman M et al. 2007). Further, the interaction of KPNA2 with the viral 6 protein localizes KPNA2 to the membranes of endoplasmic reticulum (ER)/Golgi intermediate compartment (ERGIC) where 6 is localized. The binding of KPNA2 to 6 allows KPNB1 to be tethered to the 6:KPNA2 complex on ERGIC thus limiting free KPNB1 in the cytoplasm (Frieman M et al. 2007). SARS-CoV-1 6 is thought to block the nuclear import of STAT1 by tethering KPNA2 and KPNB1 to ERGIC and reducing the STAT1:KPNA1:KPNB1 complex formation (Frieman M et al. 2007). Similar findings were reported for SARS-CoV-2 orf6 which selectively interacted with KPNA2 to block IRF3 nuclear translocation (Xia H et al. 2020).
Literature References
PubMed ID Title Journal Year
17596301 Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane

Heise, M, Palese, P, Kopecky-Bromberg, SA, Yount, B, Baric, RS, Frieman, M

J Virol 2007
Participants
Participates
Disease
Name Identifier Synonyms
severe acute respiratory syndrome DOID:2945 SARS-CoV infection, SARS
Authored
Reviewed
Created
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