p-STAT1dimer:KPNA1 binds KPNB1

Stable Identifier
R-HSA-9710963
Type
Reaction [transition]
Species
Homo sapiens
Compartment
ReviewStatus
5/5
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Upon viral infection, type I interferons (IFNs) (such as IFN-a/b) stimulate the transcription of antiviral interferon-stimulated genes (ISGs) by triggering phosphorylation, dimerization of signal transducer and activator of transcription 1 (STAT1) and STAT2, formation of interferon-stimulated gene factor 3 (ISGF3) complex with interferon regulatory factor 9 (IRF9), and nuclear translocation of of ISGF3 complex (Stark GR et al. 2012). STAT1 contains a nonclassical nuclear localization signal (NLS) sequence which is exposed only upon phosphorylation‑induced homo‑ or heterodimerization of STAT1 (Nardozzi J et al. 2010; Fagerlund R et al. 2002; McBride KM et al. 2002). In the cytoplasm, the nonclassical NLS of STAT1 dimers is initially recognized by an adaptor molecule, importin subunit α‑5 (also known as karyopherin subunit α‑1 or KPNA1) (McBride KM et al. 2002; Nardozzi J et al. 2010). KPNA1 then recruits importin β‑1 (karyopherin subunit β‑1 or KPNB1) via the N‑terminal importin β binding (IBB) domain of KPNA1 to form the NLS‑cargo:KPNA1:KPNB1 ternary complex (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). Many viruses encode proteins that subvert nuclear transport of activated STAT1 to antagonize the IFN signaling pathway (Shen Q et al. 2021). For example, severe acute respiratory syndrome coronavirus type 1 (SARS‑CoV-1) encodes an accessory protein orf6 which is thought to block the nuclear import of STAT1 by binding and tethering KPNA2 and KPNB1 to the endoplasmic reticulum (ER)/Golgi intermediate compartment (ERGIC) thus limiting free KPNB1 in the cytoplasm and reducing the p-STAT1:KPNA1:KPNB1 complex formation (Frieman M et al. 2007). Similar findings were reported for SARS-CoV-2 orf6 which interacts with KPNA2 (Xia H et al. 2020) and blocks the nuclear import of STAT1 (Lei X et al. 2020). In addition, SARS-CoV-2 orf6 also blocks STAT1 nuclear translocation by interacting with the NUP98:RAE1 complex. This disrupts the interaction between NUP98 and the p-STAT1:KPNA1:KPNB1 complex, thus preventing the docking of this complex at the nuclear pore (Miorin L et al. 2020).
Literature References
PubMed ID Title Journal Year
20643137 Molecular basis for the recognition of phosphorylated STAT1 by importin alpha5

Yasuhara, N, Cingolani, G, Nardozzi, J, Wenta, N, Vinkemeier, U

J Mol Biol 2010
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