FIG. 9.

Model for ORF6 function. Upon IFN-α or -β stimulation of the IFN receptor on the surface of a cell, the STAT1:STAT2:IRF9 complex is formed. The NLS formed from STAT1 and STAT2 is recognized by KPNA1 (Kα1) for import into the nucleus. SARS-CoV-infected cells that are ER/Golgi membrane localized (shown here only on the ER membrane for clarity) bind to KPNA2, which recruits KPNB1 to the membrane complex as well. This creates a concentration-dependent competition between the ORF6:KPNA2 and ISGF3:KPNA1 complexes for the free unbound KPNB1 in the cytoplasm. This depletion of free KPNB1 in the cytoplasm produces a block in import of the ISGF3 complex in response to both IFN-β and IFN-γ and leaves KPNB1 bound to KPNA2 and ORF6 on the ER/Golgi membrane.