Fig. 5.

ORF6 binds to the Nup98-Rae1 complex and blocks bidirectional nucleocytoplasmic transport.

ORF6 obstructs nuclear pore trafficking by binding to mRNA export proteins Nup98 and Rae1 (Kimura et al., 2021; Kato et al., 2021; Miorin et al., 2020; Gordon et al., 2020). ORF6 binding to the Nup98-Rae1 complex prevents nuclear translocation of transcription factors including IRF3 and STATs (Kimura et al., 2021; Addetia et al., 2021; Kato et al., 2021; Miorin et al., 2020). Mutation of methionine 58 to an arginine (M58R) prevents ORF6 binding to Nup98-Rae1, but does not affect interactions with importins (KPNA1 and KPNA2) (Miorin et al., 2020). The M85R mutation rescues the effect of ORF6 on STAT1/2 translocation to the nucleus, demonstrating that SARS-CoV-2 ORF6 activity does not depend on interactions with importins, unlike that of its SARS-CoV ortholog (Frieman et al., 2007; Miorin et al., 2020). In addition to preventing nuclear entry of proteins, ORF6/Nup98-Rae1 binding inhibits nuclear export of mRNAs and results in an accumulation of polyA + mRNAs in the nucleus (Addetia et al., 2021).