tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2020 Oct 23;202016650.
doi: 10.1073/pnas.2016650117. Online ahead of print.
SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling
Lisa Miorin[SUP] 1 2 [/SUP], Thomas Kehrer[SUP] 3 2 [/SUP], Maria Teresa Sanchez-Aparicio[SUP] 3 2 [/SUP], Ke Zhang[SUP] 4 [/SUP], Phillip Cohen[SUP] 3 [/SUP], Roosheel S Patel[SUP] 3 [/SUP], Anastasija Cupic[SUP] 3 2 [/SUP], Tadashi Makio[SUP] 5 [/SUP], Menghan Mei[SUP] 6 [/SUP], Elena Moreno[SUP] 3 2 [/SUP], Oded Danziger[SUP] 3 [/SUP], Kris M White[SUP] 3 2 [/SUP], Raveen Rathnasinghe[SUP] 3 2 [/SUP], Melissa Uccellini[SUP] 3 2 [/SUP], Shengyan Gao[SUP] 4 [/SUP], Teresa Aydillo[SUP] 3 2 [/SUP], Ignacio Mena[SUP] 3 2 [/SUP], Xin Yin[SUP] 7 [/SUP], Laura Martin-Sancho[SUP] 7 [/SUP], Nevan J Krogan[SUP] 3 8 9 10 [/SUP], Sumit K Chanda[SUP] 7 [/SUP], Michael Schotsaert[SUP] 3 2 [/SUP], Richard W Wozniak[SUP] 5 [/SUP], Yi Ren[SUP] 6 [/SUP], Brad R Rosenberg[SUP] 3 [/SUP], Beatriz M A Fontoura[SUP] 4 [/SUP], Adolfo Garc?a-Sastre[SUP] 1 2 11 12 [/SUP]
Affiliations
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that is a serious global health problem. Evasion of IFN-mediated antiviral signaling is a common defense strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of IFN-stimulated genes (ISGs). Our results demonstrate that the viral accessory protein Orf6 exerts this anti-IFN activity. We found that SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) and directly interacts with Nup98-Rae1 via its C-terminal domain to impair docking of cargo-receptor (karyopherin/importin) complex and disrupt nuclear import. In addition, we show that a methionine-to-arginine substitution at residue 58 impairs Orf6 binding to the Nup98-Rae1 complex and abolishes its IFN antagonistic function. All together our data unravel a mechanism of viral antagonism in which a virus hijacks the Nup98-Rae1 complex to overcome the antiviral action of IFN.
Keywords: Nup98; ORF6; SARS-CoV-2; STATs; interferon signaling antagonism.
. 2020 Oct 23;202016650.
doi: 10.1073/pnas.2016650117. Online ahead of print.
SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling
Lisa Miorin[SUP] 1 2 [/SUP], Thomas Kehrer[SUP] 3 2 [/SUP], Maria Teresa Sanchez-Aparicio[SUP] 3 2 [/SUP], Ke Zhang[SUP] 4 [/SUP], Phillip Cohen[SUP] 3 [/SUP], Roosheel S Patel[SUP] 3 [/SUP], Anastasija Cupic[SUP] 3 2 [/SUP], Tadashi Makio[SUP] 5 [/SUP], Menghan Mei[SUP] 6 [/SUP], Elena Moreno[SUP] 3 2 [/SUP], Oded Danziger[SUP] 3 [/SUP], Kris M White[SUP] 3 2 [/SUP], Raveen Rathnasinghe[SUP] 3 2 [/SUP], Melissa Uccellini[SUP] 3 2 [/SUP], Shengyan Gao[SUP] 4 [/SUP], Teresa Aydillo[SUP] 3 2 [/SUP], Ignacio Mena[SUP] 3 2 [/SUP], Xin Yin[SUP] 7 [/SUP], Laura Martin-Sancho[SUP] 7 [/SUP], Nevan J Krogan[SUP] 3 8 9 10 [/SUP], Sumit K Chanda[SUP] 7 [/SUP], Michael Schotsaert[SUP] 3 2 [/SUP], Richard W Wozniak[SUP] 5 [/SUP], Yi Ren[SUP] 6 [/SUP], Brad R Rosenberg[SUP] 3 [/SUP], Beatriz M A Fontoura[SUP] 4 [/SUP], Adolfo Garc?a-Sastre[SUP] 1 2 11 12 [/SUP]
Affiliations
- PMID: 33097660
- DOI: 10.1073/pnas.2016650117
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic that is a serious global health problem. Evasion of IFN-mediated antiviral signaling is a common defense strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to efficiently block STAT1 and STAT2 nuclear translocation in order to impair transcriptional induction of IFN-stimulated genes (ISGs). Our results demonstrate that the viral accessory protein Orf6 exerts this anti-IFN activity. We found that SARS-CoV-2 Orf6 localizes at the nuclear pore complex (NPC) and directly interacts with Nup98-Rae1 via its C-terminal domain to impair docking of cargo-receptor (karyopherin/importin) complex and disrupt nuclear import. In addition, we show that a methionine-to-arginine substitution at residue 58 impairs Orf6 binding to the Nup98-Rae1 complex and abolishes its IFN antagonistic function. All together our data unravel a mechanism of viral antagonism in which a virus hijacks the Nup98-Rae1 complex to overcome the antiviral action of IFN.
Keywords: Nup98; ORF6; SARS-CoV-2; STATs; interferon signaling antagonism.