tetano
Editor, Senior Moderator
Front Mol Biosci
. 2022 Jan 12;8:813248.
doi: 10.3389/fmolb.2021.813248. eCollection 2021.
Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1-Nup98 Complex to Compete With mRNA Nuclear Export
Tinghan Li[SUP] 1 [/SUP], Yibo Wen[SUP] 1 [/SUP], Hangtian Guo[SUP] 1 [/SUP], Tingting Yang[SUP] 1 [/SUP], Haitao Yang[SUP] 2 3 4 5 [/SUP], Xiaoyun Ji[SUP] 1 6 [/SUP]
Affiliations
Abstract
The accessory protein Orf6 is uniquely expressed in sarbecoviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is an ongoing pandemic. SARS-CoV-2 Orf6 antagonizes host interferon signaling by inhibition of mRNA nuclear export through its interactions with the ribonucleic acid export 1 (Rae1)-nucleoporin 98 (Nup98) complex. Here, we confirmed the direct tight binding of Orf6 to the Rae1-Nup98 complex, which competitively inhibits RNA binding. We determined the crystal structures of both SARS-CoV-2 and SARS-CoV-1 Orf6 C-termini in complex with the Rae1-Nup98 heterodimer. In each structure, SARS-CoV Orf6 occupies the same potential mRNA-binding groove of the Rae1-Nup98 complex, comparable to the previously reported structures of other viral proteins complexed with Rae1-Nup98, indicating that the Rae1-Nup98 complex is a common target for different viruses to impair the nuclear export pathway. Structural analysis and biochemical studies highlight the critical role of the highly conserved methionine (M58) of SARS-CoVs Orf6. Altogether our data unravel a mechanistic understanding of SARS-CoVs Orf6 targeting the mRNA-binding site of the Rae1-Nup98 complex to compete with the nuclear export of host mRNA, which further emphasizes that Orf6 is a critical virulence factor of SARS-CoVs.
Keywords: ORF6; Rae1-Nup98 complex; SARS-CoV-2; crystal structure; mRNA nuclear export.
. 2022 Jan 12;8:813248.
doi: 10.3389/fmolb.2021.813248. eCollection 2021.
Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1-Nup98 Complex to Compete With mRNA Nuclear Export
Tinghan Li[SUP] 1 [/SUP], Yibo Wen[SUP] 1 [/SUP], Hangtian Guo[SUP] 1 [/SUP], Tingting Yang[SUP] 1 [/SUP], Haitao Yang[SUP] 2 3 4 5 [/SUP], Xiaoyun Ji[SUP] 1 6 [/SUP]
Affiliations
- PMID: 35096974
- PMCID: PMC8790125
- DOI: 10.3389/fmolb.2021.813248
Abstract
The accessory protein Orf6 is uniquely expressed in sarbecoviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is an ongoing pandemic. SARS-CoV-2 Orf6 antagonizes host interferon signaling by inhibition of mRNA nuclear export through its interactions with the ribonucleic acid export 1 (Rae1)-nucleoporin 98 (Nup98) complex. Here, we confirmed the direct tight binding of Orf6 to the Rae1-Nup98 complex, which competitively inhibits RNA binding. We determined the crystal structures of both SARS-CoV-2 and SARS-CoV-1 Orf6 C-termini in complex with the Rae1-Nup98 heterodimer. In each structure, SARS-CoV Orf6 occupies the same potential mRNA-binding groove of the Rae1-Nup98 complex, comparable to the previously reported structures of other viral proteins complexed with Rae1-Nup98, indicating that the Rae1-Nup98 complex is a common target for different viruses to impair the nuclear export pathway. Structural analysis and biochemical studies highlight the critical role of the highly conserved methionine (M58) of SARS-CoVs Orf6. Altogether our data unravel a mechanistic understanding of SARS-CoVs Orf6 targeting the mRNA-binding site of the Rae1-Nup98 complex to compete with the nuclear export of host mRNA, which further emphasizes that Orf6 is a critical virulence factor of SARS-CoVs.
Keywords: ORF6; Rae1-Nup98 complex; SARS-CoV-2; crystal structure; mRNA nuclear export.