Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1–Nup98 Complex to Compete With mRNA Nuclear Export

Li, Tinghan; Wen, Yibo; Guo, Hangtian; Yang, Tingting; Yang, Haitao; Ji, Xiaoyun

doi:10.3389/fmolb.2021.813248

Cited by 34 publications

(47 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ORF6 blocks STAT1 nuclear translocation by interacting with the Nup98-RAE1 complex and disrupts the interaction between Nup98 and importin-β1/importin-α1/PY STAT1 complex, thus preventing the binding of this complex at the nuclear pore. Moreover, SARS-CoV ORF6 binds to the Nup98-RAE1 complex, and ORF6s from both viruses share the same binding site on this complex ( 10 ). Nup98 is identified as a critical factor hijacked by SARS-CoV-2 to inhibit IFN signaling.…”

Section: Orf6 Inhibits Irf3 Nuclear Translocation and Hampers Ifn-i S...mentioning

confidence: 99%

“…The structural proteins assemble and help in the budding of new virions at the ER to Golgi compartment that are suggested to exit the infected cells by exocytosis. S protein recognizes and binds to the receptor, angiotensin-converting enzyme 2 (ACE2) of the host cell, mediating the penetration of the virus into the host cell ( 7 , 10 ). N protein is multifunctional; its main function is to assemble genomic RNA of the virus into a ribonucleoprotein complex and regulate viral replication ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Roles and functions of SARS-CoV-2 proteins in host immune evasion

et al. 2022

View full text Add to dashboard Cite

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades the host immune system through a variety of regulatory mechanisms. The genome of SARS-CoV-2 encodes 16 non-structural proteins (NSPs), four structural proteins, and nine accessory proteins that play indispensable roles to suppress the production and signaling of type I and III interferons (IFNs). In this review, we discussed the functions and the underlying mechanisms of different proteins of SARS-CoV-2 that evade the host immune system by suppressing the IFN-β production and TANK-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3)/signal transducer and activator of transcription (STAT)1 and STAT2 phosphorylation. We also described different viral proteins inhibiting the nuclear translocation of IRF3, nuclear factor-κB (NF-κB), and STATs. To date, the following proteins of SARS-CoV-2 including NSP1, NSP6, NSP8, NSP12, NSP13, NSP14, NSP15, open reading frame (ORF)3a, ORF6, ORF8, ORF9b, ORF10, and Membrane (M) protein have been well studied. However, the detailed mechanisms of immune evasion by NSP5, ORF3b, ORF9c, and Nucleocapsid (N) proteins are not well elucidated. Additionally, we also elaborated the perspectives of SARS-CoV-2 proteins.

show abstract

Section: Orf6 Inhibits Irf3 Nuclear Translocation and Hampers Ifn-i S...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Roles and functions of SARS-CoV-2 proteins in host immune evasion

et al. 2022

View full text Add to dashboard Cite

show abstract

“…However, as our studies show that the ORF6 interaction with Nup98 is indirect, any cross-linking would have to be via Rae1 binding. Thus, we think it more likely that ORF6 inhibits nuclear export via preventing RNA accessing the pore, as suggested in a recent publication of the structure of ORF6 interacting with the Rae1-Nup98 complex [ 31 ].…”

Section: Discussionmentioning

confidence: 93%

SARS-CoV-2 ORF6 disrupts innate immune signalling by inhibiting cellular mRNA export

et al. 2022

View full text Add to dashboard Cite

SARS-CoV-2 is a betacoronavirus and the etiological agent of COVID-19, a devastating infectious disease. Due to its far-reaching effect on human health, there is an urgent and growing need to understand the viral molecular biology of SARS-CoV-2 and its interaction with the host cell. SARS-CoV-2 encodes 9 predicted accessory proteins, which are presumed to be dispensable for in vitro replication, most likely having a role in modulating the host cell environment to aid viral replication. Here we show that the ORF6 accessory protein interacts with cellular Rae1 to inhibit cellular protein production by blocking mRNA export. We utilised cell fractionation coupled with mRNAseq to explore which cellular mRNA species are affected by ORF6 expression and show that ORF6 can inhibit the export of many mRNA including those encoding antiviral factors such as IRF1 and RIG-I. We also show that export of these mRNA is blocked in the context of SARS-CoV-2 infection. Together, our studies identify a novel mechanism by which SARS-CoV-2 can manipulate the host cell environment to supress antiviral responses, providing further understanding to the replication strategies of a virus that has caused an unprecedented global health crisis.

show abstract

“…2e , right). During our manuscript in revision, another group published the crystal structures of ORF6 CTT-Rae1-Nup98 complex from SARS-CoV-2 and SARS-CoV 24 . Comparing our crystal structures with theirs revealed similar features, including the specific interaction between ORF6 M58 and the M-cavity in Rae1-Nup98.…”

Section: Resultsmentioning

confidence: 99%

Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport

et al. 2022

View full text Add to dashboard Cite

The emergence of heavily mutated SARS-CoV-2 variants of concern (VOCs) place the international community on high alert. In addition to numerous mutations that map in the spike protein of VOCs, expression of the viral accessory proteins ORF6 and ORF9b also elevate; both are potent interferon antagonists. Here, we present the crystal structures of Rae1-Nup98 in complex with the C-terminal tails (CTT) of SARS-CoV-2 and SARS-CoV ORF6 to 2.85 Å and 2.39 Å resolution, respectively. An invariant methionine (M) 58 residue of ORF6 CTT extends its side chain into a hydrophobic cavity in the Rae1 mRNA binding groove, resembling a bolt-fitting-hole; acidic residues flanking M58 form salt-bridges with Rae1. Our mutagenesis studies identify key residues of ORF6 important for its interaction with Rae1-Nup98 in vitro and in cells, of which M58 is irreplaceable. Furthermore, we show that ORF6-mediated blockade of mRNA and STAT1 nucleocytoplasmic transport correlate with the binding affinity between ORF6 and Rae1-Nup98. Finally, binding of ORF6 to Rae1-Nup98 is linked to ORF6-induced interferon antagonism. Taken together, this study reveals the molecular basis for the antagonistic function of Sarbecovirus ORF6, and implies a strategy of using ORF6 CTT-derived peptides for immunosuppressive drug development.

show abstract

Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1–Nup98 Complex to Compete With mRNA Nuclear Export

Cited by 34 publications

References 41 publications

Roles and functions of SARS-CoV-2 proteins in host immune evasion

Roles and functions of SARS-CoV-2 proteins in host immune evasion

SARS-CoV-2 ORF6 disrupts innate immune signalling by inhibiting cellular mRNA export

Structural basis for Sarbecovirus ORF6 mediated blockage of nucleocytoplasmic transport

Contact Info

Product

Resources

About