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SARS-CoV-2 proteins

ORF6 (1)


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    SARS-CoV-2 ORF6 PROTEIN disrupts nucleocytoplasmic transport through interactions with Rae1 HGNC and Nup98

    Authors: Amin Addetia; Nicole A.P. Lieberman; Quynh Phung; Hong Xie; Pavitra Roychoudhury; Michelle A Loprieno; Meeili Huang; Lasata Shrestha; Keith R. Jerome; Alexander L. Greninger

    doi:10.1101/2020.08.03.234559 Date: 2020-08-03 Source: bioRxiv

    RNA viruses that replicate in the cytoplasm often disrupt nucleocytoplasmic transport to preferentially translate their own transcripts and prevent host antiviral responses. The Sarbecovirus accessory protein ORF6 PROTEIN has previously been shown to be the major inhibitor of interferon production in both SARS-CoV and SARS-CoV-2 MESHD. SARS-CoV-2 ORF6 PROTEIN was recently shown to co-purify with the host mRNA export factors Rae1 HGNC and Nup98 HGNC. Here, we demonstrate SARS-CoV-2 ORF6 PROTEIN strongly represses protein expression of co-transfected reporter constructs and imprisons host mRNA in the nucleus, which is associated with its ability to co-purify with Rae1 HGNC and Nup98 HGNC. These protein-protein interactions map to the C-terminus of ORF6 PROTEIN and can be abolished by a single amino acid mutation in Met58. Overexpression of Rae1 HGNC restores reporter expression in the presence of SARS-CoV-2 ORF6 PROTEIN. We further identify an ORF6 PROTEIN mutant containing a 9-amino acid deletion, ORF6 PROTEIN {Delta}22-30, in multiple SARS-CoV-2 clinical isolates that can still downregulate the expression of a co-transfected reporter and interact with Rae1 HGNC and Nup98 HGNC. SARS-CoV MESHD ORF6 PROTEIN also interacts with Rae1 HGNC and Nup98 HGNC. However, SARS-CoV-2 ORF6 PROTEIN more strongly co-purifies with Rae1 HGNC and Nup98 HGNC and results in significantly reduced expression of reporter proteins compared to SARS-CoV ORF6 MESHD ORF6 PROTEIN, a potential mechanism for the delayed symptom onset and pre-symptomatic transmission uniquely associated with the SARS-CoV-2 pandemic. ImportanceSARS-CoV-2, the causative agent of COVID-19 MESHD, is an RNA virus with a large genome that encodes accessory proteins. While these accessory proteins are not required for growth in vitro, they can contribute to the pathogenicity of the virus. One of SARS-CoV-2s accessory proteins, ORF6 PROTEIN, was recently shown to co-purify with two host proteins, Rae1 HGNC and Nup98 HGNC, involved in mRNA nuclear export. We demonstrate SARS-CoV-2 ORF6 PROTEIN interaction with these proteins is associated with reduced expression of a reporter protein and accumulation of poly-A mRNA within the nucleus. SARS-CoV ORF6 PROTEIN also shows the same interactions with Rae1 HGNC and Nup98 HGNC. However, SARS-CoV-2 ORF6 PROTEIN more strongly represses reporter expression and co-purifies with Rae1 HGNC and Nup98 HGNC compared to SARS-CoV ORF6 PROTEIN. The ability of SARS-CoV-2 ORF6 PROTEIN to more strongly disrupt nucleocytoplasmic transport than SARS-CoV ORF6 PROTEIN may partially explain critical differences in clinical presentation between the two viruses.

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MeSH Disease
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