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      SARS-CoV-2 viral protein Nsp2 stimulates translation under normal and hypoxic conditions

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          Abstract

          When viruses like SARS-CoV-2 infect cells, they reprogram the repertoire of cellular and viral transcripts that are being translated to optimize their strategy of replication, often targeting host translation initiation factors, particularly eIF4F complex consisting of eIF4E, eIF4G and eIF4A. A proteomic analysis of SARS-CoV-2/human proteins interaction revealed viral Nsp2 and initiation factor eIF4E2, but a role of Nsp2 in regulating translation is still controversial. HEK293T cells stably expressing Nsp2 were tested for protein synthesis rates of synthetic and endogenous mRNAs known to be translated via cap- or IRES-dependent mechanism under normal and hypoxic conditions. Both cap- and IRES-dependent translation were increased in Nsp2-expressing cells under normal and hypoxic conditions, especially mRNAs that require high levels of eIF4F. This could be exploited by the virus to maintain high translation rates of both viral and cellular proteins, particularly in hypoxic conditions as may arise in SARS-CoV-2 patients with poor lung functioning.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12985-023-02021-2.

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          A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug-Repurposing

          David E Gordon, Gwendolyn M Jang, Mehdi Bouhaddou … (2020)
          SUMMARY The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
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            Coronavirus biology and replication: implications for SARS-CoV-2

            Philip V’kovski, Annika Kratzel, Silvio Steiner … (2020)
            The SARS-CoV-2 pandemic and its unprecedented global societal and economic disruptive impact has marked the third zoonotic introduction of a highly pathogenic coronavirus into the human population. Although the previous coronavirus SARS-CoV and MERS-CoV epidemics raised awareness of the need for clinically available therapeutic or preventive interventions, to date, no treatments with proven efficacy are available. The development of effective intervention strategies relies on the knowledge of molecular and cellular mechanisms of coronavirus infections, which highlights the significance of studying virus–host interactions at the molecular level to identify targets for antiviral intervention and to elucidate critical viral and host determinants that are decisive for the development of severe disease. In this Review, we summarize the first discoveries that shape our current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle and relate that to our knowledge of coronavirus biology. The elucidation of similarities and differences between SARS-CoV-2 and other coronaviruses will support future preparedness and strategies to combat coronavirus infections.
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              Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China

              Aiping Wu, Yousong Peng, Baoying Huang … (2020)
              An in-depth annotation of the newly discovered coronavirus (2019-nCoV) genome has revealed differences between 2019-nCoV and severe acute respiratory syndrome (SARS) or SARS-like coronaviruses. A systematic comparison identified 380 amino acid substitutions between these coronaviruses, which may have caused functional and pathogenic divergence of 2019-nCoV.
              Article 0 comments Cited 1130 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Arrigo De Benedetti: arrigo.debenedetti@lsuhs.edu
                Journal
                Journal ID (nlm-ta): Virol J
                Journal ID (iso-abbrev): Virol J
                Title: Virology Journal
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1743-422X
                Publication date (Electronic): 30 March 2023
                Publication date PMC-release: 30 March 2023
                Publication date Collection: 2023
                Volume: 20
                Electronic Location Identifier: 55
                Affiliations
                [1 ]GRID grid.411417.6, ISNI 0000 0004 0443 6864, Department of Emergency Medicine, , Louisiana State University Health, ; Shreveport, LA 71103 USA
                [2 ]GRID grid.411417.6, ISNI 0000 0004 0443 6864, Department of Biochemistry and Molecular Biology, , Louisiana State University Health, ; Shreveport, LA 71103 USA
                Article
                Publisher ID: 2021
                DOI: 10.1186/s12985-023-02021-2
                PMC ID: 10060939
                PubMed ID: 36998012
                SO-VID: 3706b2ee-ae9b-48b8-a4ab-8cdef9ed836e
                Copyright © © The Author(s) 2023
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 20 February 2023
                Date accepted : 23 March 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100015194, Feist-Weiller Cancer Center;
                Award ID: Covid-2021
                Award ID: Covid-2021
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100014039, DOD Prostate Cancer Research Program;
                Award ID: W81XWH-17-1-0417
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2023

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: coronavirus,covid-19,eif4e2,eif4f,hypoxia,nsp2,sars-cov-2,translation
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: coronavirus, covid-19, eif4e2, eif4f, hypoxia, nsp2, sars-cov-2, translation

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