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      Venezuelan equine encephalitis virus non-structural protein 3 (nsP3) interacts with RNA helicases DDX1 and DDX3 in infected cells

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          Abstract

          The mosquito-borne New World alphavirus, Venezuelan equine encephalitis virus (VEEV) is a Category B select agent with no approved vaccines or therapies to treat infected humans. Therefore it is imperative to identify novel targets that can be targeted for effective therapeutic intervention. We aimed to identify and validate interactions of VEEV nonstructural protein 3 (nsP3) with host proteins and determine the consequences of these interactions to viral multiplication. We used a HA tagged nsP3 infectious clone (rTC-83-nsP3-HA) to identify and validate two RNA helicases: DDX1 and DDX3 that interacted with VEEV-nsP3. In addition, DDX1 and DDX3 knockdown resulted in a decrease in infectious viral titers. Furthermore, we propose a functional model where the nsP3:DDX3 complex interacts with the host translational machinery and is essential in the viral life cycle. This study will lead to future investigations in understanding the importance of VEEV-nsP3 to viral multiplication and apply the information for the discovery of novel host targets as therapeutic options.

          Highlights

          • •

            VEEV nsP3 interacted with the host helicases DDX1 and DDX3 in infected cells.

          • •

            Depletion of DDX1 or DDX3 negatively impacted viral multiplication and decreased infectious viral titers.

          • •

            nsP3 may interact with the host translational machinery through DDX3.

          • •

            The small molecule DDX3 inhibitor RK33 negatively impacted VEEV multiplication.

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          Stress granules: the Tao of RNA triage.

          Paul. Anderson, Nancy Kedersha (2008)
          Cytoplasmic RNA structures such as stress granules (SGs) and processing bodies (PBs) are functional byproducts of mRNA metabolism, sharing substrate mRNA, dynamic properties and many proteins, but also housing separate components and performing independent functions. Each can exist independently, but when coordinately induced they are often tethered together in a cytosolic dance. Although both self-assemble in response to stress-induced perturbations in translation, several recent reports reveal novel proteins and RNAs that are components of these structures but also perform other cellular functions. Proteins that mediate splicing, transcription, adhesion, signaling and development are all integrated with SG and PB assembly. Thus, these ephemeral bodies represent more than just the dynamic sorting of mRNA between translation and decay.
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            A structural and functional perspective of alphavirus replication and assembly.

            William Kuhn, Joyce Jose, Robert Snyder (2009)
            Alphaviruses are small, spherical, enveloped, positive-sense ssRNA viruses responsible for a considerable number of human and animal diseases. Alphavirus members include Chikungunya virus, Sindbis virus, Semliki Forest virus, the western, eastern and Venezuelan equine encephalitis viruses, and the Ross River virus. Alphaviruses can cause arthritic diseases and encephalitis in humans and animals and continue to be a worldwide threat. The viruses are transmitted by blood-sucking arthropods, and replicate in both arthropod and vertebrate hosts. Alphaviruses form spherical particles (65-70 nm in diameter) with icosahedral symmetry and a triangulation number of four. The icosahedral structures of alphaviruses have been defined to very high resolutions by cryo-electron microscopy and crystallographic studies. In this review, we summarize the major events in alphavirus infection: entry, replication, assembly and budding. We focus on data acquired from structural and functional studies of the alphaviruses. These structural and functional data provide a broader perspective of the virus lifecycle and structure, and allow additional insight into these important viruses.
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              Nucleocapsid Phosphorylation and RNA Helicase DDX1 Recruitment Enables Coronavirus Transition from Discontinuous to Continuous Transcription

              Chia-Hsin Wu, Pei-Jer Chen, Shiou-Hwei Yeh (2014)
              Summary Coronaviruses contain a positive-sense single-stranded genomic (g) RNA, which encodes nonstructural proteins. Several subgenomic mRNAs (sgmRNAs) encoding structural proteins are generated by template switching from the body transcription regulatory sequence (TRS) to the leader TRS. The process preferentially generates shorter sgmRNA. Appropriate readthrough of body TRSs is required to produce longer sgmRNAs and full-length gRNA. We find that phosphorylation of the viral nucleocapsid (N) by host glycogen synthase kinase-3 (GSK-3) is required for template switching. GSK-3 inhibition selectively reduces the generation of gRNA and longer sgmRNAs, but not shorter sgmRNAs. N phosphorylation allows recruitment of the RNA helicase DDX1 to the phosphorylated-N-containing complex, which facilitates template readthrough and enables longer sgmRNA synthesis. DDX1 knockdown or loss of helicase activity markedly reduces the levels of longer sgmRNAs. Thus, coronaviruses employ a unique strategy for the transition from discontinuous to continuous transcription to ensure balanced sgmRNAs and full-length gRNA synthesis.
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                Author and article information

                Contributors
                Aarthi Narayanan
                Journal
                Journal ID (nlm-ta): Antiviral Res
                Journal ID (iso-abbrev): Antiviral Res
                Title: Antiviral Research
                Publisher: Elsevier B.V.
                ISSN (Print): 0166-3542
                ISSN (Electronic): 1872-9096
                Publication date PMC-release: 20 April 2016
                Publication date (Print): July 2016
                Publication date (Electronic): 20 April 2016
                Volume: 131
                Pages: 49-60
                Affiliations
                [a ]National Center for Biodefense and Infectious Diseases, George Mason University, Manassas, VA, United States
                [b ]Johns Hopkins University, Departments of Radiology and Oncology, Maryland, United States
                Author notes
                [∗ ]Corresponding author. anaraya1@ 123456gmu.edu
                Article
                Publisher ID: S0166-3542(16)30140-1
                DOI: 10.1016/j.antiviral.2016.04.008
                PMC ID: 7113772
                PubMed ID: 27105836
                SO-VID: 4ac6d8b6-2bf3-4d44-a097-c072d0665ee1
                Copyright © © 2016 Elsevier B.V. All rights reserved.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 8 March 2016
                Date revision received : 12 April 2016
                Date accepted : 13 April 2016
                Categories
                Subject: Article

                ScienceOpen disciplines: Infectious disease & Microbiology
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology

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