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      Zika Virus Subverts Stress Granules To Promote and Restrict Viral Gene Expression

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          Abstract

          Many viruses inhibit SGs. In this study, we observed that ZIKV restricts SG assembly, likely by relocalizing and subverting specific SG proteins to modulate ZIKV replication. This ZIKV-SG protein interaction is interesting, as many SG proteins are also known to function in neuronal granules, which are critical in neural development and function. Moreover, dysregulation of different SG proteins in neurons has been shown to play a role in the progression of neurodegenerative diseases. The likely consequences of ZIKV modulating SG assembly and subverting specific SG proteins are alterations to cellular mRNA transcription, splicing, stability, and translation. Such changes in cellular ribostasis could profoundly affect neural development and contribute to the devastating developmental and neurological anomalies observed following intrauterine ZIKV infection. Our study provides new insights into virus-host interactions and the identification of the SG proteins that may contribute to the unusual pathogenesis associated with this reemerging arbovirus.

          ABSTRACT

          Flaviviruses limit the cell stress response by preventing the formation of stress granules (SGs) and modulate viral gene expression by subverting different proteins involved in the stress granule pathway. In this study, we investigated the formation of stress granules during Zika virus (ZIKV) infection and the role stress granule proteins play during the viral life cycle. Using immunofluorescence and confocal microscopy, we determined that ZIKV disrupted the formation of arsenite-induced stress granules and changed the subcellular distribution, but not the abundance or integrity, of stress granule proteins. We also investigated the role of different stress granule proteins in ZIKV infection by using target-specific short interfering RNAs to deplete Ataxin2, G3BP1, HuR, TIA-1, TIAR, and YB1. Knockdown of TIA-1 and TIAR affected ZIKV protein and RNA levels but not viral titers. Conversely, depletion of Ataxin2 and YB1 decreased virion production despite having only a small effect on ZIKV protein expression. Notably, however, depletion of G3BP1 and HuR decreased and increased ZIKV gene expression and virion production, respectively. Using an MR766 Gaussia Luciferase reporter genome together with knockdown and overexpression assays, G3BP1 and HuR were found to modulate ZIKV replication. These data indicate that ZIKV disrupts the formation of stress granules by sequestering stress granule proteins required for replication, where G3BP1 functions to promote ZIKV infection while HuR exhibits an antiviral effect. The results of ZIKV relocalizing and subverting select stress granule proteins might have broader consequences on cellular RNA homeostasis and contribute to cellular gene dysregulation and ZIKV pathogenesis.

          IMPORTANCE Many viruses inhibit SGs. In this study, we observed that ZIKV restricts SG assembly, likely by relocalizing and subverting specific SG proteins to modulate ZIKV replication. This ZIKV-SG protein interaction is interesting, as many SG proteins are also known to function in neuronal granules, which are critical in neural development and function. Moreover, dysregulation of different SG proteins in neurons has been shown to play a role in the progression of neurodegenerative diseases. The likely consequences of ZIKV modulating SG assembly and subverting specific SG proteins are alterations to cellular mRNA transcription, splicing, stability, and translation. Such changes in cellular ribostasis could profoundly affect neural development and contribute to the devastating developmental and neurological anomalies observed following intrauterine ZIKV infection. Our study provides new insights into virus-host interactions and the identification of the SG proteins that may contribute to the unusual pathogenesis associated with this reemerging arbovirus.

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          Most cited references34

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          Stress granules: the Tao of RNA triage.

          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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            Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013.

            Zika fever, considered as an emerging disease of arboviral origin, because of its expanding geographic area, is known as a benign infection usually presenting as an influenza-like illness with cutaneous rash. So far, Zika virus infection has never led to hospitalisation. We describe the first case of Guillain-Barré syndrome (GBS) occurring immediately after a Zika virus infection, during the current Zika and type 1 and 3 dengue fever co-epidemics in French Polynesia.
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              Diverse molecular functions of Hu proteins.

              Hu proteins are RNA-binding proteins involved in diverse biological processes. The neuronal members of the Hu family, HuB, HuC, and HuD play important roles in neuronal differentiation and plasticity, while the ubiquitously expressed family member, HuR, has numerous functions mostly related to cellular stress response. The pivotal roles of Hu proteins are dictated by their molecular functions affecting a large number of target genes. Hu proteins affect many post-transcriptional aspects of RNA metabolism, from splicing to translation. In this communication, we will focus on these molecular events and review our current understanding of how Hu proteins mediate them. In particular, emphasis will be put on the nuclear functions of these proteins, which were recently discovered. Three examples including calcitonin/calcitonin gene-related peptide, neurofibromatosis type 1, and Ikaros will be discussed in detail. In addition, an intriguing theme of antagonism between Hu proteins and other AU-rich sequence binding proteins will be discussed.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                J Virol
                J. Virol
                jvi
                jvi
                JVI
                Journal of Virology
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0022-538X
                1098-5514
                3 April 2019
                29 May 2019
                15 June 2019
                29 May 2019
                : 93
                : 12
                : e00520-19
                Affiliations
                [a ]Department of Biological Sciences, The RNA Institute, University at Albany-SUNY, Albany, New York, USA
                [b ]Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                Instituto de Biotecnologia/UNAM
                Author notes
                Address correspondence to Cara T. Pager, ctpager@ 123456albany.edu .

                Citation Bonenfant G, Williams N, Netzband R, Schwarz MC, Evans MJ, Pager CT. 2019. Zika virus subverts stress granules to promote and restrict viral gene expression. J Virol 93:e00520-19. https://doi.org/10.1128/JVI.00520-19.

                Article
                00520-19
                10.1128/JVI.00520-19
                6613768
                30944179
                06c3381e-168b-46f4-84e9-000bc67e0894
                Copyright © 2019 Bonenfant et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 28 March 2019
                : 28 March 2019
                Page count
                Figures: 6, Tables: 2, Equations: 0, References: 88, Pages: 22, Words: 14984
                Funding
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
                Award ID: R21 AI133617
                Award Recipient :
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
                Award ID: R21 AI133649
                Award ID: R21 AI140196
                Award Recipient :
                Funded by: HHS | NIH | National Institute of General Medical Sciences (NIGMS), https://doi.org/10.13039/100000057;
                Award ID: R01 GM123050
                Award Recipient :
                Funded by: Burroughs Wellcome Fund (BWF), https://doi.org/10.13039/100000861;
                Award Recipient :
                Categories
                Virus-Cell Interactions
                Custom metadata
                June 2019

                Microbiology & Virology
                g3bp1,hur,stress granule,zika virus
                Microbiology & Virology
                g3bp1, hur, stress granule, zika virus

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