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      Strategies for Success. Viral Infections and Membraneless Organelles


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          Regulation of RNA homeostasis or “RNAstasis” is a central step in eukaryotic gene expression. From transcription to decay, cellular messenger RNAs (mRNAs) associate with specific proteins in order to regulate their entire cycle, including mRNA localization, translation and degradation, among others. The best characterized of such RNA-protein complexes, today named membraneless organelles, are Stress Granules (SGs) and Processing Bodies (PBs) which are involved in RNA storage and RNA decay/storage, respectively. Given that SGs and PBs are generally associated with repression of gene expression, viruses have evolved different mechanisms to counteract their assembly or to use them in their favor to successfully replicate within the host environment. In this review we summarize the current knowledge about the viral regulation of SGs and PBs, which could be a potential novel target for the development of broad-spectrum antiviral therapies.

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          Distinct stages in stress granule assembly and disassembly

          Stress granules are non-membrane bound RNA-protein (RNP) assemblies that form when translation initiation is limited and contain a biphasic structure with stable core structures surrounded by a less concentrated shell. The order of assembly and disassembly of these two structures remains unknown. Time course analysis of granule assembly suggests that core formation is an early event in granule assembly. Stress granule disassembly is also a stepwise process with shell dissipation followed by core clearance. Perturbations that alter liquid-liquid phase separations (LLPS) driven by intrinsically disordered protein regions (IDR) of RNA binding proteins in vitro have the opposite effect on stress granule assembly in vivo. Taken together, these observations argue that stress granules assemble through a multistep process initiated by stable assembly of untranslated mRNPs into core structures, which could provide sufficient high local concentrations to allow for a localized LLPS driven by IDRs on RNA binding proteins. DOI: http://dx.doi.org/10.7554/eLife.18413.001
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            Altered ribostasis: RNA-protein granules in degenerative disorders.

            The molecular processes that contribute to degenerative diseases are not well understood. Recent observations suggest that some degenerative diseases are promoted by the accumulation of nuclear or cytoplasmic RNA-protein (RNP) aggregates, which can be related to endogenous RNP granules. RNP aggregates arise commonly in degenerative diseases because RNA-binding proteins commonly self-assemble, in part through prion-like domains, which can form self-propagating amyloids. RNP aggregates may be toxic due to multiple perturbations of posttranscriptional control, thereby disrupting the normal "ribostasis" of the cell. This suggests that understanding and modulating RNP assembly or clearance may be effective approaches to developing therapies for these diseases. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells.

              The severe acute respiratory syndrome coronavirus (SARS-CoV) nsp1 protein has unique biological functions that have not been described in the viral proteins of any RNA viruses; expressed SARS-CoV nsp1 protein has been found to suppress host gene expression by promoting host mRNA degradation and inhibiting translation. We generated an nsp1 mutant (nsp1-mt) that neither promoted host mRNA degradation nor suppressed host protein synthesis in expressing cells. Both a SARS-CoV mutant virus, encoding the nsp1-mt protein (SARS-CoV-mt), and a wild-type virus (SARS-CoV-WT) replicated efficiently and exhibited similar one-step growth kinetics in susceptible cells. Both viruses accumulated similar amounts of virus-specific mRNAs and nsp1 protein in infected cells, whereas the amounts of endogenous host mRNAs were clearly higher in SARS-CoV-mt-infected cells than in SARS-CoV-WT-infected cells, in both the presence and absence of actinomycin D. Further, SARS-CoV-WT replication strongly inhibited host protein synthesis, whereas host protein synthesis inhibition in SARS-CoV-mt-infected cells was not as efficient as in SARS-CoV-WT-infected cells. These data revealed that nsp1 indeed promoted host mRNA degradation and contributed to host protein translation inhibition in infected cells. Notably, SARS-CoV-mt infection, but not SARS-CoV-WT infection, induced high levels of beta interferon (IFN) mRNA accumulation and high titers of type I IFN production. These data demonstrated that SARS-CoV nsp1 suppressed host innate immune functions, including type I IFN expression, in infected cells and suggested that SARS-CoV nsp1 most probably plays a critical role in SARS-CoV virulence.

                Author and article information

                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                11 October 2019
                : 9
                : 336
                [1] 1Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile , Santiago, Chile
                [2] 2HIV/AIDS Workgroup, Faculty of Medicine, Universidad de Chile , Santiago, Chile
                [3] 3Emerging Viruses Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile , Santiago, Chile
                Author notes

                Edited by: Siew Pheng Lim, Denka Life Innovation Research (DLIR), Singapore

                Reviewed by: Mitsutoshi Yoneyama, Chiba University, Japan; Paulina Niedzwiedzka-Rystwej, University of Szczecin, Poland; Graciela Lidia Boccaccio, Leloir Institute Foundation (FIL), Argentina

                *Correspondence: Fernando Valiente-Echeverría fvaliente@ 123456uchile.cl

                This article was submitted to Virus and Host, a section of the journal Frontiers in Cellular and Infection Microbiology

                †These authors have contributed equally to this work

                Copyright © 2019 Gaete-Argel, Márquez, Barriga, Soto-Rifo and Valiente-Echeverría.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 28 May 2019
                : 18 September 2019
                Page count
                Figures: 1, Tables: 3, Equations: 0, References: 277, Pages: 28, Words: 24341
                Funded by: Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación Tecnológica 10.13039/501100010751
                Award ID: 1180798
                Cellular and Infection Microbiology

                Infectious disease & Microbiology
                rnastasis,rna granules,membraneless organelles,stress granules,p-bodies,anti-viral host immune response


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