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      Viral Reorganization of the Secretory Pathway Generates Distinct Organelles for RNA Replication

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          Summary

          Many RNA viruses remodel intracellular membranes to generate specialized sites for RNA replication. How membranes are remodeled and what properties make them conducive for replication are unknown. Here we show how RNA viruses can manipulate multiple components of the cellular secretory pathway to generate organelles specialized for replication that are distinct in protein and lipid composition from the host cell. Specific viral proteins modulate effector recruitment by Arf1 GTPase and its guanine nucleotide exchange factor GBF1, promoting preferential recruitment of phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) to membranes over coat proteins, yielding uncoated phosphatidylinositol-4-phosphate (PI4P) lipid-enriched organelles. The PI4P-rich lipid microenvironment is essential for both enteroviral and flaviviral RNA replication; PI4KIIIβ inhibition interferes with this process; and enteroviral RNA polymerases specifically bind PI4P. These findings reveal how RNA viruses can selectively exploit specific elements of the host to form specialized organelles where cellular phosphoinositide lipids are key to regulating viral RNA replication.

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          ► RNA viruses generate specialized RNA replication organelles enriched in PI4P lipids ► Host PI4KIIIβ enzyme is co-opted by the virus to generate PI4P lipid-rich organelles ► Enteroviral RNA polymerases specifically and preferentially bind PI4P lipids ► PI4P microenvironment is essential for enteroviral and flaviviral RNA synthesis

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          Most cited references 48

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          The lipid droplet is an important organelle for hepatitis C virus production.

          The lipid droplet (LD) is an organelle that is used for the storage of neutral lipids. It dynamically moves through the cytoplasm, interacting with other organelles, including the endoplasmic reticulum (ER). These interactions are thought to facilitate the transport of lipids and proteins to other organelles. The hepatitis C virus (HCV) is a causative agent of chronic liver diseases. HCV capsid protein (Core) associates with the LD, envelope proteins E1 and E2 reside in the ER lumen, and the viral replicase is assumed to localize on ER-derived membranes. How and where HCV particles are assembled, however, is poorly understood. Here, we show that the LD is involved in the production of infectious virus particles. We demonstrate that Core recruits nonstructural (NS) proteins and replication complexes to LD-associated membranes, and that this recruitment is critical for producing infectious viruses. Furthermore, virus particles were observed in close proximity to LDs, indicating that some steps of virus assembly take place around LDs. This study reveals a novel function of LDs in the assembly of infectious HCV and provides a new perspective on how viruses usurp cellular functions.
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            Membrane recognition by phospholipid-binding domains.

             J M Lemmon (2008)
            Many different globular domains bind to the surfaces of cellular membranes, or to specific phospholipid components in these membranes, and this binding is often tightly regulated. Examples include pleckstrin homology and C2 domains, which are among the largest domain families in the human proteome. Crystal structures, binding studies and analyses of subcellular localization have provided much insight into how members of this diverse group of domains bind to membranes, what features they recognize and how binding is controlled. A full appreciation of these processes is crucial for understanding how protein localization and membrane topography and trafficking are regulated in cells.
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              Modification of intracellular membrane structures for virus replication

              Key Points Plus-stranded RNA viruses induce large membrane structures that might support the replication of their genomes. Similarly, cytoplasmic replication of poxviruses (large DNA viruses) occurs in associated membranes. These membranes originate from the endoplasmic reticulum (ER) or endosomes. Membrane vesicles that support viral replication are induced by a number of RNA viruses. Similarly, the poxvirus replication site is surrounded by a double-membraned cisterna that is derived from the ER. Analogies to autophagy have been proposed since the finding that autophagy cellular processes involve the formation of double-membrane vesicles. However, molecular evidence to support this hypothesis is lacking. Membrane association of the viral replication complex is mediated by the presence of one or more viral proteins that contain sequences which associate with, or integrate into, membranes. Replication-competent membranes might contain viral or cellular proteins that contain amphipathic helices, which could mediate the membrane bending that is required to form spherical vesicles. Whereas poxvirus DNA replication occurs inside the ER-enclosed site, for most RNA viruses the topology of replication is not clear. Preliminary results for some RNA viruses suggest that their replication could also occur inside double-membrane vesicles. We speculate that cytoplasmic replication might occur inside sites that are 'enwrapped' by an ER-derived cisterna, and that these cisternae are open to the cytoplasm. Thus, RNA and DNA viruses could use a common mechanism for replication that involves membrane wrapping by cellular cisternal membranes. We propose that three-dimensional analyses using high-resolution electron-microscopy techniques could be useful for addressing this issue. High-throughput small-interfering-RNA screens should also shed light on molecular requirements for virus-induced membrane modifications.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Elsevier Inc.
                0092-8674
                1097-4172
                27 May 2010
                28 May 2010
                27 May 2010
                : 141
                : 5
                : 799-811
                Affiliations
                [1 ]Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA
                [2 ]Laboratory of Infectious Diseases, NIAID, National Institutes of Health, Bethesda, MD 20892, USA
                [3 ]Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, PO Box 9101 6500 HB Nijmegen, The Netherlands
                [4 ]Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of Newark, Newark, NJ 07101, USA
                [5 ]Section on Molecular Signal Transduction, NICHD, National Institutes of Health, Bethesda, MD 20892, USA
                [6 ]Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, PA 16803, USA
                Author notes
                []Corresponding author nabonnet@ 123456andromeda.rutgers.edu
                [7]

                These authors contributed equally to this work

                Article
                S0092-8674(10)00369-7
                10.1016/j.cell.2010.03.050
                2982146
                20510927
                Copyright © 2010 Elsevier Inc. All rights reserved.

                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.

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                Cell biology

                cellbio, microbio

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