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      Role of host reticulon proteins in rearranging membranes for positive-strand RNA virus replication

      review-article
      1 , * , 1 , 2 , 3
      Current Opinion in Microbiology
      Elsevier Ltd.

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          Highlights

          ► The reticulon family is involved in shaping and bending the endoplasmic reticulum. ► Reticulons interact with proteins of several positive-strand RNA viruses. ► Reticulons are involved in forming the replication compartments of brome mosaic virus. ► We hypothesize on the role of reticulons in forming the replication compartments of other RNA viruses.

          Abstract

          Positive-strand RNA [(+)RNA] viruses are responsible for numerous human, animal, and plant diseases. Because of the limiting coding capacity of (+)RNA viruses, their replication requires a complex orchestration of interactions between the viral genome, viral proteins and exploited host factors. To replicate their genomic RNAs, (+)RNA viruses induce membrane rearrangements that create membrane-linked RNA replication compartments. Along with substantial advances on the ultrastructure of the membrane-bound RNA replication compartments, recent results have shed light into the role that host factors play in rearranging these membranes. This review focuses on recent insights that have driven a new understanding of the role that the membrane-shaping host reticulon homology domain proteins (RHPs) play in facilitating the replication of various (+)RNA viruses.

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          Most cited references38

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          Composition and Three-Dimensional Architecture of the Dengue Virus Replication and Assembly Sites

          Summary Positive-strand RNA viruses are known to rearrange cellular membranes to facilitate viral genome replication. The biogenesis and three-dimensional organization of these membranes and the link between replication and virus assembly sites is not fully clear. Using electron microscopy, we find Dengue virus (DENV)-induced vesicles, convoluted membranes, and virus particles to be endoplasmic reticulum (ER)-derived, and we detect double-stranded RNA, a presumed marker of RNA replication, inside virus-induced vesicles. Electron tomography (ET) shows DENV-induced membrane structures to be part of one ER-derived network. Furthermore, ET reveals vesicle pores that could enable release of newly synthesized viral RNA and reveals budding of DENV particles on ER membranes directly apposed to vesicle pores. Thus, DENV modifies ER membrane structure to promote replication and efficient encapsidation of the genome into progeny virus. This architecture of DENV replication and assembly sites could explain the coordination of distinct steps of the flavivirus replication cycle.
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            A class of membrane proteins shaping the tubular endoplasmic reticulum.

            How is the characteristic shape of a membrane bound organelle achieved? We have used an in vitro system to address the mechanism by which the tubular network of the endoplasmic reticulum (ER) is generated and maintained. Based on the inhibitory effect of sulfhydryl reagents and antibodies, network formation in vitro requires the integral membrane protein Rtn4a/NogoA, a member of the ubiquitous reticulon family. Both in yeast and mammalian cells, the reticulons are largely restricted to the tubular ER and are excluded from the continuous sheets of the nuclear envelope and peripheral ER. Upon overexpression, the reticulons form tubular membrane structures. The reticulons interact with DP1/Yop1p, a conserved integral membrane protein that also localizes to the tubular ER. These proteins share an unusual hairpin topology in the membrane. The simultaneous absence of the reticulons and Yop1p in S. cerevisiae results in disrupted tubular ER. We propose that these "morphogenic" proteins partition into and stabilize highly curved ER membrane tubules.
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              Mechanisms determining the morphology of the peripheral ER.

              The endoplasmic reticulum (ER) consists of the nuclear envelope and a peripheral network of tubules and membrane sheets. The tubules are shaped by the curvature-stabilizing proteins reticulons and DP1/Yop1p, but how the sheets are formed is unclear. Here, we identify several sheet-enriched membrane proteins in the mammalian ER, including proteins that translocate and modify newly synthesized polypeptides, as well as coiled-coil membrane proteins that are highly upregulated in cells with proliferated ER sheets, all of which are localized by membrane-bound polysomes. These results indicate that sheets and tubules correspond to rough and smooth ER, respectively. One of the coiled-coil proteins, Climp63, serves as a "luminal ER spacer" and forms sheets when overexpressed. More universally, however, sheet formation appears to involve the reticulons and DP1/Yop1p, which localize to sheet edges and whose abundance determines the ratio of sheets to tubules. These proteins may generate sheets by stabilizing the high curvature of edges. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Curr Opin Microbiol
                Curr. Opin. Microbiol
                Current Opinion in Microbiology
                Elsevier Ltd.
                1369-5274
                1879-0364
                21 May 2012
                August 2012
                21 May 2012
                : 15
                : 4
                : 519-524
                Affiliations
                [1 ]Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706, United States
                [2 ]Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53706, United States
                [3 ]Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI 53706, United States
                Author notes
                [*]

                Present address: Immunobiology and Microbial Pathogenesis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, United States.

                Article
                S1369-5274(12)00050-1
                10.1016/j.mib.2012.04.007
                3670673
                22621853
                c437e5a1-de25-4bf9-b7b5-6fb924667065
                Copyright © 2012 Elsevier Ltd. 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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                Microbiology & Virology
                Microbiology & Virology

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