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      Regulation of positive-strand RNA virus replication: The emerging role of phosphorylation

      review-article
      1 , *
      Virus Research
      Elsevier B.V.
      Positive-strand RNA virus, Replication, Phosphorylation, Regulation

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          Abstract

          Protein phosphorylation is a reversible post-translational modification that plays a fundamental role in the regulation of many cellular processes. Phosphorylation can modulate protein properties such as enzymatic activity, stability, subcellular localization or interaction with binding partners. The importance of phosphorylation of the replication proteins of negative-strand RNA viruses has previously been documented but recent evidence suggests that replication of positive-strand RNA viruses – the largest class of viruses, including significant human, animal and plant pathogens – may also be regulated by phosphorylation events. The objective of this review is to summarize current knowledge regarding the various regulatory roles played by phosphorylation of nonstructural viral proteins in the replication of positive-strand RNA viruses.

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          Most cited references52

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          PEST sequences and regulation by proteolysis.

          In 1986, we proposed that polypeptide sequences enriched in proline (P), glutamic acid (E), serine (S) and threonine (T) target proteins for rapid destruction. For much of the past decade there were only sporadic experimental tests of the hypothesis. This situation changed markedly during the past two years with a number of papers providing strong evidence that PEST regions do, in fact, serve as proteolytic signals. Here, we briefly review the properties of PEST regions and some interesting examples of the conditional nature of such signals. Most of the article, however, focuses on recent experimental support for the hypothesis and on mechanisms responsible for the rapid degradation of proteins that contain PEST regions.
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            Efficient initiation of HCV RNA replication in cell culture.

            Hepatitis C virus (HCV) infection is a global health problem affecting an estimated 170 million individuals worldwide. We report the identification of multiple independent adaptive mutations that cluster in the HCV nonstructural protein NS5A and confer increased replicative ability in vitro. Among these adaptive mutations were a single amino acid substitution that allowed HCV RNA replication in 10% of transfected hepatoma cells and a deletion of 47 amino acids encompassing the interferon (IFN) sensitivity determining region (ISDR). Independent of the ISDR, IFN-alpha rapidly inhibited HCV RNA replication in vitro. This work establishes a robust, cell-based system for genetic and functional analyses of HCV replication.
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              Identification of four conserved motifs among the RNA-dependent polymerase encoding elements.

              Four consensus sequences are conserved with the same linear arrangement in RNA-dependent DNA polymerases encoded by retroid elements and in RNA-dependent RNA polymerases encoded by plus-, minus- and double-strand RNA viruses. One of these motifs corresponds to the YGDD span previously described by Kamer and Argos (1984). These consensus sequences altogether lead to 4 strictly and 18 conservatively maintained amino acids embedded in a large domain of 120 to 210 amino acids. As judged from secondary structure predictions, each of the 4 motifs, which may cooperate to form a well-ordered domain, places one invariant amino acid in or proximal to turn structures that may be crucial for their correct positioning in a catalytic process. We suggest that this domain may constitute a prerequisite 'polymerase module' implicated in template seating and polymerase activity. At the evolutionary level, the sequence similarities, gap distribution and distances between each motif strongly suggest that the ancestral polymerase module was encoded by an individual genetic element which was most closely related to the plus-strand RNA viruses and the non-viral retroposons. This polymerase module gene may have subsequently propagated in the viral kingdom by distinct gene set recombination events leading to the wide viral variety observed today.
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                Author and article information

                Contributors
                Journal
                Virus Res
                Virus Res
                Virus Research
                Elsevier B.V.
                0168-1702
                1872-7492
                30 August 2007
                November 2007
                30 August 2007
                : 129
                : 2
                : 73-79
                Affiliations
                Laboratoire de Virologie Moléculaire, Institut Jacques Monod, UMR 7592, CNRS-Universités Paris 6-Paris 7, 2 Place Jussieu, 75251 Paris Cedex 05, France
                Author notes
                [* ]Corresponding author. Tel.: +33 1 44 27 40 99; fax: +33 1 44 27 57 16. jupin@ 123456ijm.jussieu.fr
                [1]

                Present address: The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

                Article
                S0168-1702(07)00275-4
                10.1016/j.virusres.2007.07.012
                7132427
                17764774
                549470be-74b8-4be6-93a2-54781c871ca4
                Copyright © 2007 Elsevier B.V. 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.

                History
                : 27 June 2007
                : 20 July 2007
                : 20 July 2007
                Categories
                Article

                Microbiology & Virology
                positive-strand rna virus,replication,phosphorylation,regulation
                Microbiology & Virology
                positive-strand rna virus, replication, phosphorylation, regulation

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