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      The ubiquitin‐proteasome system in positive‐strand RNA virus infection

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          SUMMARY

          Positive‐stranded RNA viruses, like many other viruses, have evolved to exploit the host cellular machinery to their own advantage. In eukaryotic cells, the ubiquitin‐proteasome system (UPS) that serves as the major intracellular pathway for protein degradation and modification plays a crucial role in the regulation of many fundamental cellular functions. A growing amount of evidence has suggested that the UPS can be utilized by positive‐sense RNA viruses. The UPS eliminates excess viral proteins that prevent viral replication and modulates the function of viral proteins through post‐translational modification mediated by ubiquitin or ubiquitin‐like proteins. This review will discuss the current understanding of how positive RNA viruses have evolved various mechanisms to usurp the host UPS to modulate the function and stability of viral proteins. In addition to the pro‐viral function, UPS‐mediated viral protein degradation may also constitute a host defense process against some positive‐stranded RNA viral infections. This issue will also be discussed in the current review. Copyright © 2012 John Wiley & Sons, Ltd.

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          Mechanism and function of deubiquitinating enzymes.

          Attachment of ubiquitin to proteins is a crucial step in many cellular regulatory mechanisms and contributes to numerous biological processes, including embryonic development, the cell cycle, growth control, and prevention of neurodegeneration. In these diverse regulatory settings, the most widespread mechanism of ubiquitin action is probably in the context of protein degradation. Polyubiquitin attachment targets many intracellular proteins for degradation by the proteasome, and (mono)ubiquitination is often required for down-regulating plasma membrane proteins by targeting them to the vacuole (lysosome). Ubiquitin-protein conjugates are highly dynamic structures. While an array of enzymes directs the conjugation of ubiquitin to substrates, there are also dozens of deubiquitinating enzymes (DUBs) that can reverse the process. Several lines of evidence indicate that DUBs are important regulators of the ubiquitin system. These enzymes are responsible for processing inactive ubiquitin precursors, proofreading ubiquitin-protein conjugates, removing ubiquitin from cellular adducts, and keeping the 26S proteasome free of inhibitory ubiquitin chains. The present review focuses on recent discoveries that have led to a better understanding the mechanisms and physiological roles of this diverse and still poorly understood group of enzymes. We also discuss briefly some of the proteases that act on ubiquitin-like protein (UBL) conjugates and compare them to DUBs.
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            Ubiquitin and ubiquitin-like proteins as multifunctional signals.

            Protein ubiquitylation is a recognized signal for protein degradation. However, it is increasingly realized that ubiquitin conjugation to proteins can be used for many other purposes. Furthermore, there are many ubiquitin-like proteins that control the activities of proteins. The central structural element of these post-translational modifications is the ubiquitin superfold. A common ancestor based on this superfold has evolved to give various proteins that are involved in diverse activities in the cell.
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              In vivo half-life of a protein is a function of its amino-terminal residue.

              When a chimeric gene encoding a ubiquitin-beta-galactosidase fusion protein is expressed in the yeast Saccharomyces cerevisiae, ubiquitin is cleaved off the nascent fusion protein, yielding a deubiquitinated beta-galactosidase (beta gal). With one exception, this cleavage takes place regardless of the nature of the amino acid residue of beta gal at the ubiquitin-beta gal junction, thereby making it possible to expose different residues at the amino-termini of the otherwise identical beta gal proteins. The beta gal proteins thus designed have strikingly different half-lives in vivo, from more than 20 hours to less than 3 minutes, depending on the nature of the amino acid at the amino-terminus of beta gal. The set of individual amino acids can thus be ordered with respect to the half-lives that they confer on beta gal when present at its amino-terminus (the "N-end rule"). The currently known amino-terminal residues in long-lived, noncompartmentalized intracellular proteins from both prokaryotes and eukaryotes belong exclusively to the stabilizing class as predicted by the N-end rule. The function of the previously described posttranslational addition of single amino acids to protein amino-termini may also be accounted for by the N-end rule. Thus the recognition of an amino-terminal residue in a protein may mediate both the metabolic stability of the protein and the potential for regulation of its stability.
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                Author and article information

                Journal
                Rev Med Virol
                Rev. Med. Virol
                10.1002/(ISSN)1099-1654
                RMV
                Reviews in Medical Virology
                John Wiley and Sons Inc. (Hoboken )
                1052-9276
                1099-1654
                11 July 2012
                March 2013
                : 23
                : 2 ( doiID: 10.1002/rmv.v23.2 )
                : 85-96
                Affiliations
                [ 1 ] UBC James Hogg Research Centre, Institute for Heart + Lung Health, St. Paul's Hospital, Department of Pathology and Laboratory Medicine University of British Columbia Vancouver BC Canada
                Author notes
                [*] [* ] Corresponding author: Honglin Luo, MD, UBC James Hogg Research Centre, Institute for Heart + Lung Health, University of British Columbia – St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6.

                E‐mail: honglin.luo@ 123456hli.ubc.ca

                Article
                RMV1725
                10.1002/rmv.1725
                7169083
                22782620
                834f3641-e1b5-4f8e-b47b-59a1b45edaf2
                Copyright © 2012 John Wiley & Sons, Ltd.

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                : 23 January 2012
                : 29 May 2012
                : 18 June 2012
                Page count
                Pages: 12
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                March 2013
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020

                Microbiology & Virology
                Microbiology & Virology

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