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      The ubiquitin proteasome system in Caenorhabditis elegans and its regulation

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          Abstract

          Protein degradation constitutes a major cellular function that is responsible for maintenance of the normal cellular physiology either through the degradation of normal proteins or through the elimination of damaged proteins. The Ubiquitin–Proteasome System (UPS) 1 is one of the main proteolytic systems that orchestrate protein degradation. Given that up- and down- regulation of the UPS system has been shown to occur in various normal (such as ageing) and pathological (such as neurodegenerative diseases) processes, the exogenous modulation of the UPS function and activity holds promise of (a) developing new therapeutic interventions against various diseases and (b) establishing strategies to maintain cellular homeostasis. Since the proteasome genes are evolutionarily conserved, their role can be dissected in simple model organisms, such as the nematode , Caenorhabditis elegans. In this review, we survey findings on the redox regulation of the UPS in C. elegans showing that the nematode is an instrumental tool in the identification of major players in the UPS pathway. Moreover, we specifically discuss UPS-related genes that have been modulated in the nematode and in human cells and have resulted in similar effects thus further exhibiting the value of this model in the study of the UPS.

          Graphical abstract

          Genes, pathways and compounds that have been identified to alter the UPS function in C. elegans. Molecular pathways and natural or chemical compounds along with alterations in the various components of the UPS system (e.g. proteasome subunits, E2 and E3 ligases, DUBs) that have been revealed to affect the UPS function in C. elegans in terms of proteasome activities and/or assembly and/or expression. Positive regulators are shown in green whereas negative regulators are shown in red.

          Highlights

          • UPS is one of the main proteolytic systems that orchestrate protein degradation.

          • Proteasome function can be dissected in Caenorhabditis elegans.

          • Nematodes can be used in the identification of major players in the UPS pathway.

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          Most cited references180

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          A genomic and functional inventory of deubiquitinating enzymes.

          Posttranslational modification of proteins by the small molecule ubiquitin is a key regulatory event, and the enzymes catalyzing these modifications have been the focus of many studies. Deubiquitinating enzymes, which mediate the removal and processing of ubiquitin, may be functionally as important but are less well understood. Here, we present an inventory of the deubiquitinating enzymes encoded in the human genome. In addition, we review the literature concerning these enzymes, with particular emphasis on their function, specificity, and the regulation of their activity.
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            Defining the human deubiquitinating enzyme interaction landscape.

            Deubiquitinating enzymes (Dubs) function to remove covalently attached ubiquitin from proteins, thereby controlling substrate activity and/or abundance. For most Dubs, their functions, targets, and regulation are poorly understood. To systematically investigate Dub function, we initiated a global proteomic analysis of Dubs and their associated protein complexes. This was accomplished through the development of a software platform called CompPASS, which uses unbiased metrics to assign confidence measurements to interactions from parallel nonreciprocal proteomic data sets. We identified 774 candidate interacting proteins associated with 75 Dubs. Using Gene Ontology, interactome topology classification, subcellular localization, and functional studies, we link Dubs to diverse processes, including protein turnover, transcription, RNA processing, DNA damage, and endoplasmic reticulum-associated degradation. This work provides the first glimpse into the Dub interaction landscape, places previously unstudied Dubs within putative biological pathways, and identifies previously unknown interactions and protein complexes involved in this increasingly important arm of the ubiquitin-proteasome pathway.
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              Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes.

              Deubiquitinating enzymes (DUBs) are proteases that process ubiquitin or ubiquitin-like gene products, reverse the modification of proteins by a single ubiquitin(-like) protein, and remodel polyubiquitin(-like) chains on target proteins. The human genome encodes nearly 100 DUBs with specificity for ubiquitin in five gene families. Most DUB activity is cryptic, and conformational rearrangements often occur during the binding of ubiquitin and/or scaffold proteins. DUBs with specificity for ubiquitin contain insertions and extensions modulating DUB substrate specificity, protein-protein interactions, and cellular localization. Binding partners and multiprotein complexes with which DUBs associate modulate DUB activity and substrate specificity. Quantitative studies of activity and protein-protein interactions, together with genetic studies and the advent of RNAi, have led to new insights into the function of yeast and human DUBs. This review discusses ubiquitin-specific DUBs, some of the generalizations emerging from recent studies of the regulation of DUB activity, and their roles in various cellular processes.
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                Author and article information

                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                18 January 2014
                18 January 2014
                2014
                : 2
                : 333-347
                Affiliations
                [0005]Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., Athens 11635, Greece
                Author notes
                [* ]Corresponding author. Tel.: +30 210 7273768. nikichon@ 123456eie.gr
                Article
                S2213-2317(14)00022-6
                10.1016/j.redox.2014.01.007
                3926112
                24563851
                6df43581-32b9-45f1-b141-afc258df4d4a
                © 2014 The Authors

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 December 2013
                : 8 January 2014
                : 10 January 2014
                Categories
                Review Article

                ups, ubiquitin–proteasome system,iis, insulin/igf-1 signaling pathway,protein,ubiquitin-proteasome system (ups),c. elegans,egf, epidermal growth factor,proteasome regulation

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