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      Crosstalk and Interplay between the Ubiquitin-Proteasome System and Autophagy

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          Abstract

          Proteolysis in eukaryotic cells is mainly mediated by the ubiquitin (Ub)-proteasome system (UPS) and the autophagylysosome system (hereafter autophagy). The UPS is a selective proteolytic system in which substrates are recognized and tagged with ubiquitin for processive degradation by the proteasome. Autophagy is a bulk degradative system that uses lysosomal hydrolases to degrade proteins as well as various other cellular constituents. Since the inception of their discoveries, the UPS and autophagy were thought to be independent of each other in components, action mechanisms, and substrate selectivity. Recent studies suggest that cells operate a single proteolytic network comprising of the UPS and autophagy that share notable similarity in many aspects and functionally cooperate with each other to maintain proteostasis. In this review, we discuss the mechanisms underlying the crosstalk and interplay between the UPS and autophagy, with an emphasis on substrate selectivity and compensatory regulation under cellular stresses.

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          Systematic and quantitative assessment of the ubiquitin-modified proteome.

          Woong Kim, Eric J. Bennett, Edward L. Huttlin … (2011)
          Despite the diverse biological pathways known to be regulated by ubiquitylation, global identification of substrates that are targeted for ubiquitylation has remained a challenge. To globally characterize the human ubiquitin-modified proteome (ubiquitinome), we utilized a monoclonal antibody that recognizes diglycine (diGly)-containing isopeptides following trypsin digestion. We identify ~19,000 diGly-modified lysine residues within ~5000 proteins. Using quantitative proteomics we monitored temporal changes in diGly site abundance in response to both proteasomal and translational inhibition, indicating both a dependence on ongoing translation to observe alterations in site abundance and distinct dynamics of individual modified lysines in response to proteasome inhibition. Further, we demonstrate that quantitative diGly proteomics can be utilized to identify substrates for cullin-RING ubiquitin ligases. Interrogation of the ubiquitinome allows for not only a quantitative assessment of alterations in protein homeostasis fidelity, but also identification of substrates for individual ubiquitin pathway enzymes. Copyright © 2011 Elsevier Inc. All rights reserved.
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            A role for NBR1 in autophagosomal degradation of ubiquitinated substrates.

            Vladimir Kirkin, Trond Lamark, Yu-Shin Sou … (2009)
            Autophagy is a catabolic process where cytosolic cellular components are delivered to the lysosome for degradation. Recent studies have indicated the existence of specific receptors, such as p62, which link ubiquitinated targets to autophagosomal degradation pathways. Here we show that NBR1 (neighbor of BRCA1 gene 1) is an autophagy receptor containing LC3- and ubiquitin (Ub)-binding domains. NBR1 is recruited to Ub-positive protein aggregates and degraded by autophagy depending on an LC3-interacting region (LIR) and LC3 family modifiers. Although NBR1 and p62 interact and form oligomers, they can function independently, as shown by autophagosomal clearance of NBR1 in p62-deficient cells. NBR1 was localized to Ub-positive inclusions in patients with liver dysfunction, and depletion of NBR1 abolished the formation of Ub-positive p62 bodies upon puromycin treatment of cells. We propose that NBR1 and p62 act as receptors for selective autophagosomal degradation of ubiquitinated targets.
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              In vivo half-life of a protein is a function of its amino-terminal residue.

              A Bachmair, Kim Finley, A Varshavsky (1986)
              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
                Journal ID (nlm-ta): Mol Cells
                Journal ID (iso-abbrev): Mol. Cells
                Journal ID (publisher-id): ksmcb
                Title: Molecules and Cells
                Publisher: Korean Society for Molecular and Cellular Biology
                ISSN (Print): 1016-8478
                ISSN (Electronic): 0219-1032
                Publication date (Print): 31 July 2017
                Publication date (Electronic): 24 July 2017
                Volume: 40
                Issue: 7
                Pages: 441-449
                Affiliations
                [1 ]Protein Metabolism Medical Research Center and Department of Biomedical Sciences, Seoul National University, Seoul 03080, Korea
                [2 ]Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080, Korea
                Author notes
                [* ]Correspondence: yok5@ 123456snu.ac.kr
                Article
                Publisher ID: molce-40-7-441
                DOI: 10.14348/molcells.2017.0115
                PMC ID: 5547213
                PubMed ID: 28743182
                SO-VID: e7672e2b-4773-4c4a-8c64-ca35838e9a9e
                Copyright © © The Korean Society for Molecular and Cellular Biology. All rights reserved.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

                History
                Date received : 06 July 2017
                Date accepted : 12 July 2017
                Categories
                Subject: Minireview

                Keywords: degradation signal (degron),macroautophagy,n-end rule pathway,n-terminal arginylation,proteolysis,protein quality control,ubiquitin code
                Data availability:
                Keywords: degradation signal (degron), macroautophagy, n-end rule pathway, n-terminal arginylation, proteolysis, protein quality control, ubiquitin code

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