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• W2099161824 abstract "Any of seven lysine residues on ubiquitin can serve as the base for chain-extension, resulting in a sizeable spectrum of ubiquitin modifications differing in chain length or linkage type. By optimizing a procedure for rapid lysis, we charted the profile of conjugated cellular ubiquitin directly from whole cell extract. Roughly half of conjugated ubiquitin (even at high molecular weights) was nonextended, consisting of monoubiquitin modifications and chain terminators (endcaps). Of extended ubiquitin, the primary linkages were via Lys48 and Lys63. All other linkages were detected, contributing a relatively small portion that increased at lower molecular weights. In vivo expression of lysineless ubiquitin (K0 Ub) perturbed the ubiquitin landscape leading to elevated levels of conjugated ubiquitin, with a higher mono-to-poly ratio. Affinity purification of these trapped conjugates identified a comprehensive list of close to 900 proteins including novel targets. Many of the proteins enriched by K0 ubiquitination were membrane-associated, or involved in cellular trafficking. Prime among them are components of the ESCRT machinery and adaptors of the Rsp5 E3 ubiquitin ligase. Ubiquitin chains associated with these substrates were enriched for Lys63 linkages over Lys48, indicating that K0 Ub is unevenly distributed throughout the ubiquitinome. Biological assays validated the interference of K0 Ub with protein trafficking and MVB sorting, minimally affecting Lys48-dependent turnover of proteasome substrates. We conclude that despite the shared use of the ubiquitin molecule, the two branches of the ubiquitin machinery—the ubiquitin-proteasome system and the ubiquitin trafficking system—were unevenly perturbed by expression of K0 ubiquitin. Any of seven lysine residues on ubiquitin can serve as the base for chain-extension, resulting in a sizeable spectrum of ubiquitin modifications differing in chain length or linkage type. By optimizing a procedure for rapid lysis, we charted the profile of conjugated cellular ubiquitin directly from whole cell extract. Roughly half of conjugated ubiquitin (even at high molecular weights) was nonextended, consisting of monoubiquitin modifications and chain terminators (endcaps). Of extended ubiquitin, the primary linkages were via Lys48 and Lys63. All other linkages were detected, contributing a relatively small portion that increased at lower molecular weights. In vivo expression of lysineless ubiquitin (K0 Ub) perturbed the ubiquitin landscape leading to elevated levels of conjugated ubiquitin, with a higher mono-to-poly ratio. Affinity purification of these trapped conjugates identified a comprehensive list of close to 900 proteins including novel targets. Many of the proteins enriched by K0 ubiquitination were membrane-associated, or involved in cellular trafficking. Prime among them are components of the ESCRT machinery and adaptors of the Rsp5 E3 ubiquitin ligase. Ubiquitin chains associated with these substrates were enriched for Lys63 linkages over Lys48, indicating that K0 Ub is unevenly distributed throughout the ubiquitinome. Biological assays validated the interference of K0 Ub with protein trafficking and MVB sorting, minimally affecting Lys48-dependent turnover of proteasome substrates. We conclude that despite the shared use of the ubiquitin molecule, the two branches of the ubiquitin machinery—the ubiquitin-proteasome system and the ubiquitin trafficking system—were unevenly perturbed by expression of K0 ubiquitin. Post-translational modification of cellular proteins with ubiquitin determines their fate by influencing protein-protein interactions, altering recognition, targeting to cellular compartments, or by promoting their degradation at the 26S proteasomes (1Hicke L. Dunn R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins.Annu. Rev. Cell Dev. Biol. 2003; 19: 141-172Crossref PubMed Scopus (917) Google Scholar, 2Ikeda F. Dikic I. Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series.EMBO Rep. 2008; 9: 536-542Crossref PubMed Scopus (580) Google Scholar, 3Mukhopadhyay D. Riezman H. Proteasome-independent functions of ubiquitin in endocytosis and signaling.Science. 2007; 315: 201-205Crossref PubMed Scopus (856) Google Scholar, 4Pickart C.M. Fushman D. Polyubiquitin chains: polymeric protein signals.Curr. Opin. Chem. Biol. 2004; 8: 610-616Crossref PubMed Scopus (777) Google Scholar, 5Glickman M.H. Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction.Physiol. Rev. 2002; 82: 373-428Crossref PubMed Google Scholar, 6Finley D. Recognition and processing of ubiquitin-protein conjugates by the proteasome.Annu. Rev. Biochem. 2009; 78: 477-513Crossref PubMed Scopus (1117) Google Scholar). In order to carry out, in parallel, such diverse cellular functions, downstream components must differentiate between ubiquitin-conjugates destined for alternative fates. This is made possible because ubiquitin polymerizes into chains and therefore does not represent a single signal embodied by a single molecule, but rather a family of polymeric signals differing in chain length, linkage type, and spatial conformation. Any of seven lysine residues (Lys6, Lys11, Lys27, Lys29, Lys33, Lys48, and Lys63) on the surface of ubiquitin can be linked via a covalent amide bond to the free carboxy-terminus of a distal ubiquitin, resulting in a sizeable spectrum of configurations. Structurally distinct surfaces presented by different linkage types can be selected for by dedicated down-stream ubiquitin-binding proteins (2Ikeda F. Dikic I. Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series.EMBO Rep. 2008; 9: 536-542Crossref PubMed Scopus (580) Google Scholar, 4Pickart C.M. Fushman D. Polyubiquitin chains: polymeric protein signals.Curr. Opin. Chem. Biol. 2004; 8: 610-616Crossref PubMed Scopus (777) Google Scholar, 7Li W. Ye Y. Polyubiquitin chains: functions, structures, and mechanisms.Cell Mol. Life Sci. 2008; 65: 2397-2406Crossref PubMed Scopus (159) Google Scholar). Recent advances in mass spectrometry (MS) have provided a powerful tool for accurate, direct determination of modified lysines on ubiquitin or on the target substrate allowing for insightful analysis of ubiquitin signals and their cellular correlations (8Xu P. Duong D.M. Seyfried N.T. Cheng D. Xie Y. Robert J. Rush J. Hochstrasser M. Finley D. Peng J. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation.Cell. 2009; 137: 133-145Abstract Full Text Full Text PDF PubMed Scopus (753) Google Scholar, 9Seyfried N.T. Xu P. Duong D.M. Cheng D. Hanfelt J. Peng J. Systematic approach for validating the ubiquitinated proteome.Anal. Chem. 2008; 80: 4161-4169Crossref PubMed Scopus (58) Google Scholar, 10Kirkpatrick D.S. Denison C. Gygi S.P. Weighing in on ubiquitin: the expanding role of mass-spectrometry-based proteomics.Nat. Cell Biol. 2005; 7: 750-757Crossref PubMed Scopus (179) Google Scholar, 11Kirkpatrick D.S. Weldon S.F. Tsaprailis G. Liebler D.C. Gandolfi A.J. Proteomic identification of ubiquitinated proteins from human cells expressing His-tagged ubiquitin.Proteomics. 2005; 5: 2104-2111Crossref PubMed Scopus (77) Google Scholar, 12Kirkpatrick D.S. Gerber S.A. Gygi S.P. The absolute quantification strategy: a general procedure for the quantification of proteins and post-translational modifications.Methods. 2005; 35: 265-273Crossref PubMed Scopus (452) Google Scholar, 13Denison C. Kirkpatrick D.S. Gygi S.P. Proteomic insights into ubiquitin and ubiquitin-like proteins.Curr. Opin. Chem. Biol. 2005; 9: 69-75Crossref PubMed Scopus (42) Google Scholar). Indeed MS analysis has provided lists of ubiquitinated substrates (9Seyfried N.T. Xu P. Duong D.M. Cheng D. Hanfelt J. Peng J. Systematic approach for validating the ubiquitinated proteome.Anal. Chem. 2008; 80: 4161-4169Crossref PubMed Scopus (58) Google Scholar, 14Tagwerker C. Flick K. Cui M. Guerrero C. Dou Y. Auer B. Baldi P. Huang L. Kaiser P. A tandem affinity tag for two-step purification under fully denaturing conditions: application in ubiquitin profiling and protein complex identification combined with in vivo cross-linking.Mol. Cell Proteomics. 2006; 5: 737-748Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 15Mayor T. Graumann J. Bryan J. MacCoss M.J. Deshaies R.J. Quantitative profiling of ubiquitylated proteins reveals proteasome substrates and the substrate repertoire influenced by the Rpn10 receptor pathway.Mol. Cell Proteomics. 2007; 6: 1885-1895Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 16Mayor T. Lipford J.R. Graumann J. Smith G.T. Deshaies R.J. Analysis of polyubiquitin conjugates reveals that the Rpn10 substrate receptor contributes to the turnover of multiple proteasome targets.Mol. Cell Proteomics. 2005; 4: 741-751Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 17Peng J. Schwartz D. Elias J.E. Thoreen C.C. Cheng D. Marsischky G. Roelofs J. Finley D. Gygi S.P. A proteomics approach to understanding protein ubiquitination.Nat. Biotechnol. 2003; 21: 921-926Crossref PubMed Scopus (1193) Google Scholar) and recognized ubiquitin chains (8Xu P. Duong D.M. Seyfried N.T. Cheng D. Xie Y. Robert J. Rush J. Hochstrasser M. Finley D. Peng J. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation.Cell. 2009; 137: 133-145Abstract Full Text Full Text PDF PubMed Scopus (753) Google Scholar, 17Peng J. Schwartz D. Elias J.E. Thoreen C.C. Cheng D. Marsischky G. Roelofs J. Finley D. Gygi S.P. A proteomics approach to understanding protein ubiquitination.Nat. Biotechnol. 2003; 21: 921-926Crossref PubMed Scopus (1193) Google Scholar, 18Matiuhin Y. Kirkpatrick D.S. Ziv I. Kim W. Dakshinamurthy A. Kleifeld O. Gygi S.P. Reis N. Glickman M.H. Extraproteasomal Rpn10 restricts access of the polyubiquitin-binding protein Dsk2 to proteasome.Mol. Cell. 2008; 32: 415-425Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). An essential outcome of ubiquitination is targeting to the 26S proteasome, which is responsible for the degradation of most cytosolic, nuclear, endoplasmic reticulum lumenal or membrane proteins, and even mitochondrial proteins (5Glickman M.H. Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction.Physiol. Rev. 2002; 82: 373-428Crossref PubMed Google Scholar, 6Finley D. Recognition and processing of ubiquitin-protein conjugates by the proteasome.Annu. Rev. Biochem. 2009; 78: 477-513Crossref PubMed Scopus (1117) Google Scholar, 19Matiuhin Y. Matiuhin G.M.H. Ubiquitin and Ubiquitination: an overview of the Ubiquitin-proteasome system for protein degradation.in: The UPS in the nervous system: from Physiology to Pathology. Nova science publishers Inc, 2006Google Scholar, 20Livnat-Levanon N. Glickman M.H. Ubiquitin-proteasome system and mitochondria - Reciprocity.Biochim. Biophys. Acta. 2010; PubMed Google Scholar). The majority of proteasome substrates are tagged not by a single ubiquitin (monoUb) 1The abbreviations used are:monoUbsingle ubiquitinpolyUbpolyubiquitinUbubiquitinWCEwhole cell extractSILACstable isotope labeling with amino acids in cell cultureMWmolecular weightERADER-associated degradation., but by a polyubiquitin (polyUb) chain. Lys48 is the only lysine on ubiquitin whose substitution to arginine is lethal, pointing to a unique and essential role for Lys48-linked chains (21Finley D. Sadis S. Monia B.P. Boucher P. Ecker D.J. Crooke S.T. Chau V. Inhibition of proteolysis and cell cycle progression in a multiubiquitination-deficient yeast mutant.Mol. Cellular Biol. 1994; 14: 5501-5509Crossref PubMed Google Scholar). It is generally thought that such Lys48-linked polyUb chains longer than four ubiquitin molecules are the preferred signal for efficient recognition and degradation by 26S proteasomes (22Thrower J.S. Hoffman L. Rechsteiner M. Pickart C.M. Recognition of the polyubiquitin proteolytic signal.EMBO J. 2000; 19: 94-102Crossref PubMed Google Scholar). Once bound by proteasomes, substrate-conjugates are deubiquitinated, unfolded, and subsequently degraded. single ubiquitin polyubiquitin ubiquitin whole cell extract stable isotope labeling with amino acids in cell culture molecular weight ER-associated degradation. Other biological pathways that are regulated by ubiquitination include endocytosis and intracellular trafficking (23Madshus I.H. Ubiquitin binding in endocytosis–how tight should it be and where does it happen?.Traffic. 2006; 7: 258-261Crossref PubMed Scopus (0) Google Scholar, 24Mosesson Y. Yarden Y. Monoubiquitylation: a recurrent theme in membrane protein transport.Isr. Med. Assoc. J. 2006; 8: 233-237PubMed Google Scholar, 25Saksena S. Sun J. Chu T. Emr S.D. ESCRTing proteins in the endocytic pathway.Trends Biochem. Sci. 2007; 32: 561-573Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar), histone and transcriptional regulation (26Kodadek T. No Splicing, no dicing: non-proteolytic roles of the ubiquitin-proteasome system in transcription.J. Biol. Chem. 2010; 285: 2221-2226Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), autophagy (27Kirkin V. McEwan D.G. Novak I. Dikic I. A role for ubiquitin in selective autophagy.Mol. Cell. 2009; 34: 259-269Abstract Full Text Full Text PDF PubMed Scopus (892) Google Scholar), DNA repair (28Thomson T.M. Guerra-Rebollo M. Ubiquitin and SUMO signalling in DNA repair.Biochem. Soc. Trans. 2010; 38: 116-131Crossref PubMed Scopus (0) Google Scholar), and diverse cell signaling (29Chen Z.J. Sun L.J. Nonproteolytic functions of ubiquitin in cell signaling.Mol. Cell. 2009; 33: 275-286Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar, 30Kawadler H. Yang X. Lys63-linked polyubiquitin chains: linking more than just ubiquitin.Cancer Biol. Ther. 2006; 5: 1273-1274Crossref PubMed Scopus (0) Google Scholar, 31Haglund K. Dikic I. Ubiquitylation and cell signaling.EMBO J. 2005; 24: 3353-3359Crossref PubMed Scopus (541) Google Scholar). Most of these nonproteolytic roles are carried out by so called “alternative” ubiquitin signals, such as embodied by conjugation of a single ubiquitin molecule (monoubiquitination), or by non-Lys48-linked polyUb chains. For instance, nonproteolytic processes associated with Lys63 chains have been documented in protein trafficking, DNA damage tolerance, the inflammatory response, and ribosomal protein function (4Pickart C.M. Fushman D. Polyubiquitin chains: polymeric protein signals.Curr. Opin. Chem. Biol. 2004; 8: 610-616Crossref PubMed Scopus (777) Google Scholar). In protein trafficking, Lys63-linked polyUb serves as a signal mediating the internalization of plasma membrane receptors and transporters, intracellular transport, and subsequent lysosomal and vacuolar degradation (32Duncan L.M. Piper S. Dodd R.B. Saville M.K. Sanderson C.M. Luzio J.P. Lehner P.J. Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules.EMBO J. 2006; 25: 1635-1645Crossref PubMed Scopus (200) Google Scholar, 33Paiva S. Vieira N. Nondier I. Haguenauer-Tsapis R. Casal M. Urban-Grimal D. Glucose-induced ubiquitylation and endocytosis of the yeast Jen1 transporter: role of lysine 63-linked ubiquitin chains.J. Biol. Chem. 2009; 284: 19228-19236Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 34Barriere H. Nemes C. Du K. Lukacs G.L. Plasticity of polyubiquitin recognition as lysosomal targeting signals by the endosomal sorting machinery.Mol. Biol. Cell. 2007; 18: 3952-3965Crossref PubMed Scopus (67) Google Scholar, 35Huang F. Kirkpatrick D. Jiang X. Gygi S. Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain.Mol. Cell. 2006; 21: 737-748Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar, 36Kamsteeg E.J. Hendriks G. Boone M. Konings I.B. Oorschot V. van der Sluijs P. Klumperman J. Deen P.M. Short-chain ubiquitination mediates the regulated endocytosis of the aquaporin-2 water channel.Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 18344-18349Crossref PubMed Scopus (164) Google Scholar, 37Geetha T. Jiang J. Wooten M.W. Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling.Mol. Cell. 2005; 20: 301-312Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 38Li J.G. Haines D.S. Liu-Chen L.Y. Agonist-promoted Lys63-linked polyubiquitination of the human kappa-opioid receptor is involved in receptor down-regulation.Mol. Pharmacol. 2008; 73: 1319-1330Crossref PubMed Scopus (0) Google Scholar, 39Varghese B. Barriere H. Carbone C.J. Banerjee A. Swaminathan G. Plotnikov A. Xu P. Peng J. Goffin V. Lukacs G.L. Fuchs S.Y. Polyubiquitination of prolactin receptor stimulates its internalization, postinternalization sorting, and degradation via the lysosomal pathway.Mol. Cell. Biol. 2008; 28: 5275-5287Crossref PubMed Scopus (62) Google Scholar). Lys63-linked chains function also as a trafficking signal at the endosomal level for MVB sorting (40Lauwers E. Erpapazoglou Z. Haguenauer-Tsapis R. André B. The ubiquitin code of yeast permease trafficking.Trends Cell Biol. 2010; 20: 196-204Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). By promoting Lys63-linked polymerization, Rsp5, an E3 ubiquitin ligase of the Nedd4 HECT family, has been shown to have a prevailing role in ubiquitination of plasma-membrane transporters in yeast cells (41Belgareh-Touzé N. Léon S. Erpapazoglou Z. Stawiecka-Mirota M. Urban-Grimal D. Haguenauer-Tsapis R. Versatile role of the yeast ubiquitin ligase Rsp5p in intracellular trafficking.Biochem. Soc. Trans. 2008; 36: 791-796Crossref PubMed Scopus (0) Google Scholar, 42Kee Y. Muñoz W. Lyon N. Huibregtse J.M. The deubiquitinating enzyme Ubp2 modulates Rsp5-dependent Lys63-linked polyubiquitin conjugates in Saccharomyces cerevisiae.J. Biol. Chem. 2006; 281: 36724-36731Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 43Kim H.C. Huibregtse J.M. Polyubiquitination by HECT E3s and the determinants of chain type specificity.Mol. Cell. Biol. 2009; 29: 3307-3318Crossref PubMed Scopus (164) Google Scholar, 44Saeki Y. Kudo T. Sone T. Kikuchi Y. Yokosawa H. Toh-e A. Tanaka K. Lysine 63-linked polyubiquitin chain may serve as a targeting signal for the 26S proteasome.EMBO J. 2009; 28: 359-371Crossref PubMed Scopus (176) Google Scholar). In most cases, this ligase does not bind its substrates directly, but is recruited to them via a subset of specific adaptors some of which were shown to undergo Rsp5-dependent ubiquitination themselves (40Lauwers E. Erpapazoglou Z. Haguenauer-Tsapis R. André B. The ubiquitin code of yeast permease trafficking.Trends Cell Biol. 2010; 20: 196-204Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 45Léon S. Haguenauer-Tsapis R. Ubiquitin ligase adaptors: regulators of ubiquitylation and endocytosis of plasma membrane proteins.Exp. Cell Res. 2009; 315: 1574-1583Crossref PubMed Scopus (75) Google Scholar, 46Lin C.H. MacGurn J.A. Chu T. Stefan C.J. Emr S.D. Arrestin-related ubiquitin-ligase adaptors regulate endocytosis and protein turnover at the cell surface.Cell. 2008; 135: 714-725Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar, 47Shearwin-Whyatt L. Dalton H.E. Foot N. Kumar S. Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins.Bioessays. 2006; 28: 617-628Crossref PubMed Scopus (122) Google Scholar). Complicating the ability to attribute specific functions to Lys63 linkages, many membrane processes associated with Lys63 linkages are also driven by monoubiquitination. Often the same substrates are documented to be targets of both Lys63 polyUb or monoUb modifications. Both signals may partially overlap, though mild discrepancies between samples may also arise from rapid deubiquitination of Lys63 chains (48Cooper E.M. Cutcliffe C. Kristiansen T.Z. Pandey A. Pickart C.M. Cohen R.E. K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1.EMBO J. 2009; 28: 621-631Crossref PubMed Scopus (161) Google Scholar, 49Sims J.J. Cohen R.E. Linkage-specific avidity defines the lysine 63-linked polyubiquitin-binding preference of rap80.Mol. Cell. 2009; 33: 775-783Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Notably Ubp2, specifically deubiquitinates Lys63-linked ubiquitin chains on Rsp5-substrates leading to an increase in monoubiquitinated substrates (42Kee Y. Muñoz W. Lyon N. Huibregtse J.M. The deubiquitinating enzyme Ubp2 modulates Rsp5-dependent Lys63-linked polyubiquitin conjugates in Saccharomyces cerevisiae.J. Biol. Chem. 2006; 281: 36724-36731Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). Sample preparation may thus influence efficiency of trapping of polyUb chains, in particular the relatively labile Lys63 linkages. Understanding the relative prevalence and relative efficiency of monoubiquitination versus Lys63 chains in intracellular transport and endocytosis is a subject of intense investigation and great scrutiny. The precise biological differences between polyUb chains of various topologies have not been broadly understood yet, though sporadic observations keep coming in. Recent studies have spotlighted Lys11-linked ubiquitin chains, revealing their involvement in endoplasmic reticulum associated degradation (ERAD) as modifiers of the E2 Ubc6, which has also been proposed to participate in the synthesis of these chains (8Xu P. Duong D.M. Seyfried N.T. Cheng D. Xie Y. Robert J. Rush J. Hochstrasser M. Finley D. Peng J. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation.Cell. 2009; 137: 133-145Abstract Full Text Full Text PDF PubMed Scopus (753) Google Scholar). Other studies have related Lys11 chains to regulation of mitotic protein degradation and cell cycle control (50Kirkpatrick D.S. Hathaway N.A. Hanna J. Elsasser S. Rush J. Finley D. King R.W. Gygi S.P. Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology.Nat. Cell Biol. 2006; 8: 700-710Crossref PubMed Scopus (325) Google Scholar, 51Matsumoto M.L. Wickliffe K.E. Dong K.C. Yu C. Bosanac I. Bustos D. Phu L. Kirkpatrick D.S. Hymowitz S.G. Rape M. Kelley R.F. Dixit V.M. K11-Linked Polyubiquitination in Cell Cycle Control Revealed by a K11 Linkage-Specific Antibody.Mol. Cell. 2010; Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar). Lys6 chains were shown to be synthesized by the BRCA1/BARD1 complex (52Nishikawa H. Ooka S. Sato K. Arima K. Okamoto J. Klevit R.E. Fukuda M. Ohta T. Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase.J. Biol. 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Cell. 2008; 19: 4588-4601Crossref PubMed Google Scholar); Lys33 chains were recently reported to modify TCR-ζ thereby regulating cell-surface-receptor-mediated signal transduction; involvement of Lys29 chains was demonstrated in protein degradation and recruitment of a chain elongating factor E4 (55Johnson E.S. Ma P.C. Ota I.M. Varshavsky A. A proteolytic pathway that recognizes ubiquitin as a degradation signal.J. Biol. Chem. 1995; 270: 17442-17456Abstract Full Text Full Text PDF PubMed Scopus (640) Google Scholar, 56Mastrandrea L.D. You J. Niles E.G. Pickart C.M. E2/E3-mediated assembly of lysine 29-linked polyubiquitin chains.J. Biol. Chem. 1999; 274: 27299-27306Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Two different substrates of AIP4/Itch were also described to be modified by K29-linked ubiquitin chains in the context of Notch trafficking and signaling (57Chastagner P. Israël A. Brou C. AIP4/Itch regulates Notch receptor degradation in the absence of ligand.PLoS One. 2008; 3e2735 Crossref PubMed Scopus (97) Google Scholar). Adding yet another layer of complexity to the conjugated ubiquitin landscape, there are additional modifications by ubiquitin, including: mono- and multiple-mono ubiquitinations (58Haglund K. Sigismund S. Polo S. Szymkiewicz I. Di Fiore P.P. Dikic I. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation.Nat. Cell Biol. 2003; 5: 461-466Crossref PubMed Scopus (627) Google Scholar, 59Hicke L. Protein regulation by monoubiquitin.Nat. Rev. Mol. Cell Biol. 2001; 2: 195-201Crossref PubMed Scopus (941) Google Scholar, 60Hicke L. A New Ticket for Entry into Budding Vesicles–Ubiquitin.Cell. 2001; 106: 527-530Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar), mixed or branched ubiquitin chains (61Ziv I. Kleifeld O. Glickman M. Nonconformity in ubiquitin compliance.EMBO J. 2009; 28: 1825-1827Crossref PubMed Scopus (2) Google Scholar, 62Kim H.T. Kim K.P. Lledias F. Kisselev A.F. Scaglione K.M. Skowyra D. Gygi S.P. Goldberg A.L. Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages.J. Biol. Chem. 2007; 282: 17375-17386Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar, 63Uchiki T. Kim H.T. Zhai B. Gygi S.P. Johnston J.A. O'Bryan J.P. Goldberg A.L. The ubiquitin-interacting motif protein, S5a, is ubiquitinated by all types of ubiquitin ligases by a mechanism different from typical substrate recognition.J. Biol. Chem. 2009; 284: 12622-12632Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 64Ben-Saadon R. Zaaroor D. Ziv T. Ciechanover A. The polycomb protein Ring1B generates self atypical mixed ubiquitin chains required for its in vitro histone H2A ligase activity.Mol. Cell. 2006; 24: 701-711Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 65Boname J.M. Thomas M. Stagg H.R. Xu P. Peng J. Lehner P.J. Efficient internalization of MHC I requires lysine-11 and lysine-63 mixed linkage polyubiquitin chains.Traffic. 2010; 11: 210-220Crossref PubMed Scopus (98) Google Scholar), and linear chains (66Tokunaga F. Sakata S. Saeki Y. Satomi Y. Kirisako T. Kamei K. Nakagawa T. Kato M. Murata S. Yamaoka S. Yamamoto M. Akira S. Takao T. Tanaka K. Iwai K. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation.Nat. Cell Biol. 2009; 11: 123-132Crossref PubMed Scopus (646) Google Scholar). As linkages via lysines other than Lys48 are not strictly essential, these “alternative” chains may be less specific for a unique outcome allowing some overlap in signaling. Alternatively, polymerization quality control may be less rigidly enforced generating mixed signals in these pathways. Utilization of ubiquitin mutants is a strategy used to study the role or different ubiquitin chains. Substituting lysine residues in the ubiquitin molecule with arginine blocks specific chain extensions and thereby inhibits downstream consequences associated with a specific ubiquitin linkage (67Volk S. Wang M. Pickart C.M. Chemical and genetic strategies for manipulating polyubiquitin chain structure.Methods Enzymol. 2005; 399: 3-20Crossref PubMed Scopus (18) Google Scholar). Single-lysine ubiquitin mutants and a lysine-less, nonextendable mutant (K0 Ub) (68Arnason T. Ellison M.J. Stress resistance in Saccharomyces cerevisiae is strongly correlated with assembly of a novel type of multiubiquitin chain.Mol. Cell. Biol. 1994; 14: 7876-7883Crossref PubMed Google Scholar) are commonly used in vivo and in vitro for defining chain structure and for directing cellular ubiquitinations toward a specific ubiquitin modification. Because of the complicated dynamics of polyUb chains, when expressing ubiquitin mutants in living cells, the ratio of mutant to wild-type ubiquitin is likely to be a critical factor in the outcome of these types of experiments (67Volk S. Wang M. Pickart C.M. Chemical and genetic strategies for manipulating polyubiquitin chain structure.Methods Enzymol. 2005; 399: 3-20Crossref PubMed Scopus (18) Google Scholar). A phenotypic analysis of all single K-to-R substitutions (excluding K48R-Ub) revealed hypersensitivity to DNA damaging agents specific for K63R mutation (69Spence J. Sadis S. Haas A.L. Finley D. A ubiquitin mutant with specific defects in DNA repair and multiubiquitination.Mol. Cell. Biol. 1995; 15: 1265-1273Crossref PubMed Google Scholar). 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• W2099161824 creator A5089712556 @default.
• W2099161824 date "2011-05-01" @default.
• W2099161824 modified "2023-10-11" @default.
• W2099161824 title "A Perturbed Ubiquitin Landscape Distinguishes Between Ubiquitin in Trafficking and in Proteolysis" @default.
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