title: Non-canonical ubiquitin-based signals for proteasomal degradation.
abstract: Regulated cellular proteolysis is mediated largely by the ubiquitin-proteasome system (UPS). It is a highly specific process that is time- (e.g. cell cycle), compartment- (e.g. nucleus or endoplasmic reticulum) and substrate quality- (e.g. denatured or misfolded proteins) dependent, and allows fast adaptation to changing conditions. Degradation by the UPS is carried out through two successive steps: the substrate is covalently tagged with ubiquitin and subsequently degraded by the 26S proteasome. The accepted 'canonical' signal for proteasomal recognition is a polyubiquitin chain that is anchored to a lysine residue in the target substrate, and is assembled through isopeptide bonds involving lysine 48 of ubiquitin. However, several 'non-canonical' ubiquitin-based signals for proteasomal targeting have also been identified. These include chains anchored to residues other than internal lysine in the substrates, chains assembled through linking residues other than lysine 48 in ubiquitin, and mixed chains made of both ubiquitin and a ubiquitin-like protein. Furthermore, some proteins can be degraded following modification by a single ubiquitin (monoubiquitylation) or multiple single ubiquitins (multiple monoubiquitylation). Finally, some proteins can be proteasomally degraded without prior ubiquitylation (the process is also often referred to as ubiquitination). In this Commentary, we describe these recent findings and discuss the possible physiological roles of these diverse signals. Furthermore, we discuss the possible impact of this signal diversity on drug development.
authors.affiliation: Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Efron Street, Bat Galim, PO Box 9649, Haifa 31096, Israel. yelenaiv@tx.technion.ac.il
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kravtsova-Ivantsiv
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
mesh_terms: D000818:Animals; D001665:Binding Sites; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D025842:SUMO-1 Protein / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D025842:SUMO-1 Protein; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine