title: Numerous proteins with unique characteristics are degraded by the 26S proteasome following monoubiquitination.
abstract: The "canonical" proteasomal degradation signal is a substrate-anchored polyubiquitin chain. However, a handful of proteins were shown to be targeted following monoubiquitination. In this study, we established-in both human and yeast cells-a systematic approach for the identification of monoubiquitination-dependent proteasomal substrates. The cellular wild-type polymerizable ubiquitin was replaced with ubiquitin that cannot form chains. Using proteomic analysis, we screened for substrates that are nevertheless degraded under these conditions compared with those that are stabilized, and therefore require polyubiquitination for their degradation. For randomly sampled representative substrates, we confirmed that their cellular stability is in agreement with our screening prediction. Importantly, the two groups display unique features: monoubiquitinated substrates are smaller than the polyubiquitinated ones, are enriched in specific pathways, and, in humans, are structurally less disordered. We suggest that monoubiquitination-dependent degradation is more widespread than assumed previously, and plays key roles in various cellular processes.
authors.affiliation: Technion Integrated Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, 3109602, Israel;
authors.forename: Ori
authors.initials: O
authors.lastname: Braten
authors.affiliation: Technion Integrated Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, 3109602, Israel;
authors.forename: Ido
authors.initials: I
authors.lastname: Livneh
authors.affiliation: Smoler Proteomic Center, Technion-Israel Institute of Technology, Haifa, 3200003, Israel; Faculty of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel;
authors.forename: Tamar
authors.initials: T
authors.lastname: Ziv
authors.affiliation: Smoler Proteomic Center, Technion-Israel Institute of Technology, Haifa, 3200003, Israel; Faculty of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel;
authors.forename: Arie
authors.initials: A
authors.lastname: Admon
authors.affiliation: Department of Physiology, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, 3109602, Israel;
authors.forename: Izhak
authors.initials: I
authors.lastname: Kehat
authors.affiliation: Department of Physiology, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, 3109602, Israel;
authors.forename: Lilac H
authors.initials: LH
authors.lastname: Caspi
authors.affiliation: Technion Integrated Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, 3109602, Israel;
authors.forename: Hedva
authors.initials: H
authors.lastname: Gonen
authors.affiliation: Technion Integrated Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, 3109602, Israel;
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bercovich
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;
authors.forename: Adam
authors.initials: A
authors.lastname: Godzik
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;
authors.forename: Samad
authors.initials: S
authors.lastname: Jahandideh
authors.affiliation: Bioinformatics and Systems Biology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;
authors.forename: Lukasz
authors.initials: L
authors.lastname: Jaroszewski
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Sommer
authors.affiliation: Protein Metabolism Medical Research Center, College of Medicine, Seoul National University, Seoul 110-799, South Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, South Korea;
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
authors.affiliation: Vlaams Instituut voor Biotechnologie Structural Biology Research Center, Vrije Universiteit Brussel, 1050 Brussels, Belgium;
authors.forename: Mainak
authors.initials: M
authors.lastname: Guharoy
authors.affiliation: Vlaams Instituut voor Biotechnologie Structural Biology Research Center, Vrije Universiteit Brussel, 1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium; Institute of Enzymology, Research Center for Natural Sciences of the Hungarian Academy of Sciences, 1117 Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Tompa
authors.affiliation: Technion Integrated Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, 3109602, Israel; Protein Metabolism Medical Research Center, College of Medicine, Seoul National University, Seoul 110-799, South Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, South Korea; aaroncie@technion.ac.il.
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
mesh_terms: D006801:Humans; D061986:MCF-7 Cells; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D040901:Proteomics; D054875:Ubiquitination
chemical_list: D011506:Proteins; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: 26S proteasome; monoubiquitination; protein degradation; ubiquitin replacement