title: Deubiquitinase activity is required for the proteasomal degradation of misfolded cytosolic proteins upon heat-stress.
abstract: Elimination of misfolded proteins is crucial for proteostasis and to prevent proteinopathies. Nedd4/Rsp5 emerged as a major E3-ligase involved in multiple quality control pathways that target misfolded plasma membrane proteins, aggregated polypeptides and cytosolic heat-induced misfolded proteins for degradation. It remained unclear how in one case cytosolic heat-induced Rsp5 substrates are destined for proteasomal degradation, whereas other Rsp5 quality control substrates are otherwise directed to lysosomal degradation. Here we find that Ubp2 and Ubp3 deubiquitinases are required for the proteasomal degradation of cytosolic misfolded proteins targeted by Rsp5 after heat-shock (HS). The two deubiquitinases associate more with Rsp5 upon heat-stress to prevent the assembly of K63-linked ubiquitin on Rsp5 heat-induced substrates. This activity was required to promote the K48-mediated proteasomal degradation of Rsp5 HS-induced substrates. Our results indicate that ubiquitin chain editing is key to the cytosolic protein quality control under stress conditions.
authors.affiliation: Department of Biochemistry and Molecular Biology, Michael Smith Laboratories, University of British Columbia, 2125 East Mall, Vancouver, British Columbia, Canada V6T1Z4.
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Fang
authors.affiliation: Department of Biochemistry and Molecular Biology, Michael Smith Laboratories, University of British Columbia, 2125 East Mall, Vancouver, British Columbia, Canada V6T1Z4.
authors.forename: Mang
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Biology, Michael Smith Laboratories, University of British Columbia, 2125 East Mall, Vancouver, British Columbia, Canada V6T1Z4.
authors.forename: Amalia
authors.initials: A
authors.lastname: Rose
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Kuen-Phon
authors.identifier: 0000-0002-1525-6004
authors.initials: KP
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Michael Smith Laboratories, University of British Columbia, 2125 East Mall, Vancouver, British Columbia, Canada V6T1Z4.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mayor
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism*; D000072017:Deubiquitinating Enzymes / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D059748:Proteolysis; D011994:Recombinant Proteins / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013696:Temperature; D015534:Trans-Activators; D025801:Ubiquitin / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056827:Endosomal Sorting Complexes Required for Transport; D006360:Heat-Shock Proteins; D010455:Peptides; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D025801:Ubiquitin; C106908:WBP2 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; D000072017:Deubiquitinating Enzymes; D046988:Proteasome Endopeptidase Complex; C101111:UBP3 protein, S cerevisiae; C059237:ubiquitin-Nalpha-protein hydrolase; C469287:RSP5 protein, S cerevisiae