title: HSJ1 is a neuronal shuttling factor for the sorting of chaperone clients to the proteasome.
abstract: Protein degradation in eukaryotic cells usually involves the attachment of a ubiquitin chain to a substrate protein and its subsequent sorting to the proteasome. Molecular mechanisms underlying the sorting process only recently began to emerge and rely on a cooperation of chaperone machineries and ubiquitin-chain recognition factors [1-3]. Here, we identify isoforms of the cochaperone HSJ1 as neuronal shuttling factors for ubiquitylated proteins. HSJ1 combines a J-domain that stimulates substrate loading onto the Hsc70 chaperone with ubiquitin interaction motifs (UIMs) involved in binding ubiquitylated chaperone clients. HSJ1 prevents client aggregation, shields clients against chain trimming by ubiquitin hydrolases, and stimulates their sorting to the proteasome. In this way, HSJ1 isoforms participate in ER-associated degradation (ERAD) and protect neurons against cytotoxic protein aggregation.
authors.affiliation: Institute for Cell Biology, Rheinische Friedrich-Wilhelms University Bonn, Ulrich-Haberland-Strasse 61a, D-53121 Bonn, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Westhoff
authors.forename: J Paul
authors.initials: JP
authors.lastname: Chapple
authors.forename: Jacqueline
authors.initials: J
authors.lastname: van der Spuy
authors.forename: Jörg
authors.initials: J
authors.lastname: Höhfeld
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D005982:Glutathione Transferase; D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D010455:Peptides; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D011506:Proteins / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C121958:DNAJB2 protein, human; D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010455:Peptides; D020033:Protein Isoforms; D011506:Proteins; D025801:Ubiquitin; C097188:polyglutamine; D008156:Luciferases; D005982:Glutathione Transferase; D046988:Proteasome Endopeptidase Complex