title: The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins.
abstract: Misfolded proteins of the secretory pathway are extracted from the endoplasmic reticulum (ER), polyubiquitylated by a protein complex termed the Hmg-CoA reductase degradation ligase (HRD-ligase), and degraded by cytosolic 26S proteasomes. This process is termed ER-associated protein degradation (ERAD). We previously showed that the membrane protein Der1, which is a subunit of the HRD-ligase, is involved in the export of aberrant polypeptides from the ER. Unexpectedly, we also uncovered a close spatial proximity of Der1 and the substrate receptor Hrd3 in the ER lumen. We report here on a mutant Hrd3KR that is selectively defective for ERAD of soluble proteins. Hrd3KR displays subtle structural changes that affect its positioning toward Der1. Furthermore, increased quantities of the ER-resident Hsp70-type chaperone Kar2 and the Hsp40-type cochaperone Scj1 bind to Hrd3KR. Of note, deletion of SCJ1 impairs ERAD of model substrates and causes the accumulation of client proteins at Hrd3. Our data imply a function of Scj1 in the removal of malfolded proteins from the receptor Hrd3, which facilitates their delivery to downstream-acting components like Der1.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Mehnert
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Sommermeyer
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Berger
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Sathish
authors.initials: S
authors.lastname: Kumar Lakshmipathy
authors.affiliation: Institute of Microbiology, Department of Biology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Gauss
authors.affiliation: Institute of Microbiology, Department of Biology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Aebi
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Jarosch
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany Institute of Biology, Humboldt Universität zu Berlin, 10115 Berlin, Germany tsommer@mdc-berlin.de ejarosch@mdc-berlin.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sommer
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: C098515:DER1 protein, S cerevisiae; D005656:Fungal Proteins; C104622:HRD3 protein, S cerevisiae; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C060153:KAR2 protein, yeast; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C067634:SCJ1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins