title: Quality control autophagy degrades soluble ERAD-resistant conformers of the misfolded membrane protein GnRHR.
abstract: Molecular chaperones triage misfolded proteins via action as substrate selectors for quality control (QC) machines that fold or degrade clients. Herein, the endoplasmic reticulum (ER)-associated Hsp40 JB12 is reported to participate in partitioning mutant conformers of gonadotropin-releasing hormone receptor (GnRHR), a G protein-coupled receptor, between ER-associated degradation (ERAD) and an ERQC autophagy pathway. ERQC autophagy degrades E90K-GnRHR because pools of its partially folded and detergent-soluble degradation intermediates are resistant to ERAD. S168R-GnRHR is globally misfolded and disposed of via ERAD, but inhibition of p97, the protein retrotranslocation motor, shunts S168R-GnRHR from ERAD to ERQC autophagy. Partially folded and grossly misfolded forms of GnRHR associate with JB12 and Hsp70. Elevation of JB12 promotes ERAD of S168R-GnRHR, with E90K-GnRHR being resistant. E90K-GnRHR elicits association of the Vps34 autophagy initiation complex with JB12. Interaction between ER-associated Hsp40s and the Vps34 complex permits the selective degradation of ERAD-resistant membrane proteins via ERQC autophagy.
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Houck
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Hong Yu
authors.initials: HY
authors.lastname: Ren
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Madden
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jacob N
authors.initials: JN
authors.lastname: Bonner
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Conlin
authors.affiliation: Departments of Internal Medicine and Cell Biology, Texas Tech University Health Science Center, Lubbock, TX 79430-6252, USA.
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Janovick
authors.affiliation: Departments of Internal Medicine and Cell Biology, Texas Tech University Health Science Center, Lubbock, TX 79430-6252, USA.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conn
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: douglas_cyr@med.unc.edu.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Cyr
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation / Q000187:drug effects; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011487:Protein Conformation; D017510:Protein Folding / Q000187:drug effects; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D011966:Receptors, LHRH / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: C484844:GNRHR protein, human; D050956:HSP40 Heat-Shock Proteins; D061988:Proteasome Inhibitors; D011966:Receptors, LHRH; D011993:Recombinant Fusion Proteins; D058546:Class III Phosphatidylinositol 3-Kinases