title: OS-9 facilitates turnover of nonnative GRP94 marked by hyperglycosylation.
abstract: The tight coupling of protein folding pathways with disposal mechanisms promotes the efficacy of protein production in the endoplasmic reticulum (ER). It has been hypothesized that the ER-resident molecular chaperone glucose-regulated protein 94 (GRP94) is part of this quality control coupling because it supports folding of select client proteins yet also robustly associates with the lectin osteosarcoma amplified 9 (OS-9), a component involved in ER-associated degradation (ERAD). To explore this possibility, we investigated potential functions for the GRP94/OS-9 complex in ER quality control. Unexpectedly, GRP94 does not collaborate with OS-9 in ERAD of misfolded substrates, nor is the chaperone required directly for OS-9 folding. Instead, OS-9 binds preferentially to a subpopulation of GRP94 that is hyperglycosylated on cryptic N-linked glycan acceptor sites. Hyperglycosylated GRP94 forms have nonnative conformations and are less active. As a result, these species are degraded much faster than the major, monoglycosylated form of GRP94 in an OS-9-mediated, ERAD-independent, lysosomal-like mechanism. This study therefore clarifies the role of the GRP94/OS-9 complex and describes a novel pathway by which glycosylation of cryptic acceptor sites influences the function and fate of an ER-resident chaperone.
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Devin
authors.initials: D
authors.lastname: Dersh
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Jones
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
authors.forename: Davide
authors.initials: D
authors.lastname: Eletto
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, United Kingdom yargon@mail.med.upenn.edu john.christianson@ludwig.ox.ac.uk.
authors.forename: John C
authors.initials: JC
authors.lastname: Christianson
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 yargon@mail.med.upenn.edu john.christianson@ludwig.ox.ac.uk.
authors.forename: Yair
authors.initials: Y
authors.lastname: Argon
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D037102:Lectins / Q000737:chemistry / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D059748:Proteolysis
chemical_list: D037102:Lectins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C098898:OS9 protein, human; C053387:endoplasmin; D000255:Adenosine Triphosphate