title: Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease.
abstract: Gaucher disease (GD), the most common lysosomal storage disease, is caused by mutations in GBA1 encoding of β-glucocerebrosidase (GCase). Recently it was reported that progranulin (PGRN) insufficiency and deficiency associated with GD in human and mice, respectively. However the underlying mechanisms remain unknown. Here we report that PGRN binds directly to GCase and its deficiency results in aggregation of GCase and its receptor LIMP2. Mass spectrometry approaches identified HSP70 as a GCase/LIMP2 complex-associated protein upon stress, with PGRN as an indispensable adaptor. Additionally, 98 amino acids of C-terminal PGRN, referred to as Pcgin, are required and sufficient for the binding to GCase and HSP70. Pcgin effectively ameliorates the disease phenotype in GD patient fibroblasts and animal models. These findings not only demonstrate that PGRN is a co-chaperone of HSP70 and plays an important role in GCase lysosomal localization, but may also provide new therapeutic interventions for lysosomal storage diseases, in particular GD.
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Jinlong
authors: J
authors: Jian
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Qing-Yun
authors: QY
authors: Tian
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Aubryanna
authors: A
authors: Hettinghouse
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Shuai
authors: S
authors: Zhao
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Helen
authors: H
authors: Liu
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States.
authors: Jianlu
authors: J
authors: Wei
authors: Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, United States.
authors: Gabriele
authors: G
authors: Grunig
authors: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States.
authors: Wujuan
authors: W
authors: Zhang
authors: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States.
authors: Kenneth D R
authors: KDR
authors: Setchell
authors: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, United States.
authors: Ying
authors: Y
authors: Sun
authors: Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA Leiden, The Netherlands.
authors: Herman S
authors: HS
authors: Overkleeft
authors: Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA 02115, United States.
authors: Gerald L
authors: GL
authors: Chan
authors: Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, United States; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, United States. Electronic address: chuanju.liu@nyumc.org.
authors: Chuan-Ju
authors: CJ
authors: Liu
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005776:Gaucher Disease / Q000188:drug therapy* / Q000378:metabolism*; D005962:Glucosylceramidase / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D000077153:Progranulins; D066329:Protein Aggregates; D011485:Protein Binding; D011994:Recombinant Proteins / Q000494:pharmacology; D013312:Stress, Physiological
chemical_list: C492314:GRN protein, human; D018840:HSP70 Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051907:Lysosomal Membrane Proteins; D000077153:Progranulins; D066329:Protein Aggregates; D011994:Recombinant Proteins; D005962:Glucosylceramidase
keywords: Gaucher disease; HSP70; Lysosomal storage diseases; Pcgin; Progranulin; β-glucocerebrosidase