title: Mutant glucocerebrosidase in Gaucher disease recruits Hsp27 to the Hsp90 chaperone complex for proteasomal degradation.
abstract: Gaucher disease is caused by mutations of the GBA1 gene, which encodes the lysosomal anchored gluococerebrosidase (GCase). GBA1 mutations commonly result in protein misfolding, abnormal chaperone recognition, and premature degradation, but are less likely to affect catalytic activity. In the present study, we demonstrate that the Hsp90/HOP/Cdc37 complex recruits Hsp27 after recognition of GCase mutants with subsequent targeting of GCase mutant peptides to degradation mechanisms such as VCP and the 26S proteasome. Inhibition of Hsp27 not only increased the quantity of enzyme but also enhanced GCase activity in fibroblasts derived from patients with Gaucher disease. These findings provide insight into a possible therapeutic strategy for protein misfolding diseases by correcting chaperone binding and altering subsequent downstream patterns of protein degradation.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892 bradyr@ninds.nih.gov yangc2@ninds.nih.gov zhuangp@ninds.nih.gov.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
authors.forename: Herui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
authors.forename: Dongwang
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hong
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
authors.forename: Pauline
authors.initials: P
authors.lastname: Dmitriev
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ikejiri
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892 bradyr@ninds.nih.gov yangc2@ninds.nih.gov zhuangp@ninds.nih.gov.
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892 bradyr@ninds.nih.gov yangc2@ninds.nih.gov zhuangp@ninds.nih.gov.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D018833:Chaperonins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005776:Gaucher Disease / Q000235:genetics / Q000378:metabolism*; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006360:Heat-Shock Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D059748:Proteolysis; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; C476884:HOPX protein, human; D055551:HSP27 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018398:Homeodomain Proteins; D018832:Molecular Chaperones; D025521:Tumor Suppressor Proteins; D005962:Glucosylceramidase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D018833:Chaperonins
keywords: Gaucher disease; heat shock protein; hsp27; hsp90; molecular chaperone