title: FKBP10 depletion enhances glucocerebrosidase proteostasis in Gaucher disease fibroblasts.
abstract: Lysosomal storage diseases (LSDs) are often caused by mutations compromising lysosomal enzyme folding in the endoplasmic reticulum (ER), leading to degradation and loss of function. Mass spectrometry analysis of Gaucher fibroblasts treated with mechanistically distinct molecules that increase LSD enzyme folding, trafficking, and function resulted in the identification of nine commonly downregulated and two jointly upregulated proteins, which we hypothesized would be critical proteostasis network components for ameliorating loss-of-function diseases. LIMP-2 and FK506 binding protein 10 (FKBP10) were validated as such herein. Increased FKBP10 levels accelerated mutant glucocerebrosidase degradation over folding and trafficking, whereas decreased ER FKBP10 concentration led to more LSD enzyme partitioning into the calnexin profolding pathway, enhancing folding and activity to levels thought to ameliorate LSDs. Thus, targeting FKBP10 appears to be a heretofore unrecognized therapeutic strategy to ameliorate LSDs.
authors: Departments of Chemistry and Molecular and Experimental Medicine and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Derrick Sek Tong
authors: DS
authors: Ong
authors: Ya-Juan
authors: YJ
authors: Wang
authors: Yun Lei
authors: YL
authors: Tan
authors: John R
authors: JR
authors: Yates
authors: Ting-Wei
authors: TW
authors: Mu
authors: Jeffery W
authors: JW
authors: Kelly
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005776:Gaucher Disease / Q000473:pathology*; D005962:Glucosylceramidase / Q000737:chemistry / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D037102:Lectins / Q000378:metabolism; D008969:Molecular Sequence Data; D009113:Muramidase / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D017510:Protein Folding; D021381:Protein Transport; D059748:Proteolysis; D040901:Proteomics; D015203:Reproducibility of Results; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism; D043323:alpha-Mannosidase / Q000378:metabolism
chemical_list: D037102:Lectins; D009363:Neoplasm Proteins; C098898:OS9 protein, human; D009113:Muramidase; D043323:alpha-Mannosidase; D005962:Glucosylceramidase; D022021:Tacrolimus Binding Proteins; C110054:FKBP10 protein, human