title: Lipid thioesters derived from acylated proteins accumulate in infantile neuronal ceroid lipofuscinosis: correction of the defect in lymphoblasts by recombinant palmitoyl-protein thioesterase.
abstract: Palmitoyl-protein thioesterase is a lysosomal long-chain fatty acyl hydrolase that removes fatty acyl groups from modified cysteine residues in proteins. Mutations in palmitoyl-protein thioesterase were recently found to cause the neurodegenerative disorder infantile neuronal ceroid lipofuscinosis, a disease characterized by accumulation of amorphous granular deposits in cortical neurons, leading to blindness, seizures, and brain death by the age of three. In the current study, we demonstrate that [35S]cysteine-labeled lipid thioesters accumulate in immortalized lymphoblasts of patients with infantile neuronal ceroid lipofuscinosis. The accumulation in cultured cells is reversed by the addition of recombinant palmitoyl-protein thioesterase that is competent for lysosomal uptake through the mannose-6-phosphate receptor. The [35S]cysteine-labeled lipids are substrates for palmitoyl-protein thioesterase in vitro, and their formation requires prior protein synthesis. These data support a role for palmitoyl-protein thioesterase in the lysosomal degradation of S-acylated proteins and define a major new pathway for the catabolism of acylated proteins in the lysosome.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8593, USA.
authors.forename: J Y
authors.initials: JY
authors.lastname: Lu
authors.forename: L A
authors.initials: LA
authors.lastname: Verkruyse
authors.forename: S L
authors.initials: SL
authors.lastname: Hofmann
mesh_terms: D000818:Animals; D001402:B-Lymphocytes; D019556:COS Cells; D002461:Cell Line, Transformed; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000378:metabolism; D004854:Herpesvirus 4, Human; D006801:Humans; D019811:Hydroxylamine; D006898:Hydroxylamines / Q000494:pharmacology; D007700:Kinetics; D050356:Lipid Metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000201:enzymology* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*; D014162:Transfection
chemical_list: D006898:Hydroxylamines; D011994:Recombinant Proteins; D013438:Sulfhydryl Compounds; D019811:Hydroxylamine; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase; D003545:Cysteine