title: A key enzyme in the biogenesis of lysosomes is a protease that regulates cholesterol metabolism.
abstract: Mucolipidosis II is a severe lysosomal storage disorder caused by defects in the α and β subunits of the hexameric N-acetylglucosamine-1-phosphotransferase complex essential for the formation of the mannose 6-phosphate targeting signal on lysosomal enzymes. Cleavage of the membrane-bound α/β-subunit precursor by an unknown protease is required for catalytic activity. Here we found that the α/β-subunit precursor is cleaved by the site-1 protease (S1P) that activates sterol regulatory element-binding proteins in response to cholesterol deprivation. S1P-deficient cells failed to activate the α/β-subunit precursor and exhibited a mucolipidosis II-like phenotype. Thus, S1P functions in the biogenesis of lysosomes, and lipid-independent phenotypes of S1P deficiency may be caused by lysosomal dysfunction.
authors: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Katrin
authors: K
authors: Marschner
authors: Katrin
authors: K
authors: Kollmann
authors: Michaela
authors: M
authors: Schweizer
authors: Thomas
authors: T
authors: Braulke
authors: Sandra
authors: S
authors: Pohl
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D019902:Chondrocytes / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D004792:Enzyme Precursors / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D008360:Mannosephosphates / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D009081:Mucolipidoses / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000378:metabolism; D010012:Osteogenesis; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004792:Enzyme Precursors; D008360:Mannosephosphates; D021122:Protein Subunits; D034741:RNA, Small Interfering; C027693:mannose-6-phosphate; D002784:Cholesterol; D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human; C030012:UDP-N-acetylglucosamine-lysosomal-enzyme-N-acetylglucosaminephosphotransferase; D020051:N-Acetylgalactosamine-4-Sulfatase; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1