A key enzyme in the biogenesis of lysosomes is a protease that regulates cholesterol metabolism

Science. 2011 Jul 1;333(6038):87-90. doi: 10.1126/science.1205677.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line
  • Cholesterol / metabolism*
  • Chondrocytes / cytology
  • Cricetinae
  • Cricetulus
  • Enzyme Precursors / chemistry
  • Enzyme Precursors / metabolism*
  • HeLa Cells
  • Humans
  • Lipid Metabolism
  • Lysosomes / enzymology
  • Lysosomes / metabolism*
  • Lysosomes / ultrastructure
  • Mannosephosphates / metabolism
  • Mice
  • Morphogenesis
  • Mucolipidoses / enzymology
  • Mucolipidoses / genetics
  • Mucolipidoses / metabolism
  • Mucolipidoses / pathology
  • N-Acetylgalactosamine-4-Sulfatase / metabolism
  • Osteogenesis
  • Proprotein Convertases / genetics
  • Proprotein Convertases / metabolism*
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • RNA, Small Interfering
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Transferases (Other Substituted Phosphate Groups) / chemistry
  • Transferases (Other Substituted Phosphate Groups) / metabolism*

Substances

  • Enzyme Precursors
  • Mannosephosphates
  • Protein Subunits
  • RNA, Small Interfering
  • mannose-6-phosphate
  • Cholesterol
  • Transferases (Other Substituted Phosphate Groups)
  • GNPTAB protein, human
  • UDP-N-acetylglucosamine-lysosomal-enzyme-N-acetylglucosaminephosphotransferase
  • N-Acetylgalactosamine-4-Sulfatase
  • Proprotein Convertases
  • Serine Endopeptidases
  • membrane-bound transcription factor peptidase, site 1