A Key Enzyme in the Biogenesis of Lysosomes Is a Protease That Regulates Cholesterol Metabolism.
Marschner, Katrin 1; Kollmann, Katrin 1; Schweizer, Michaela 2; Braulke, Thomas 1,*; Pohl, Sandra 1
[Article]
Science.
333(6038):87-90, July 1, 2011.
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: Mucolipidosis II is a severe lysosomal storage disorder caused by defects in the a and [beta] 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 [alpha]/[beta]-subunit precursor by an unknown protease is required for catalytic activity, Here we found that the [alpha]/[beta]-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 [alpha]/[beta]-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.
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