PerspectiveCell Biology

Protease Sets Site-1 on Lysosomes

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Science  01 Jul 2011:
Vol. 333, Issue 6038, pp. 50-51
DOI: 10.1126/science.1209417

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One of the defining features of how animal cells maintain cholesterol homeostasis is the complex signaling mechanism that releases transcription factors called sterol regulatory element–binding proteins (SREBPs) from their membrane-bound precursors through proteolysis to control the expression of key metabolic enzymes. One of the proteases that catalyze the cleavage is site-1 protease (S1P), a serine protease that is itself membrane bound. One curious phenotype of cultured mammalian cells lacking S1P has been a defect in lysosomes—instead of being targeted to the organelle, certain lysosomal enzymes are secreted out of the cells. On page 87 of this issue, Marschner et al. (1) provide one possible explanation—S1P is required for the biogenesis of lysosomes. The authors show that the protease cleaves a precursor form of N-acetylglucosamine (GlcNAc)-1-phosphotransferase, an enzyme that catalyzes an essential step in forming the mannose 6-phosphate signal that targets many enzymes to lysosomes.