Doing Double Duty

摘要

W-acetylglucosamine (GlcNAc)-l-phosphotransferase is the crucial enzyme in the generation of mannose 6-phosphate (M6P) residues on lysosomal enzymes required for their efficient transport to lysosomes. Defects in the GlcNAc-1-phosphotransferase lead to a fatal lysosomal storage disorder. GlcNAc-1-phosphotransferase is synthesized as an inactive precursor protein that is activated by proteolytic cleavage in the Golgi complex. Marschner et at. (p. 87; see the Perspective by Ye) now report that the protease involved in GlcNAc-1-phosphotransferase cleavage is the site-1 protease (SIP), a Golgi-localized protease that plays a central role in cholesterol homeostasis. Loss of SIP resulted in missorting of newly synthesized lysosomal enzymes due to the lack of M6P residues, which may contribute to the defective cartilage phenotype in SIP defective animals.