The Golgi-resident site-1 protease (S1P) is a key regulator of cholesterol homeostasis and ER stress responses by converting latent transcription factors sterol regulatory element binding proteins (SREPBs) and activating transcription factor 6 (ATF6), as well as viral glycoproteins to their active forms. S1P is also essential for lysosome biogenesis via proteolytic activation of the hexameric GlcNAc-1-phosphotransferase complex required for modification of newly synthesized lysosomal enzymes with the lysosomal targeting signal, mannose 6-phosphate. In the absence of S1P, the catalytically inactive α/β-subunit precursor of GlcNAc-1-phosphotransferase fails to be activated and results in missorting of newly synthesized lysosomal enzymes, and lysosomal accumulation of non-degraded material, which are biochemical features of defective GlcNAc-1-phosphotransferase subunits and the associated pediatric lysosomal diseases mucolipidosis type II and III. The early embryonic death of S1P-deficient mice and the importance of various S1P-regulated biological processes, including lysosomal homeostasis, cautioned for clinical inhibition of S1P. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
