Zn2+-stimulated sphingomyelinase is secreted by many cell types and is a product of the acid sphingomyelinase gene.
Mammalian sphingomyelinases have been implicated in many important physiological and pathophysiological processes. Although several mammalian sphingomyelinases have been identified and studied, one of these, an acidic Zn2+-stimulated sphingomyelinase (Zn-SMase) originally found in fetal bovine serum, has received little attention since its first and only report 7 years ago. We now show that Zn-SMase activity is secreted by human and murine macrophages, human skin fibroblasts, microglial cells, and several other cells in culture and is markedly up-regulated during differentiation of human monocytes to macrophages. Remarkably, peritoneal macrophages from mice in which the acid SMase gene had been disrupted by homologous recombination secreted no Zn-SMase activity, indicating that this enzyme and the intracellular lysosomal SMase, which is Zn-independent, arise from the same gene. Furthermore, skin fibroblasts from patients with types A and B Niemann-Pick disease, which are known to lack lysosomal SMase activity, also lack Zn-SMase activity in their conditioned media. Chinese hamster ovary cells stably transfected with a cDNA encoding lysosomal SMase massively overexpress both cellular lysosomal SMase and secreted Zn-SMase activities. Thus, Zn-SMase arises independently of alternative splicing, suggesting a post-translational process. In summary, a wide variety of cell types secrete Zn-SMase activity, which arises from the same gene as lysosomal SMase. This secreted enzyme may play roles in physiological and pathophysiological processes involving extracellular sphingomyelin hydrolysis.
Schissel
S L
SL
Department of Anatomy, Columbia University, New York, New York 10032, USA.
Schuchman
E H
EH
Williams
K J
KJ
Tabas
I
I
D000818:Animals; D016466:CHO Cells; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008247:Lysosomes / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009542:Niemann-Pick Diseases / Q000201:enzymology / Q000235:genetics; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D015032:Zinc / Q000494:pharmacology
D013108:Sphingomyelin Phosphodiesterase; D015032:Zinc