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J Biol Chem, Vol. 273, Issue 29, 18250-18259, July 17, 1998

The Cellular Trafficking and Zinc Dependence of Secretory and Lysosomal Sphingomyelinase, Two Products of the Acid Sphingomyelinase Gene

Scott L. Schissel, George A. Keesler^¶, Edward H. Schuchman, Kevin Jon Williams^**, and Ira Tabas

From the Departments of  Anatomy & Cell Biology and  Medicine, Columbia University, New York, New York 10032, ^¶ Amgen, Boulder, Colorado 80301, the  Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, and the ^** Dorrance H. Hamilton Research Laboratories, Division of Endocrinology, Diabetes, and Metabolic Diseases, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

The acid sphingomyelinase (ASM) gene, which has been implicated in ceramide-mediated cell signaling and atherogenesis, gives rise to both lysosomal SMase (L-SMase), which is reportedly cation-independent, and secretory SMase (S-SMase), which is fully or partially dependent on Zn²⁺ for enzymatic activity. Herein we present evidence for a model to explain how a single mRNA gives rise to two forms of SMase with different cellular trafficking and apparent differences in Zn²⁺ dependence. First, we show that both S-SMase and L-SMase, which contain several highly conserved zinc-binding motifs, are directly activated by zinc. In addition, SMase assayed from a lysosome-rich fraction of Chinese hamster ovary cells was found to be partially zinc-dependent, suggesting that intact lysosomes from these cells contain subsaturating levels of Zn²⁺. Analysis of Asn-linked oligosaccharides and of N-terminal amino acid sequence indicated that S-SMase arises by trafficking through the Golgi secretory pathway, not by cellular release of L-SMase during trafficking to lysosomes or after delivery to lysosomes. Most importantly, when Zn²⁺-dependent S-SMase was incubated with SMase-negative cells, the enzyme was internalized, trafficked to lysosomes, and became zinc-independent. We conclude that L-SMase is exposed to cellular Zn²⁺ during trafficking to lysosomes, in lysosomes, and/or during cell homogenization. In contrast, the pathway targeting S-SMase to secretion appears to be relatively sequestered from cellular pools of Zn²⁺; thus S-SMase requires exogeneous Zn²⁺ for full activity. This model provides important information for understanding the enzymology and regulation of L- and S-SMase and for exploring possible roles of ASM gene products in cell signaling and atherogenesis.

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