Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 46, Pages 35706-35718Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.125609
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Funding
- NCI [GM08716, P01 CA97132, 1P30 CA138313-01]
- MUSC Hollings Cancer Center Abney Foundation
- American Heart Association [081509E]
- Ministerio de Educacion y Ciencia (Spain) [AP2006-02190]
- Japan Society for the Promotion of Science [21890144]
- Grants-in-Aid for Scientific Research [21890144] Funding Source: KAKEN
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The acid sphingomyelinase (aSMase) gene gives rise to two distinct enzymes, lysosomal sphingomyelinase (L-SMase) and secretory sphingomyelinase (S-SMase), via differential trafficking of a common protein precursor. However, the regulation of S-SMase and its role in cytokine-induced ceramide formation remain ill defined. To determine the role of S-SMase in cellular sphingolipid metabolism, MCF7 breast carcinoma cells stably transfected with V5-aSMase(WT) were treated with inflammatory cytokines. Interleukin-1 beta and tumor necrosis factor-alpha induced a time-and dose-dependent increase in S-SMase secretion and activity, coincident with selective elevations in cellular C-16-ceramide. To establish a role for S-SMase, we utilized a mutant of aSMase (S508A) that is shown to retain L-SMase activity, but is defective in secretion. MCF7 expressing V5-aSMaseWT exhibited increased S-SMase and L-SMase activity, as well as elevated cellular levels of specific long-chain and very long-chain ceramide species relative to vector control MCF7. Interestingly, elevated levels of only certain very long-chain ceramides were evident in V5-aSMase(S508A) MCF7. Secretion of the S508A mutant was also defective in response to IL-1 beta, as was the regulated generation of C-16-ceramide. Taken together, these data support a crucial role for Ser(508) in the regulation of S-SMase secretion, and they suggest distinct metabolic roles for S-SMase and L-SMase.
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