Regulated secretion of acid sphingomyelinase: Implications for selectivity of ceramide formation

Russell W. Jenkins, Daniel Canals, Jolanta Idkowiak-Baldys, Fabio Simbari, Patrick Roddy, David M. Perry, Kazuyuki Kitatani, Chiara Luberto, Yusuf A. Hannun

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)

Abstract

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-1β and tumor necrosis factor-α induced a time- and dose-dependent increase in S-SMase secretion and activity, coincident with selective elevations in cellular C16-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-aSMaseS508A MCF7. Secretion of the S508A mutant was also defective in response to IL-1β, as was the regulated generation of C16-ceramide. Taken together, these data support a crucial role for Ser508 in the regulation of S-SMase secretion, and they suggest distinct metabolic roles for S-SMase and L-SMase.

Original languageEnglish
Pages (from-to)35706-35718
Number of pages13
JournalJournal of Biological Chemistry
Volume285
Issue number46
DOIs
Publication statusPublished - 2010 Nov 12

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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