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Review
. 2008 Oct;22(10):3419-31.
doi: 10.1096/fj.08-108043. Epub 2008 Jun 20.

The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases

Eric L Smith  1 , Edward H Schuchman
Affiliations
Review

The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases

Eric L Smith et al. FASEB J. 2008 Oct.

Abstract

Acid sphingomyelinase (ASM; E.C. 3.1.4.12) is best known for its involvement in the lysosomal storage disorder Niemann-Pick disease (NPD). Through studies that began by investigating this rare disease, recent findings have uncovered the important role of this enzyme in the initiation of ceramide-mediated signal transduction. This unique function involves translocation of the enzyme from intracellular compartments to the outer leaflet of the cell membrane, where hydrolysis of sphingomyelin into ceramide initiates membrane reorganization and facilitates the formation and coalescence of lipid microdomains. These microdomains are sites of protein-protein interactions that lead to downstream signaling, and perturbation of microdomain formation influences the pathophysiology of many common diseases. The initial observations implicating ASM in this process have come from studies using cells from patients with NPD or from ASM knockout (ASMKO) mice, where the genetic deficiency of this enzymatic activity has been shown to protect these cells and animals from stress-induced and developmental apoptosis. This review will discuss the complex biology of this enzyme in the context of these new findings and its recently reported importance in common human diseases, including cancer, sepsis, cardiovascular, pulmonary, liver, and neurological diseases as well as the potential for using ASM (or ASM inhibitors) as therapeutic agents.

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Figures

Figure 1.
Figure 1.
Sphingomyelin cleavage by ASM. ASM is a phosphodiesterase that hydrolyzes sphingomyelin to produce phosphorylcholine and ceramide.
Figure 2.
Figure 2.
Proposed involvement of ASM in cell death. In response to stress or developmental signals, ASM may participate in cell death by hydrolysis of sphingomyelin (SM) on the outer leaflet of the plasma membrane, producing ceramide (Cer). This may lead to the formation and coalescence of ceramide-rich microdomains, bringing together inactive, monomeric signaling proteins into active oligomers. In the model of Zeidan and Hannun , ASM arrives at the cell surface after phosphorylation by PKCδ within the lysosomes (A). Alternatively, PKCδ may phosphorylate a cytosolic pool of ASM (e.g., Golgi, etc.), facilitating movement to the cell surface (B). Finally, it is possible that upon stress, both ASM and PKCδ move to the cell surface, where the phosphorylation occurs (C). In all cases, phosphorylation of ASM may enhance its activity at the cell surface. Additional experiments are needed to further elucidate the role of ASM in the cell death pathway, and to confirm this hypothetical model.
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References

    1. Gulbins E. Regulation of death receptor signaling and apoptosis by ceramide. Pharmacol Res. 2003;47:393–399. - PubMed
    1. Thannhauser S J, Reichel M. Studies on animal lipids. XVI. the occurrence of sphingomyelin as a mixture of sphingomyelin fatty acid ester and free sphingomyelin, demonstrated by enzymatic hydrolysis and mild saponification. J Biol Chem. 1940;135:1–13.
    1. Gatt S. Enzymic hydrolysis and synthesis of ceramides. J Biol Chem. 1963;238:3131–3133. - PubMed
    1. Brady R O, Kanfer J N, Mock M B, Fredrickson D S. The metabolism of sphingomyelin. II. evidence of an enzymatic deficiency in Niemann-Pick disease. Proc Natl Acad Sci U S A. 1966;55:366–369. - PMC - PubMed
    1. Gatt S. Magnesium-dependent sphingomyelinase. Biochem Biophys Res Commun. 1976;68:235–241. - PubMed

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