Sphingosine-1-phosphate lyase is a widely expressed
enzyme that catalyzes the essentially irreversible cleavage of the signaling molecule
sphingosine 1-phosphate. To investigate whether
sphingosine-1-phosphate lyase influences mammalian cell fate decisions, a recombinant human
sphingosine-1-phosphate lyase fused to
green fluorescent protein was expressed in HEK293 cells. The recombinant
enzyme was active, localized to the endoplasmic reticulum, and reduced baseline
sphingosine and
sphingosine 1-phosphate levels. Stable overexpression led to diminished viability under stress, which was attributed to an increase in apoptosis and was reversible in a dose-dependent manner by exogenous
sphingosine 1-phosphate. In contrast to
sphingosine 1-phosphate, the products of the
lyase reaction had no effect on apoptosis.
Lyase enzymatic activity was required to potentiate apoptosis, because cells expressing a catalytically inactive
enzyme behaved like controls. Stress increased the amounts of long- and very long-chain
ceramides in HEK293 cells, and this was enhanced in cells overexpressing wild type but not catalytically inactive
lyase. The
ceramide increases appeared to be required for apoptosis, because inhibition of
ceramide synthase with
fumonisin B1 decreased apoptosis in
lyase-overexpressing cells. Thus,
sphingosine-1-phosphate lyase overexpression in HEK293 cells decreases
sphingosine and
sphingosine 1-phosphate amounts but elevates stress-induced
ceramide generation and apoptosis. This identifies
sphingosine-1-phosphate lyase as a dual modulator of
sphingosine 1-phosphate and
ceramide metabolism as well as a regulator of cell fate decisions and, hence, a potential target for diseases with an imbalance in these
biomodulators, such as
cancer.