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Sphingosine-induced apoptosis is dependent on lysosomal proteases
K Kågedal1, M Zhao, I Svensson
1Division of Pathology II, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
The Biochemical Journal
|October 5, 2001
Summary
Sphingosine triggers apoptosis by causing lysosomal rupture and releasing enzymes into the cell. This process, involving cathepsins, precedes caspase activation and mitochondrial changes, offering new insights into cell death mechanisms.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Sphingolipids play critical roles in cellular signaling and homeostasis.
- Sphingosine is known to induce apoptosis, but the precise mechanism remains incompletely understood.
Purpose of the Study:
- To elucidate the mechanism of sphingosine-induced apoptosis.
- To investigate the role of lysosomes and lysosomal enzymes in sphingosine-induced cell death.
Main Methods:
- Treatment of Jurkat and J774 cells with varying concentrations of sphingosine.
- Assessment of lysosomal integrity, caspase activation, and mitochondrial membrane potential.
- Inhibition studies using ammonium chloride, lysosomal protease inhibitors (pepstatin A, E-64d), and a general caspase inhibitor (Z-VAD-FMK).
Main Results:
- Sphingosine caused dose-dependent lysosomal rupture, preceding caspase activation and mitochondrial changes.
- High sphingosine doses led to necrosis, bypassing apoptosis.
- Lysosomal protease inhibitors significantly reduced sphingosine-induced caspase activity, implicating cathepsins.
Conclusions:
- Sphingosine induces apoptosis via lysosomal hydrolase relocation to the cytosol.
- Cathepsin D and cysteine proteases (cathepsins B/L) mediate sphingosine-induced apoptosis upstream of caspase activation.
- Lysosomal integrity is crucial in regulating sphingosine-induced cell fate.