We propose a new mechanism for sphingosine-induced apoptosis, involving relocation of lysosomal hydrolases to the cytosol. Owing to its lysosomotropic properties, sphingosine, which is also a detergent, especially when protonated, accumulates by proton trapping within the acidic vacuolar apparatus, where most of its action as a detergent would be exerted. When sphingosine was added in low-to-moderate concentrations to Jurkat and J774 cells, partial lysosomal rupture occurred dose-dependently, starting within a few minutes. This phenomenon preceded caspase activation, as well as changes of mitochondrial membrane potential. High sphingosine doses rapidly caused extensive lysosomal rupture and ensuing necrosis, without antecedent apoptosis or caspase activation. The sphingosine effect was prevented by pre-treatment with another, non-toxic, lysosomotropic base, ammonium chloride, at 10mM. The lysosomal protease inhibitors, pepstatin A and epoxysuccinyl-l-leucylamido-3-methyl-butane ethyl ester (‘E-64d’), inhibited markedly sphingosine-induced caspase activity to almost the same degree as the general caspase inhibitor benzyloxycarbonyl-Val-Ala-dl-Asp-fluoromethylketone (‘Z-VAD-FMK’), although they did not by themselves inhibit caspases. We conclude that cathepsin D and one or more cysteine proteases, such as cathepsins B or L, are important mediators of sphingosine-induced apoptosis, working upstream of the caspase cascade and mitochondrial membrane-potential changes.
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October 2001
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Research Article|
October 08 2001
Sphingosine-induced apoptosis is dependent on lysosomal proteases
Katarina KÅGEDAL
;
Katarina KÅGEDAL
Division of Pathology II, Faculty of Health Sciences, Linköping University, Linköping, Sweden
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Ming ZHAO
;
Ming ZHAO
Division of Pathology II, Faculty of Health Sciences, Linköping University, Linköping, Sweden
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Iréne SVENSSON
;
Iréne SVENSSON
Division of Pathology II, Faculty of Health Sciences, Linköping University, Linköping, Sweden
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Ulf T. BRUNK
Ulf T. BRUNK
1
Division of Pathology II, Faculty of Health Sciences, Linköping University, Linköping, Sweden
1To whom correspondence should be addressed (e-mail ulf.brunk@pat.liu.se).
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Biochem J (2001) 359 (2): 335–343.
Article history
Received:
March 09 2001
Revision Received:
June 18 2001
Accepted:
August 08 2001
Citation
Katarina KÅGEDAL, Ming ZHAO, Iréne SVENSSON, Ulf T. BRUNK; Sphingosine-induced apoptosis is dependent on lysosomal proteases. Biochem J 15 October 2001; 359 (2): 335–343. doi: https://doi.org/10.1042/bj3590335
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