Stress-induced apoptosis is impaired in cells with a lysosomal targeting defect but is not affected in cells synthesizing a catalytically inactive cathepsin D.
The role of cathepsin D in stress-induced cell death has been investigated by using ovine fibroblasts exhibiting a missense mutation in the active site of cathepsin D. The cathepsin D (lysosomal aspartic protease) deficiency did not protect cells against toxicity induced by doxorubicin and other cytotoxic agents, neither did it protect cells from caspase activation. Moreover, the cathepsin D inhibitor, pepstatin A, did not prevent stress-induced cell death in human fibroblasts or lymphoblasts. The possible role of lysosomal ceramide or sphingosine-mediated activation of cathepsin D in apoptosis was also excluded by using human cells either overexpressing or deficient in acid ceramidase. However, a normal lysosomal function seems to be required for efficient cell death, as indicated by the finding that fibroblasts from patients with mucolipidosis II were partially resistant to staurosporine, sphingosine and TNF-induced apoptosis, suggesting a key role of lysosomes in cell death.
Tardy
C
C
INSERM U466, Institut Louis Bugnard, Centre Hospitalier Universitaire de Rangueil, Toulouse, France.
Tyynelä
J
J
Hasilik
A
A
Levade
T
T
Andrieu-Abadie
N
N
D055573:Acid Ceramidase; D000581:Amidohydrolases / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D020134:Catalytic Domain; D002402:Cathepsin D / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002403:Cathepsins / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D055572:Ceramidases; D002518:Ceramides / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D009081:Mucolipidoses / Q000473:pathology; D020125:Mutation, Missense; D010436:Pepstatins / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D012756:Sheep
D002518:Ceramides; D010436:Pepstatins; D011480:Protease Inhibitors; D004317:Doxorubicin; D002403:Cathepsins; D020169:Caspases; D002402:Cathepsin D; D000581:Amidohydrolases; C526693:ASAH1 protein, human; D055573:Acid Ceramidase; D055572:Ceramidases; C031375:pepstatin