Ordering of ceramide formation and caspase-9 activation in CD95L-induced Jurkat leukemia T cell apoptosis

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• 作者：Elodie Lafont^a ; ^b ; Romain Dupont^a ; Nathalie Andrieu-Abadie^a ; Toshiro Okazaki^c ; Klaus Schulze-Osthoff^d ; Thierry Levade^a ; Hervé ; Benoist^a ; ^b ; Bruno Sé ; gui^a ; ^b ; ^{bruno.segui@inserm.fr}
• 关键词：Bcl-2/xL/x(s) ; B-cell lymphoma-2/xL/x(s) ; Bid ; Bcl-2 interacting domain ; DISC ; death-inducing signaling complex ; GlcCer ; glucosylceramide ; GCS ; glucosylceramide synthase ; SM ; sphingomyelin ; SMS ; sphingomyelin synthase
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：2012
• 期刊代码：18_13881981
• 类别：bio
• 出版时间：April, 2012
• 卷：1821
• 期：4
• 页码：684-693
• 文件大小：1269 K

摘要

Ceramide, a biologically active sphingolipid in cell death signaling, accumulates upon CD95L treatment, concomitantly to apoptosis induction in Jurkat leukemia T cells. Herein, we show that ceramide did not increase in caspase-8 and -10-doubly deficient Jurkat cells in response to CD95L, indicating that apical caspases are essential for CD95L-triggered ceramide formation. Jurkat cells are typically defined as type 2 cells, which require the activation of the mitochondrial pathway for efficient apoptosis induction in response to CD95L. Caspase-9-deficient Jurkat cells significantly resisted CD95L-induced apoptosis, despite ceramide accumulation. Knock-down of sphingomyelin synthase 1, which metabolizes ceramide to sphingomyelin, enhanced (i) CD95L-triggered ceramide production, (ii) cytochrome c release from the mitochondria and (iii) caspase-9 activation. Exogenous ceramide-induced caspase-3 activation and apoptosis were impaired in caspase-9-deficient Jurkat cells. Conversely, caspase-9 re-expression in caspase-9-deficient Jurkat cells restored caspase-3 activation and apoptosis upon exogenous ceramide treatment. Collectively, our data provide genetic evidence that CD95L-triggered endogenous ceramide increase in Jurkat leukemia T cells (i) is not a mere consequence of cell death and occurs mainly in a caspase-9-independent manner, (ii) is likely involved in the pro-apoptotic mitochondrial pathway leading to caspase-9 activation.