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,1
* INSERM U466, Laboratoire de Biochimie, Maladies Métaboliques, Institut Louis Bugnard, C.H.U. Rangueil, 31403 Toulouse, France;
INSERM E9910, Institut Claudius Régaud, 31052 Toulouse, France; and
Section of Hematology/Oncology, University of Illinois at Chicago, Chicago, Illinois, USA
2Correspondence: INSERM U. 466, Laboratoire de Biochimie, ‘Maladies Métaboliques’, Institut Louis Bugnard, Bât. L3, C.H.U. Rangueil, 1 Avenue Jean Poulhès, F-31403 Toulouse Cedex 4, France. E-mail: levade{at}rangueil.inserm.fr
A major lipid-signaling pathway in mammalian cells implicates the
generation of ceramide from the ubiquitous sphingolipid sphingomyelin
(SM). Hydrolysis of SM by a sphingomyelinase present in acidic
compartments has been reported to mediate, via the production of
ceramide, the apoptotic cell death triggered by stress-inducing agents.
In the present study, we investigated whether the ceramide formed
within or accumulated in lysosomes indeed triggers apoptosis. A series
of observations strongly suggests that ceramide involved in
stress-induced apoptosis is not endolysosomal: 1)
Although short-chain ceramides induced apoptosis, loading cells with
natural ceramide through receptor-mediated endocytosis did not result
in cell death. 2) Neither TNF-
nor anti-CD95 induced
the degradation to ceramide of a natural SM that had been first
introduced selectively into acidic compartments. 3)
Stimulation of SV40-transformed fibroblasts by TNF- or CD40 ligand
resulted in apoptosis equally well in cells derived from control
individuals and from patients affected with Farber disease, having a
genetic defect of acid ceramidase activity leading to lysosomal
accumulation of ceramide. Also, induction of apoptosis using anti-CD95
(Fas) or anti-CD40 antibodies, TNF-, daunorubicin, and ionizing
radiation was similar in control and Farber disease lymphoid cells. In
all cases, apoptosis was preceded by a comparable increase of
intracellular ceramide levels. 4) Retroviral-mediated
gene transfer and overexpression of acid ceramidase in Farber
fibroblasts, which led to complete metabolic correction of the ceramide
catabolic defect, did not affect the cell response to TNF- and CD40
ligand.— Ségui, B., Bezombes, C., Uro-Coste, E., Medin, J. A., Andrieu-Abadie, N., Augé, N., Brouchet, A., Laurent, G.,
Salvayre, R., Jaffrézou, J.-P., Levade, T. Stress-induced
apoptosis is not mediated by endolysosomal ceramide.
Key Words: sphingomyelin • sphingomyelinase • Farber disease • ceramidase • lysosome • signal transduction
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