Faculty Collaboration Database

Stress-induced apoptosis is not mediated by endolysosomal ceramide. FASEB J 2000 Jan;14(1):36-47

Date

01/08/2000

Pubmed ID

10627278

DOI

10.1096/fasebj.14.1.36

Scopus ID

2-s2.0-0038035591 (requires institutional sign-in at Scopus site)   51 Citations

Abstract

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-alpha 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-alpha 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-alpha, 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-alpha and CD40 ligand.

Author List

Ségui B, Bezombes C, Uro-Coste E, Medin JA, Andrieu-Abadie N, Augé N, Brouchet A, Laurent G, Salvayre R, Jaffrézou JP, Levade T

Author

Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Apoptosis
CD40 Antigens
Cell Line, Transformed
Cell Survival
Ceramides
Daunorubicin
Humans
Hydrogen-Ion Concentration
Hydrolysis
Lysosomal Storage Diseases
Lysosomes
Signal Transduction
Sphingomyelins
Stress, Physiological
Tumor Necrosis Factor-alpha
fas Receptor