Role of an acidic compartment in tumor-necrosis-factor-α-induced production of ceramide, activation of caspase-3 and apoptosis

被引:98
作者
Monney, L
Olivier, R
Otter, I
Jansen, B
Poirier, GG
Borner, C
机构
[1] Univ Fribourg, Inst Biochem, CH-1700 Fribourg, Switzerland
[2] Univ Vienna, Vienna Gen Hosp, Dept Clin Pharmacol, Vienna, Austria
[3] Univ Laval, Res Ctr, Ctr Hosp, Poly ADP Ribose Metab Grp, St Foy, PQ, Canada
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 1998年 / 251卷 / 1-2期
关键词
apoptosis; lysosome; ceramide; Bcl-2; tumor-necrosis factor-alpha;
D O I
10.1046/j.1432-1327.1998.2510295.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tumor necrosis factor-alpha (TNF-alpha) apoptosis by recruiting a complex of cytosolic proteins at its plasma membrane receptor. Among them is caspase-8, an interleukin-1 beta-converting enzyme (ICE)-like pretease that initiates an amplified protease cascade to activate the cell-death machinery. The latter comprises at least caspase-3 and caspase-7, which execute cell death by cleaving numerous protein substrates, including poly(ADP-ribose) polymerase. In addition, TNF-alpha stimulates the production of ceramide, which also activates the death machinery. Whether the signaling pathways elicited by caspase-8 and ceramide proceed independently or intersect at a specific subcellular site is unknown. Using the lysosomotropic agent NH4Cl and the vesicularization inhibitor brefeldin A, we show here the convergence of TNF-alpha-induced death signaling on an acidic, subcellular compartment reminiscent of lysosomes. This compartment generates at least two signaling pathways that account for the caspase-3 activation and apoptosis induced by TNF-alpha, one involving ceramide and caspase-unrelated adapter molecules and another involving yet unknown lysosomal mediators. The apoptosis inhibitor Bcl-2 specifically acts on the ceramide-activated pathway to block caspase-3 activation and apoptosis. The latter result explains why Bcl-2 only partially blocks TNF-alpha-induced apoptosis.
引用
收藏
页码:295 / 303
页数:9
相关论文
共 63 条
[11]   Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-alpha: CrmA and Bcl-2 target distinct components in the apoptotic pathway [J].
Dbaibo, GS ;
Perry, DK ;
Gamard, CJ ;
Platt, R ;
Poirier, GG ;
Obeid, LM ;
Hannun, YA .
JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 185 (03) :481-490
[12]   Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha [J].
Deiss, LP ;
Galinka, H ;
Berissi, H ;
Cohen, O ;
Kimchi, A .
EMBO JOURNAL, 1996, 15 (15) :3861-3870
[13]   AN ISOFORM OF THE PHOSPHATIDYLINOSITOL-TRANSFER PROTEIN TRANSFERS SPHINGOMYELIN AND IS ASSOCIATED WITH THE GOLGI SYSTEM [J].
DEVRIES, KJ ;
HEINRICHS, AAJ ;
CUNNINGHAM, E ;
BRUNINK, F ;
WESTERMAN, J ;
SOMERHARJU, PJ ;
COCKCROFT, S ;
WIRTZ, KWA ;
SNOEK, GT .
BIOCHEMICAL JOURNAL, 1995, 310 :643-649
[14]   ICE-LAP3, a novel mammalian homologue of the Caenorhabditis elegans cell death protein ced-3 is activated during fas- and tumor necrosis factor-induced apoptosis [J].
Duan, HJ ;
Chinnaiyan, AM ;
Hudson, PL ;
Wing, JP ;
He, WW ;
Dixit, VM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (03) :1621-1625
[15]  
FERNANDESALNEMRI T, 1995, CANCER RES, V55, P6045
[16]  
GarciaRuiz C, 1997, J BIOL CHEM, V272, P11369
[17]   Ceramides induce a form of apoptosis in human acute lymphoblastic leukemia cells that is inhibited by Bcl-2, but not by CrmA [J].
Geley, S ;
Hartmann, BL ;
Kofler, R .
FEBS LETTERS, 1997, 400 (01) :15-18
[18]   Functions of ceramide in coordinating cellular responses to stress [J].
Hannun, YA .
SCIENCE, 1996, 274 (5294) :1855-1859
[19]   LIPID PEROXIDE MAKES RABBIT PLATELET HYPERAGGREGABLE TO AGONISTS THROUGH PHOSPHOLIPASE-A2 ACTIVATION [J].
HASHIZUME, T ;
YAMAGUCHI, H ;
KAWAMOTO, A ;
TAMURA, A ;
SATO, T ;
FUJII, T .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1991, 289 (01) :47-52
[20]  
HAYAKAWA M, 1993, J BIOL CHEM, V268, P11290