Caspase-10-Dependent Cell Death in Fas/CD95 Signalling Is Not Abrogated by Caspase Inhibitor zVAD-fmk

被引:13
|
作者
Lafont, Elodie [1 ,2 ,3 ]
Milhas, Delphine [1 ,2 ]
Teissie, Justin [4 ]
Therville, Nicole [1 ,2 ]
Andrieu-Abadie, Nathalie [1 ,2 ]
Levade, Thierry [1 ,2 ]
Benoist, Herve [1 ,2 ,3 ]
Segui, Bruno [1 ,2 ,3 ]
机构
[1] U858 INSERM Inst Natl Sante & Rech Med, Equipe 14, Dept Canc, Toulouse, France
[2] Inst Med Mol Rangueil, Inst Federatif Rech 150, Toulouse, France
[3] Univ Toulouse 3, Fac Pharmaceut Sci, F-31062 Toulouse, France
[4] CNRS, IPBS, Inst Pharmacol & Biol Struct, Unite Mixte Rech 5089, Toulouse, France
来源
PLOS ONE | 2010年 / 5卷 / 10期
关键词
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; NF-KAPPA-B; INDUCED APOPTOSIS; EPITHELIAL-CELLS; FAS; DOMAIN; FADD; RECEPTOR; PATHWAY; PROTEIN;
D O I
10.1371/journal.pone.0013638
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Upon CD95/Fas ligation, the initiator caspase-8 is known to activate effector caspases leading to apoptosis. In the presence of zVAD-fmk, a broad-spectrum caspase inhibitor, Fas engagement can also trigger an alternative, nonapoptotic caspase-independent form of cell death, which is initiated by RIP1. Controversy exists as to the ability of caspase-10 to mediate cell death in response to FasL (CD95L or CD178). Herein, the role of caspase-10 in FasL-induced cell death has been re-evaluated. Methodology and Principal Findings: The present study shows that FasL-induced cell death was completely impaired in caspase-8- and caspase-10-doubly deficient (I9-2e) Jurkat leukaemia T-cell lines. Over-expressing of either caspase-8 or caspase-10 in I9-2e cells triggered cell death and restored sensitivity to FasL, further arguing for a role of both initiator caspases in Fas apoptotic signalling. In the presence of zVAD-fmk, FasL triggered an alternative form of cell death similarly in wild-type (A3) and in caspase-8-deficient Jurkat cells expressing endogenous caspase-10 (clone I9-2d). Cell death initiated by Fas stimulation in the presence of zVAD-fmk was abrogated in I9-2e cells as well as in HeLa cells, which did not express endogenous caspase-10, indicating that caspase-10 somewhat participates in this alternative form of cell death. Noteworthy, ectopic expression of caspase-10 in I9-2e and HeLa cells restored the ability of FasL to trigger cell death in the presence of zVAD-fmk. As a matter of fact, FasL-triggered caspase-10 processing still occurred in the presence of zVAD-fmk. Conclusions and Significance: Altogether, these data provide genetic evidence for the involvement of initiator caspase-10 in FasL-induced cell death and indicate that zVAD-fmk does not abrogate caspase-10 processing and cytotoxicity in Fas signalling. Our study also questions the existence of an alternative caspase-independent cell death pathway in Fas signalling.
引用
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页数:11
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