Zheng T S, Hunot S, Kuida K, Momoi T, Srinivasan A, Nicholson D W, Lazebnik Y, Flavell R A
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Nat Med. 2000 Nov;6(11):1241-7. doi: 10.1038/81343.
Dysregulation of apoptosis contributes to the pathogenesis of many human diseases. As effectors of the apoptotic machinery, caspases are considered potential therapeutic targets. Using an established in vivo model of Fas-mediated apoptosis, we demonstrate here that elimination of certain caspases was compensated in vivo by the activation of other caspases. Hepatocyte apoptosis and mouse death induced by the Fas agonistic antibody Jo2 required proapoptotic Bcl-2 family member Bid and used a Bid-mediated mitochondrial pathway of caspase activation; deficiency in caspases essential for this pathway, caspase-9 or caspase-3, unexpectedly resulted in rapid activation of alternate caspases after injection of Jo2, and therefore failed to protect mice against Jo2 toxicity. Moreover, both ultraviolet and gamma irradiation, two established inducers of the mitochondrial caspase-activation pathway, also elicited compensatory activation of caspases in cultured caspase-3(-/-) hepatocytes, indicating that the compensatory caspase activation was mediated through the mitochondria. Our findings provide direct experimental evidence for compensatory pathways of caspase activation. This issue should therefore be considered in developing caspase inhibitors for therapeutic applications.
细胞凋亡失调与许多人类疾病的发病机制有关。作为凋亡机制的效应器，半胱天冬酶被认为是潜在的治疗靶点。利用已建立的Fas介导的细胞凋亡体内模型，我们在此证明，某些半胱天冬酶的缺失在体内可通过其他半胱天冬酶的激活得到补偿。Fas激动性抗体Jo2诱导的肝细胞凋亡和小鼠死亡需要促凋亡Bcl-2家族成员Bid，并使用Bid介导的半胱天冬酶激活线粒体途径；该途径所必需的半胱天冬酶caspase-9或caspase-3的缺陷，在注射Jo2后意外地导致了替代半胱天冬酶的快速激活，因此未能保护小鼠免受Jo2毒性的影响。此外，紫外线和γ射线这两种已确定的线粒体半胱天冬酶激活途径诱导剂，也在培养的caspase-3(-/-)肝细胞中引发了半胱天冬酶的代偿性激活，表明代偿性半胱天冬酶激活是通过线粒体介导的。我们的研究结果为半胱天冬酶激活的代偿途径提供了直接的实验证据。因此，在开发用于治疗应用的半胱天冬酶抑制剂时应考虑这个问题。
