Muzio M, Salvesen G S, Dixit V M
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
J Biol Chem. 1997 Jan 31;272(5):2952-6. doi: 10.1074/jbc.272.5.2952.
Engagement of CD95 or tumor necrosis factor 1 receptor (TNFR-1) by ligand or agonist antibodies is capable of activating the cell death program, the effector arm of which is composed of mammalian interleukin-1beta converting enzyme (ICE)-like cysteine proteases (designated caspases) that are related to the Caenorhabditis elegans death gene, CED-3. Caspases, unlike other mammalian cysteine proteases, cleave their substrates following aspartate residues. Furthermore, proteases belonging to this family exist as zymogens that in turn require cleavage at internal aspartate residues to generate the two-subunit active enzyme. As such, family members are capable of activating each other. Remarkably, both CD95 and TNFR-1 death receptors initiate apoptosis by recruiting a novel ICE/CED-3 family member, designated FLICE/MACH, to the receptor signaling complex. Therefore, FLICE/MACH represents the apical triggering protease in the cascade. Consistent with this, recombinant FLICE was found capable of proteolytically activating downstream caspases. Furthermore, CrmA, a pox virus-encoded serpin that inhibits Fas and tumor necrosis factor-induced cell death attenuates the ability of FLICE to activate downstream caspases.
配体或激动剂抗体与CD95或肿瘤坏死因子1受体（TNFR-1）结合能够激活细胞死亡程序，该程序的效应器由与秀丽隐杆线虫死亡基因CED-3相关的哺乳动物白细胞介素-1β转化酶（ICE）样半胱氨酸蛋白酶（称为半胱天冬酶）组成。与其他哺乳动物半胱氨酸蛋白酶不同，半胱天冬酶在天冬氨酸残基之后切割其底物。此外，属于该家族的蛋白酶以酶原形式存在，而酶原又需要在内部天冬氨酸残基处切割以产生双亚基活性酶。因此，家族成员能够相互激活。值得注意的是，CD95和TNFR-1死亡受体均通过将一种名为FLICE/MACH的新型ICE/CED-3家族成员招募到受体信号复合物中来启动细胞凋亡。因此，FLICE/MACH代表级联反应中的顶端触发蛋白酶。与此一致的是，发现重组FLICE能够通过蛋白水解作用激活下游半胱天冬酶。此外，CrmA是一种痘病毒编码的丝氨酸蛋白酶抑制剂，可抑制Fas和肿瘤坏死因子诱导的细胞死亡，它会减弱FLICE激活下游半胱天冬酶的能力。
