Kaiser W J, Vucic D, Miller L K
Department of Entomology, The University of Georgia, Athens 30602, USA.
FEBS Lett. 1998 Nov 27;440(1-2):243-8. doi: 10.1016/s0014-5793(98)01465-3.
Many members of the Inhibitor of Apoptosis (IAP) family inhibit cell death and existing data suggest at least two mechanisms of action. Drosophila IAPs (D-IAP1 and D-IAP2) and a baculovirus-derived IAP, Op-IAP, physically interact with and inhibit the anti-apoptotic activity of Reaper, HID, and Grim, three genetically defined inducers of apoptosis in Drosophila, while human IAPs, c-IAP1, c-IAP2, and X-IAP interact with a number of different proteins including specific members of the caspase family of cysteine proteases which are crucial in the execution of cell death. We have examined whether insect-active IAPs can inhibit apoptosis induced by selected caspases, Drosophila drICE, Sf-caspase-1, and mammalian caspase-3, in insect SF-21 cells. D-IAP1 inhibited apoptosis induced by the active forms of all three caspases tested and physically interacted with the active, but not the proform of drICE. MIHA, the mouse homolog of X-IAP and an effective inhibitor of caspase-3, also interacted with and blocked apoptosis induced by active drICE but was relatively ineffective in blocking Sf-caspase-1. Op-IAP and D-IAP2 were unable to inhibit effectively any of the active caspases tested and failed to interact with drICE. The Drosophila IAPs and Op-IAP, but not MIHA, blocked HID-initiated activation of pro-drICE. We conclude that D-IAP1 is capable of inhibiting the activation of drICE as well as inhibiting apoptosis induced by the active form of drICE. In contrast, D-IAP2 and Op-IAP are more limited in their inhibitory targets and may be limited to inhibiting the activation of caspases.
凋亡抑制蛋白（IAP）家族的许多成员可抑制细胞死亡，现有数据表明其至少有两种作用机制。果蝇IAP（D-IAP1和D-IAP2）以及一种杆状病毒衍生的IAP，即Op-IAP，可与果蝇中三种遗传学上定义的凋亡诱导因子Reaper、HID和Grim发生物理相互作用，并抑制其抗凋亡活性，而人类IAP，即c-IAP1、c-IAP2和X-IAP，则与许多不同蛋白质相互作用，包括半胱氨酸蛋白酶caspase家族的特定成员，这些成员在细胞死亡的执行过程中至关重要。我们研究了具有昆虫活性的IAP是否能在昆虫SF-21细胞中抑制由选定的caspase，即果蝇drICE、Sf-caspase-1和哺乳动物caspase-3诱导的凋亡。D-IAP1抑制了所测试的所有三种caspase活性形式诱导的凋亡，并与活性形式的drICE发生物理相互作用，但不与drICE的前体形式相互作用。MIHA是X-IAP的小鼠同源物，也是caspase-3的有效抑制剂，它也与活性drICE相互作用并阻断其诱导的凋亡，但在阻断Sf-caspase-1方面相对无效。Op-IAP和D-IAP2不能有效抑制所测试的任何一种活性caspase，也未能与drICE相互作用。果蝇IAP和Op-IAP，但不包括MIHA，阻断了HID引发的前体drICE的激活。我们得出结论，D-IAP1能够抑制drICE的激活以及活性形式的drICE诱导的凋亡。相比之下，D-IAP2和Op-IAP的抑制靶点更为有限，可能仅限于抑制caspase的激活。
