Kiessling S, Green D R
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California, USA.
Apoptosis. 2006 Apr;11(4):497-507. doi: 10.1007/s10495-006-5341-6.
In Drosophila, the APAF-1 homolog ARK is required for the activation of the initiator caspase DRONC, which in turn cleaves the effector caspases DRICE and DCP-1. While the function of ARK is important in stress-induced apoptosis in Drosophila S2 cells, as its removal completely suppresses cell death, the decision to undergo apoptosis appears to be regulated at the level of caspase activation, which is controlled by the IAP proteins, particularly DIAP1. Here, we further dissect the apoptotic pathways induced in Drosophila S2 cells in response to stressors and in response to knock-down of DIAP1. We found that the induction of apoptosis was dependent in each case on expression of ARK and DRONC and surviving cells continued to proliferate. We noted a difference in the effects of silencing the executioner caspases DCP-1 and DRICE; knock-down of either or both of these had dramatic effects to sustain cell survival following depletion of DIAP1, but had only minor effects following cellular stress. Our results suggest that the executioner caspases are essential for death following DIAP1 knock-down, indicating that the initiator caspase DRONC may lack executioner functions. The apparent absence of mitochondrial outer membrane permeabilization (MOMP) in Drosophila apoptosis may permit the cell to thrive when caspase activation is disrupted.
在果蝇中，凋亡蛋白酶激活因子-1（APAF-1）的同源物ARK是起始胱天蛋白酶DRONC激活所必需的，而DRONC继而切割效应胱天蛋白酶DRICE和DCP-1。虽然ARK的功能在果蝇S2细胞应激诱导的凋亡中很重要，因为去除ARK会完全抑制细胞死亡，但细胞是否发生凋亡的决定似乎在胱天蛋白酶激活水平受到调控，而胱天蛋白酶激活由凋亡抑制蛋白（IAP）控制，尤其是DIAP1。在此，我们进一步剖析了果蝇S2细胞中对应激源和DIAP1敲低所诱导的凋亡途径。我们发现，在每种情况下，凋亡的诱导都依赖于ARK和DRONC的表达，存活的细胞继续增殖。我们注意到沉默效应胱天蛋白酶DCP-1和DRICE的效果存在差异；在DIAP1耗尽后，敲低其中任何一个或两者对维持细胞存活都有显著影响，但在细胞应激后只有轻微影响。我们的结果表明，效应胱天蛋白酶对于DIAP1敲低后的细胞死亡至关重要，这表明起始胱天蛋白酶DRONC可能缺乏效应功能。果蝇凋亡中明显不存在线粒体外膜通透性改变（MOMP），这可能使细胞在胱天蛋白酶激活被破坏时仍能存活。
