Leulier F, Ribeiro P S, Palmer E, Tenev T, Takahashi K, Robertson D, Zachariou A, Pichaud F, Ueda R, Meier P
The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK.
Cell Death Differ. 2006 Oct;13(10):1663-74. doi: 10.1038/sj.cdd.4401868. Epub 2006 Feb 17.
Despite the identification of numerous key players of the cell death machinery, little is known about their physiological role. Using RNA interference (RNAi) in vivo, we have studied the requirement of all Drosophila caspases and caspase-adaptors in different paradigms of apoptosis. Of the seven caspases, Dronc, drICE, Strica and Decay are rate limiting for apoptosis. Surprisingly, Hid-mediated apoptosis requires a broader range of caspases than apoptosis initiated by loss of the caspase inhibitor DIAP1, suggesting that Hid causes apoptosis not only by antagonizing DIAP1 but also by activating DIAP1-independent caspase cascades. While Hid killing requires Strica, Decay, Dronc/Dark and drICE, apoptosis triggered by DIAP1 depletion merely relied upon Dronc/Dark and drICE. Furthermore, we found that overexpression of DIAP2 can rescue diap1-RNAi-mediated apoptosis, suggesting that DIAP2 regulates caspases directly. Consistently, we show that DIAP2 binds active drICE. Since DIAP2 associates with Hid, we propose a model whereby Hid co-ordinately targets both DIAP1 and DIAP2 to unleash drICE.
尽管已经鉴定出细胞死亡机制的众多关键参与者，但对其生理作用却知之甚少。我们利用体内RNA干扰（RNAi）技术，研究了果蝇所有半胱天冬酶和半胱天冬酶衔接蛋白在不同凋亡模式中的需求。在七种半胱天冬酶中，Dronc、drICE、Strica和Decay对凋亡起限速作用。令人惊讶的是，与由半胱天冬酶抑制剂DIAP1缺失引发的凋亡相比，Hid介导的凋亡需要更广泛的半胱天冬酶参与，这表明Hid不仅通过拮抗DIAP1引发凋亡，还通过激活不依赖DIAP1的半胱天冬酶级联反应来导致凋亡。虽然Hid诱导的细胞死亡需要Strica、Decay、Dronc/Dark和drICE，但DIAP1缺失引发的凋亡仅依赖于Dronc/Dark和drICE。此外，我们发现DIAP2的过表达可以挽救diap1-RNAi介导的凋亡，这表明DIAP2直接调节半胱天冬酶。与此一致，我们证明DIAP2与活性drICE结合。由于DIAP2与Hid相关联，我们提出了一个模型，即Hid协同靶向DIAP1和DIAP2以释放drICE。
