Inactivation of effector caspases through nondegradative polyubiquitylation.
Inactivation of effector caspases through nondegradative polyubiquitylation.
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DOI：
10.1016/j.molcel.2008.09.025
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发表时间：
2008-11-21
期刊：
影响因子：
16
通讯作者：
Meier, Pascal
中科院分区：
文献类型：
--
作者：
Ditzel, Mark;Broemer, Meike;Tenev, Tencho;Boiduc, Clare;Lee, Tom V.;Rigbolt, Kristoffer T. G.;Elliot, Richard;Zvelebil, Marketa;Blagoev, Blagoy;Bergmann, Andreas;Meier, Pascal
泛素介导的半胱天冬酶失活长期以来一直被认为有助于细胞凋亡的调节。然而，caspase泛素化的详细机制和功能后果尚未得到证实。在这里，我们表明，果蝇细胞凋亡抑制剂1，DIAP 1，通过靶向多泛素化和非蛋白酶体失活阻断效应caspase。我们证明了泛素与drICE的缀合抑制了其在切割半胱天冬酶底物中的催化潜力。我们的数据表明，泛素共轭空间干扰底物进入，降低caspase的蛋白水解速度。通过DIAP 1的E3活性或drICE的泛素受体赖氨酸的突变破坏drICE泛素化，消除DIAP 1中和drICE并抑制体内细胞凋亡的能力。我们还表明，DIAP1休息在一个“非活性”的构象，需要半胱天冬酶介导的切割，随后泛素化半胱天冬酶。综上所述，我们的研究结果表明，效应半胱天冬酶调节自己的抑制通过负反馈机制，涉及DIAP 1的“激活”和非降解的多聚泛素化。
Ubiquitin-mediated inactivation of caspases has long been postulated to contribute to the regulation of apoptosis. However, detailed mechanisms and functional consequences of caspase ubiquitylation have not been demonstrated. Here we show that the Drosophila Inhibitor of Apoptosis 1, DIAP1, blocks effector caspases by targeting them for polyubiquitylation and nonproteasomal inactivation. We demonstrate that the conjugation of ubiquitin to drICE suppresses its catalytic potential in cleaving caspase substrates. Our data suggest that ubiquitin conjugation sterically interferes with substrate entry and reduces the caspase’s proteolytic velocity. Disruption of drICE ubiquitylation, either by mutation of DIAP1’s E3 activity or drICE’s ubiquitin-acceptor lysines, abrogates DIAP1’s ability to neutralize drICE and suppress apoptosis in vivo. We also show that DIAP1 rests in an “inactive” conformation that requires caspase-mediated cleavage to subsequently ubiquitylate caspases. Taken together, our findings demonstrate that effector caspases regulate their own inhibition through a negative feedback mechanism involving DIAP1 “activation” and nondegradative polyubiquitylation.
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