The Drosophila retinoblastoma protein, Rbf1, induces a Debcl- and Drp1-dependent mitochondrial apoptosis
The Drosophila retinoblastoma protein, Rbf1, induces a Debcl- and Drp1-dependent mitochondrial apoptosis
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DOI：
10.1242/jcs.169896
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发表时间：
2015-09-01
影响因子：
4
通讯作者：
Guenal, Isabelle
中科院分区：
文献类型：
--
作者：
Clavier, Amandine;Ruby, Vincent;Guenal, Isabelle
根据其抑制肿瘤的作用，视网膜母细胞瘤蛋白pRb可以确保促细胞凋亡的功能。Rbf1是Rb的果蝇同源物，在增殖细胞中也显示出促凋亡活性。我们先前已经证明，Rbf1的促凋亡活性依赖于其降低抗凋亡蛋白水平的能力，如Bcl2家族蛋白Buffy。巴菲的行为经常与另一种果蝇Bcl2家族蛋白DebCL相反。这两种蛋白质都可以定位在线粒体上，但它们控制细胞凋亡的方式仍不清楚。在这里，我们证明了在Rbf1诱导的细胞凋亡过程中，DebCL和促裂变基因Drp1是在Buffy下游触发线粒体碎裂所必需的。有趣的是，Rbf1诱导的细胞凋亡导致依赖于Debc1和Drp1的活性氧的产生，这反过来又激活了Jun Kinase途径来触发细胞死亡。此外，我们证明了Debc1和Drp1可以相互作用，而Buffy抑制了这种相互作用。值得注意的是，DebCL在细胞凋亡过程中调节Drp1线粒体的定位。这些结果提供了果蝇Bcl2家族蛋白控制细胞凋亡的机制，并阐明了Rbf1与体内线粒体动力学之间的联系。
In accordance with its tumor suppressor role, the retinoblastoma protein pRb can ensure pro-apoptotic functions. Rbf1, the Drosophila homolog of Rb, also displays a pro-apoptotic activity in proliferative cells. We have previously shown that the Rbf1 pro-apoptotic activity depends on its ability to decrease the level of anti-apoptotic proteins such as the Bcl-2 family protein Buffy. Buffy often acts in an opposite manner to Debcl, the other Drosophila Bcl-2-family protein. Both proteins can localize at the mitochondrion, but the way they control apoptosis still remains unclear. Here, we demonstrate that Debcl and the pro-fission gene Drp1 are necessary downstream of Buffy to trigger a mitochondrial fragmentation during Rbf1-induced apoptosis. Interestingly, Rbf1-induced apoptosis leads to a Debcl-and Drp1-dependent reactive oxygen species production, which in turn activates the Jun Kinase pathway to trigger cell death. Moreover, we show that Debcl and Drp1 can interact and that Buffy inhibits this interaction. Notably, Debcl modulates Drp1 mitochondrial localization during apoptosis. These results provide a mechanism by which Drosophila Bcl-2 family proteins can control apoptosis, and shed light on a link between Rbf1 and mitochondrial dynamics in vivo.