Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis
Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis
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DOI：
10.1007/s13238-010-0048-4
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发表时间：
2010-05-01
期刊：
影响因子：
21.1
通讯作者：
Chen, Quan
中科院分区：
文献类型：
--
作者：
Zhu, Yushan;Zhao, Lixia;Chen, Quan
自噬和细胞凋亡都是高度调节的生物学过程，在组织的稳态、发育和疾病中起着重要作用。自噬也被描述为死亡途径的一种机制，然而，自噬如何与细胞死亡联系的确切机制仍有待充分理解。Beclin 1是自噬和凋亡的双重调节因子。在这项研究中，我们发现Beclin 1是caspase-3的底物，分别在124和149位具有两个切割位点。此外，自噬体的形成发生，随后出现凋亡的形态学标志后，星形孢菌素治疗。Beclin 1的裂解产物在HeLa细胞和Beclin 1被特异性shRNA稳定敲低的细胞中减少自噬并促进凋亡。此外，Beclin 1的切割导致Bcl-2与Beclin 1之间的相互作用被取消，这可以被z-VAD-fatal阻断。因此，我们的研究结果表明，半胱天冬酶-3切割Beclin 1可能有助于细胞自噬，导致细胞凋亡增加。
Autophagy and apoptosis are both highly regulated biological processes that play essential roles in tissue homeostasis, development and diseases. Autophagy is also described as a mechanism of death pathways, however, the precise mechanism of how autophagy links to cell death remains to be fully understood. Beclin 1 is a dual regulator for both autophagy and apoptosis. In this study we found that Beclin 1 was a substrate of caspase-3 with two cleavage sites at positions 124 and 149, respectively. Furthermore, the autophagosome formation occurred, followed by the appearance of morphological hallmarks of apoptosis after staurosporine treatment. The cleavage products of Beclin 1 reduced autophagy and promoted apoptosis in HeLa cells and the cells in which Beclin 1 was stably knocked down by specific shRNA. In addition, the cleavage of Beclin 1 resulted in abrogating the interaction between Bcl-2 with Beclin 1, which could be blocked by z-VAD-fmk. Thus, our results suggest that the cleavage of Beclin 1 by caspase-3 may contribute to inactivate autophagy leading towards augmented apoptosis.