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首页> 外文期刊>Autophagy >Unleashing the Ambra1-Beclin 1 complex from dynein chains: Ulk1 sets Ambra1 free to induce autophagy.
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Unleashing the Ambra1-Beclin 1 complex from dynein chains: Ulk1 sets Ambra1 free to induce autophagy.

机译：从动力蛋白链释放Ambra1-Beclin 1复合物：Ulk1使Ambra1释放以诱导自噬。

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摘要

The Beclin 1-VPS34 complex plays a crucial role in the induction of the autophagic process by generating PtdIns(3)P-rich membranes, which act as platforms for ATG protein recruitment and autophagosome nucleation. Several cofactors, such as Ambra1, ATG14 and UVRAG, are necessary for Beclin 1 complex activity. However, the mechanism by which Beclin 1 complex activity is: stimulated by autophagic stimuli has not yet been fully elucidated. Recently, we reported that autophagosome formation in mammalian cells is primed by Ambra1 release from the dynein motor complex. We found that Ambra1 specifically binds the dynein motor complex under normal conditions through a direct interaction with DLC1. When autophagy is induced, Ambra1-DLC1 are released from the dynein complex in an ULK1-dependent manner, and relocalize to the endoplasmic reticulum, thus enabling autophagosome nucleation. In addition, we found that both DLC1 downregulation and Ambra1 mutations in its DLC1-binding sites strongly enhance autophagosome formation. Ambra1 is therefore not only a cofactor of Beclin 1 in favoring its kinase-associated activity, but also a crucial upstream regulator of autophagy initiation.
机译：Beclin 1-VPS34复合物通过生成富含PtdIns（3）P的膜，在自噬过程的诱导中起关键作用，该膜充当ATG蛋白募集和自噬体成核的平台。 Beclin 1复合物活性需要几种辅助因子，例如Ambra1，ATG14和UVRAG。但是，尚不能完全阐明Beclin 1复合物活性的机制：受自噬刺激的刺激。最近，我们报道哺乳动物细胞中自噬体的形成是由动力蛋白复合物释放的Ambra1引发的。我们发现，Ambra1在正常条件下通过与DLC1的直接相互作用与动力蛋白复合物特异性结合。诱导自噬时，Ambra1-DLC1以依赖于ULK1的方式从动力蛋白复合物中释放出来，并重新定位到内质网，从而实现自噬体成核。此外，我们发现DLC1的下调和其DLC1结合位点中的Ambra1突变都强烈增强自噬体的形成。因此，Ambra1不仅是Beclin 1的辅因子，有利于其激酶相关活性，而且还是自噬启动的关键上游调节剂。

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