Ambra1 regulates autophagy and development of the nervous system
Ambra1 regulates autophagy and development of the nervous system
复制标题
DOI：
10.1038/nature05925
复制
发表时间：
2007-06-28
期刊：
影响因子：
64.8
通讯作者：
Cecconi, Francesco
中科院分区：
文献类型：
--
作者：
Fimia, Gian Maria;Stoykova, Anastassia;Cecconi, Francesco
自噬是一种自我降解过程，涉及细胞组分的基础周转和对营养饥饿或细胞器损伤的响应（1-3）。在自噬过程中，细胞质的一部分被称为自噬体的双膜囊泡隔离，并在与溶酶体融合后降解，以进行随后的再循环（4）。在脊椎动物中，这一过程在不同的生理和病理条件下（例如神经退行性疾病和癌症）充当促生存或促死亡机制（2，5 -7）;然而，自噬在胚胎发育期间的作用在很大程度上仍然没有得到表征（3）。Beclin 1（Becn 1;卷曲螺旋，肌球蛋白样BCL 2相互作用蛋白）是自噬体形成的主要调节因子，其缺陷导致早期胚胎死亡（8，9）。在这里，我们表明Ambra 1（Beclin 1调节自噬的激活分子），一个大的，以前未知的蛋白质，在其氨基末端带有WD 40结构域，调节自噬，并在胚胎发生中起着至关重要的作用。我们发现Ambra 1是Becn 1依赖性自噬程序的正调节因子，正如其过表达和体外RNA干扰实验所揭示的那样。值得注意的是，小鼠胚胎中Ambra 1功能缺陷导致严重的神经管缺陷，与自噬损伤、泛素化蛋白的积累、不平衡的细胞增殖和过度的凋亡性细胞死亡相关。除了确定一个新的和必不可少的元素调节自噬程序，我们的研究结果提供了体内证据，支持存在一个复杂的相互作用之间的自噬，细胞生长和细胞死亡所需的神经发育哺乳动物。
Autophagy is a self-degradative process involved both in basal turnover of cellular components and in response to nutrient starvation or organelle damage in a wide range of eukaryotes(1-3). During autophagy, portions of the cytoplasm are sequestered by double-membraned vesicles called autophagosomes, and are degraded after fusion with lysosomes for subsequent recycling(4). In vertebrates, this process acts as a pro-survival or pro-death mechanism in different physiological and pathological conditions, such as neurodegeneration and cancer(2,5-7); however, the roles of autophagy during embryonic development are still largely uncharacterized(3). Beclin1 (Becn1; coiled-coil, myosin-like BCL2-interacting protein) is a principal regulator in autophagosome formation, and its deficiency results in early embryonic lethality(8,9). Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy, as revealed by its overexpression and by RNA interference experiments in vitro. Notably, Ambra1 functional deficiency in mouse embryos leads to severe neural tube defects associated with autophagy impairment, accumulation of ubiquitinated proteins, unbalanced cell proliferation and excessive apoptotic cell death. In addition to identifying a new and essential element regulating the autophagy programme, our results provide in vivo evidence supporting the existence of a complex interplay between autophagy, cell growth and cell death required for neural development in mammals.