Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex.
Beclin 1 is required for neuron viability and regulates endosome pathways via the UVRAG-VPS34 complex.
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DOI：
10.1371/journal.pgen.1004626
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发表时间：
2014-10
期刊：
影响因子：
4.5
通讯作者：
Yue Z
中科院分区：
文献类型：
--
作者：
McKnight NC;Zhong Y;Wold MS;Gong S;Phillips GR;Dou Z;Zhao Y;Heintz N;Zong WX;Yue Z
自噬蛋白beclin 1的缺陷与肿瘤发生和神经退行性疾病有关，但其分子机制尚不清楚。先前的研究表明，Beclin 1协调多个VPS 34复合物的组装，其不同的磷脂酰肌醇3-激酶III（PI 3 K-III）脂质激酶活性在不同的步骤调节自噬。最近的证据表明，beclin 1在调节多种VPS 34介导的自噬以外的运输途径中的功能;然而，beclin 1在自噬非依赖性细胞功能中的确切作用仍然知之甚少。在这里，我们报告说，beclin 1调节内吞作用，除了自噬，是所需的神经元活力在体内。我们发现神经元beclin 1与内体相关，并调节EEA 1/早期内体定位和晚期内体形成。Beclin 1维持适当的细胞磷脂酰肌醇3-磷酸（PI（3）P）分布和总水平，并且Beclin 1的丧失导致活性Rab 5 GTP酶相关的内体形成的破坏和内体成熟的损害，这可能是由于Rab 5未能募集VPS 34。此外，我们发现Beclin 1缺陷导致UVRAG-VPS 34复合物和相关的脂质激酶活性完全丧失。有趣的是，beclin 1缺陷会损害p40 phox连接的内体形成，这是由过表达的UVRAG或beclin 1拯救的，但不是由卷曲螺旋结构域截短的beclin 1（UVRAG结合突变体），Atg 14 L或RUBICON。因此，我们的研究揭示了beclin 1在神经元存活中的重要作用，涉及多个膜运输途径，包括内吞和自噬，并表明UVRAG-beclin 1相互作用是beclin 1在内吞作用中的功能的基础。Beclin 1不仅是第一个被描述的哺乳动物自噬蛋白，而且是自噬调控中最广泛表征的参与者之一。它与多种人类疾病有关。作为必需的脂质激酶复合物（PI 3 K-III）的核心组分，迄今为止，beclin 1在自噬的背景下通过其募集额外的自噬蛋白用于组装参与自噬体成核的PI 3 K-III复合物而在很大程度上表征。然而，关于beclin 1如何在其他膜运输途径中调节PI 3 K-III的特定功能，我们知之甚少。此外，尽管beclin 1与多种神经退行性疾病有关，但beclin 1在大脑中的功能仍然没有得到表征。在此，我们使用遗传动物模型和突变细胞系来证明beclin 1参与多种细胞器运输途径。神经元中的Beclin 1缺乏引起严重的神经变性，伴随着异常的晚期内体形成和受损的磷脂定位。我们的机制研究揭示了beclin 1在神经元存活中的重要作用，涉及多种膜运输途径，包括内吞和自噬。我们的研究阐明了beclin 1的生理功能，从而进一步了解其在肿瘤发生、感染性疾病和神经退行性疾病中的作用。
Deficiency of autophagy protein beclin 1 is implicated in tumorigenesis and neurodegenerative diseases, but the molecular mechanism remains elusive. Previous studies showed that Beclin 1 coordinates the assembly of multiple VPS34 complexes whose distinct phosphatidylinositol 3-kinase III (PI3K-III) lipid kinase activities regulate autophagy at different steps. Recent evidence suggests a function of beclin 1 in regulating multiple VPS34-mediated trafficking pathways beyond autophagy; however, the precise role of beclin 1 in autophagy-independent cellular functions remains poorly understood. Herein we report that beclin 1 regulates endocytosis, in addition to autophagy, and is required for neuron viability in vivo. We find that neuronal beclin 1 associates with endosomes and regulates EEA1/early endosome localization and late endosome formation. Beclin 1 maintains proper cellular phosphatidylinositol 3-phosphate (PI(3)P) distribution and total levels, and loss of beclin 1 causes a disruption of active Rab5 GTPase-associated endosome formation and impairment of endosome maturation, likely due to a failure of Rab5 to recruit VPS34. Furthermore, we find that Beclin 1 deficiency causes complete loss of the UVRAG-VPS34 complex and associated lipid kinase activity. Interestingly, beclin 1 deficiency impairs p40phox-linked endosome formation, which is rescued by overexpressed UVRAG or beclin 1, but not by a coiled-coil domain-truncated beclin 1 (a UVRAG-binding mutant), Atg14L or RUBICON. Thus, our study reveals the essential role for beclin 1 in neuron survival involving multiple membrane trafficking pathways including endocytosis and autophagy, and suggests that the UVRAG-beclin 1 interaction underlies beclin 1's function in endocytosis. Beclin 1 was not only the first-described mammalian autophagy protein, but is one of the most widely-characterized players in autophagy regulation. It is implicated in multiple human disease conditions. As a core component of the essential lipid kinase complex (PI3K-III), beclin 1 has largely been characterized to date in the context of autophagy through its recruitment of additional autophagy proteins for the assembly of the PI3K-III complexes involved in the nucleation of the autophagosome. Little is known, however, about how beclin 1 regulates specific functions of PI3K-III in other membrane trafficking pathways. Furthermore, although beclin 1 has been linked to multiple neurodegenerative diseases, the function of beclin 1 in the brain remains uncharacterized. Herein, we used genetic animal models and mutant cell lines to demonstrate that beclin 1 participates in multiple organelle trafficking pathways. Beclin 1 deficiency in neurons causes severe neurodegeneration, concomitant with aberrant late endosome formation and impaired phospholipid localization. Our mechanistic study reveals the essential role for beclin 1 in neuron survival involving multiple membrane trafficking pathways including endocytosis and autophagy. Our study clarifies the physiological function of beclin 1, which leads for further understanding of its role in tumorigenesis, infectious disease and neurodegenerative disease.
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影响因子：
19
作者：
Funderburk SF;Wang QJ;Yue Z
通讯作者：
Yue Z
Beclin 2在自噬中功能，G蛋白偶联受体的降解和代谢。
影响因子：
64.5
作者：
He C;Wei Y;Sun K;Li B;Dong X;Zou Z;Liu Y;Kinch LN;Khan S;Sinha S;Xavier RJ;Grishin NV;Xiao G;Eskelinen EL;Scherer PE;Whistler JL;Levine B
通讯作者：
Levine B
影响因子：
4
作者：
Kim, Hee Jin;Zhong, Qing;Jung, Jae U.
通讯作者：
Jung, Jae U.
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T
影响因子：
21.3
作者：
Liang, Chengyu;Lee, Jong-Soo;Jung, Jae U.
通讯作者：
Jung, Jae U.