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Autophagy responsible for cellular self-degradation : molecular machinery and roles in development, differentiation, and diseases

自噬负责细胞自我降解：分子机制及其在发育、分化和疾病中的作用

基本信息

批准号：
14580706
负责人：
YOSHIMORI Tamotsu
金额：
$ 2.62万
依托单位：
National Institute of Genetics
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

To degrade their own components, cells possess autophagy that. delivers part of the cytosol and organelles into lysosomes. Autophagy contributes not only turnover of cellular constituents but also reconstruction of cells and tissue; it is induced circumstantially and degrades the intracellular structure at large-scale. Since abnormal induction of autophagy has been often observed in diverse diseases, pathological role of autophagy has the attention of investigators. In this project, we aimed for elucidation of molecular machinery of autophagy and its role in development, differentiation, and diseases.Our results are as follows. 1) we identified mammalian Atg10 as a enzyme catalyzing covalent binding of Atg12 with Atg5, 2) we showed that fusion between autophagosomes and lysosomes requires transport from endosomes to autophagosomes, 3) we found a large 800kDa proteins complex including the Atg5-Atgl2 conjugate and identified a novel protein Atg16L as a component of the complex, 4) we obtained a evidence that lipidation of LC3 cause its localization to autophagosomes and demonstrated that two LC3 homologues, GABARAP and GATE16, could bind to autophagosomes like LC3, 5) we produced transgenic mouse expressing GFP-LC3 ubiquitously, which is useful to examine induction of autophagy during development and tissue differentiation,6) we found new function of autophagy ; autophagy prevents intracellular multiplication of both unfolded proteins causing degenerative diseases and pathogenic bacteria that have invaded host cells, 7) we discovered that mouse hepatitis virus related to coronavirus causing SARS utilizes autophagosomes to multiply inside host cells.

为了降解自身的成分，细胞具有自噬作用。将部分细胞质和细胞器输送到溶酶体中。自噬不仅有助于细胞成分的更新，还有助于细胞和组织的重建。它是环境诱导的并大规模降解细胞内结构。由于在多种疾病中经常观察到自噬的异常诱导，因此自噬的病理作用引起了研究者的关注。在这个项目中，我们旨在阐明自噬的分子机制及其在发育、分化和疾病中的作用。我们的结果如下。 1) 我们确定哺乳动物 Atg10 是一种催化 Atg12 与 Atg5 共价结合的酶，2) 我们表明自噬体和溶酶体之间的融合需要从内体转运到自噬体，3) 我们发现了一个包含 Atg5-Atgl2 缀合物的大型 800kDa 蛋白质复合物，并确定了一种新的蛋白质 Atg16L 作为 4) 我们获得了证据表明 LC3 的脂化导致其定位于自噬体，并证明两种 LC3 同源物 GABARAP 和 GATE16 可以与 LC3 等自噬体结合，5) 我们产生了普遍表达 GFP-LC3 的转基因小鼠，这有助于检查发育和组织分化过程中自噬的诱导，6) 我们发现了自噬；自噬可防止导致退行性疾病的未折叠蛋白和侵入宿主细胞的病原菌在细胞内增殖，7）我们发现与引起 SARS 的冠状病毒相关的小鼠肝炎病毒利用自噬体在宿主细胞内繁殖。