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Molecular Mechanism and Function of Ubiquitin-like System in Autophagy

泛素样系统在自噬中的分子机制和功能

基本信息

批准号：
12308037
负责人：
OHSUMI Yoshinori
金额：
$ 28万
依托单位：
National Institute for Basic Biology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12308037/
关键词：
autophagy Apg vacuole protein degradation ubl APG4 APG8 APG7 APG3 タンパク質の脂質修飾

项目摘要

Autophagy is a main route for sequestration of cytoplasmic components to lysosome/vacuole. Genetic analyses revealed at least 15 genes (APG and AUT) are required for the autophagy in yeast. These genes play roles on autophagosome(AP) formation, unique membrane dynamics in autophagy. Among them about half are involved in ubiquitination like conjugation systems. Apg12 is activated by Apg7 (E1), transferred to Apg10 (E2), and finally forms an isopeptide bond with Apg5. Apg12-Apg5 forms a tetrameric complex of Apg12-Apg5/Apg16. Another UBL, Apg8/Aut7 is activated by the same E1 enzyme, Apg7, transferred to Apg3/Aut1, and finally forms a conjugate with membrane phospholipid, PE via an amido bond. Modification of Apg5 by Apgl2 is constitutive and irreversible, while deconjugation of Apg8-PE by Apg4 /Aut2, a processing enzyme of nascent Apg8, is necessary for normal progression of autophagy. These two conjugation systems are similar to ubiquitination mechanistically, but quite distinct from other Ubl systems in several aspects. These two systems may function closely during AP formation, because Apg12-Apg5 and Apg8 colocalize in a perivacuolar structure named PAS and Apg8-PE level is severely reduced by the defect in Apg12 system. PAS, preautophagosomal structure in which many Apg proteins are associated, plays essential roles for AP formation, but its precise structure should be uncovered in future.

自噬是将细胞质成分隔离到溶酶体/空泡的主要途径。遗传分析显示，至少有15个基因（APG和AUT）是酵母自噬所必需的。这些基因在自噬体（AP）形成中发挥作用，这是自噬中独特的膜动力学。其中约一半参与泛素化类共轭系统。Apg 12被Apg 7（E1）激活，转移到Apg 10（E2），最后与Apg 5形成异肽键。Apg 12-Apg 5形成Apg 12-Apg 5/Apg 16的四聚体复合物。另一种UBL Apg 8/Aut 7被相同的E1酶Apg 7激活，转移到Apg 3/Aut 1，并最终通过酰胺键与膜磷脂PE形成缀合物。Apgl 2对Apg 5的修饰是组成性的和不可逆的，而Apg 4/Aut 2（新生Apg 8的加工酶）对Apg 8-PE的去缀合是自噬正常进展所必需的。这两个结合系统在机制上类似于泛素化，但在几个方面与其他Ubl系统截然不同。这两个系统可能在AP形成过程中起着密切的作用，因为Apg 12-Apg 5和Apg 8共定位于称为PAS的液泡周围结构，Apg 12系统的缺陷严重降低了Apg 8-PE水平。PAS是一种前自噬体结构，在其中结合了许多Apg蛋白，在AP的形成中起着重要的作用，但其确切的结构有待于进一步研究。