The Atg8 Conjugation System Is Indispensable for Proper Development of Autophagic Isolation Membranes in Mice
The Atg8 Conjugation System Is Indispensable for Proper Development of Autophagic Isolation Membranes in Mice
复制标题
DOI：
10.1091/mbc.e08-03-0309
复制
发表时间：
2008-11-01
影响因子：
3.3
通讯作者：
Komatsu, Masaaki
中科院分区：
文献类型：
--
作者：
Sou, Yu-shin;Waguri, Satoshi;Komatsu, Masaaki
自噬是一种进化上保守的大宗蛋白质降解途径，在该途径中，隔离膜吞噬细胞质成分，由此产生的自噬小体将它们运输到溶酶体。两个泛素样结合系统，称为Atg12和Atg8系统，对于自噬小体的形成是必不可少的。除了自噬在哺乳动物中的病理生理作用外，最近的小鼠遗传学研究表明，Atg8系统主要受Atg12系统的控制。为了阐明Atg8系统在哺乳动物自噬小体形成中的作用，我们产生了编码Atg8特异性E2酶的Atg3基因缺陷的小鼠。ATg3基因缺陷小鼠出生后1d内死亡。在突变小鼠中，哺乳动物Atg8同源物的结合形成完全缺陷。有趣的是，在Atg3基因缺陷的小鼠中，Atg12-ATG5的结合显著减少，并且其从隔离膜上的解离显著延迟。此外，Atg3的丢失与自噬小体形成过程的缺陷有关，包括隔离膜的延长和完全关闭，导致自噬小体畸形。结果表明，ATG8系统在小鼠自噬隔离膜的正常发育过程中起着重要作用。
Autophagy is an evolutionarily conserved bulk-protein degradation pathway in which isolation membranes engulf the cytoplasmic constituents, and the resulting autophagosomes transport them to lysosomes. Two ubiquitin-like conjugation systems, termed Atg12 and Atg8 systems, are essential for autophagosomal formation. In addition to the pathophysiological roles of autophagy in mammals, recent mouse genetic studies have shown that the Atg8 system is predominantly under the control of the Atg12 system. To clarify the roles of the Atg8 system in mammalian autophagosome formation, we generated mice deficient in Atg3 gene encoding specific E2 enzyme for Atg8. Atg3-deficient mice were born but died within 1 d after birth. Conjugate formation of mammalian Atg8 homologues was completely defective in the mutant mice. Intriguingly, Atg12-Atg5 conjugation was markedly decreased in Atg3-deficient mice, and its dissociation from isolation membranes was significantly delayed. Furthermore, loss of Atg3 was associated with defective process of autophagosome formation, including the elongation and complete closure of the isolation membranes, resulting in malformation of the autophagosomes. The results indicate the essential role of the Atg8 system in the proper development of autophagic isolation membranes in mice.