Nishida Yuya, Arakawa Satoko, Fujitani Kenji, Yamaguchi Hirofumi, Mizuta Takeshi, Kanaseki Toku, Komatsu Masaaki, Otsu Kinya, Tsujimoto Yoshihide, Shimizu Shigeomi
Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Nature. 2009 Oct 1;461(7264):654-8. doi: 10.1038/nature08455.
Macroautophagy is a process that leads to the bulk degradation of subcellular constituents by producing autophagosomes/autolysosomes. It is believed that Atg5 (ref. 4) and Atg7 (ref. 5) are essential genes for mammalian macroautophagy. Here we show, however, that mouse cells lacking Atg5 or Atg7 can still form autophagosomes/autolysosomes and perform autophagy-mediated protein degradation when subjected to certain stressors. Although lipidation of the microtubule-associated protein light chain 3 (LC3, also known as Map1lc3a) to form LC3-II is generally considered to be a good indicator of macroautophagy, it did not occur during the Atg5/Atg7-independent alternative process of macroautophagy. We also found that this alternative process of macroautophagy was regulated by several autophagic proteins, including Unc-51-like kinase 1 (Ulk1) and beclin 1. Unlike conventional macroautophagy, autophagosomes seemed to be generated in a Rab9-dependent manner by the fusion of isolation membranes with vesicles derived from the trans-Golgi and late endosomes. In vivo, Atg5-independent alternative macroautophagy was detected in several embryonic tissues. It also had a function in clearing mitochondria during erythroid maturation. These results indicate that mammalian macroautophagy can occur through at least two different pathways: an Atg5/Atg7-dependent conventional pathway and an Atg5/Atg7-independent alternative pathway.
巨自噬是一个通过产生自噬体/自溶酶体导致亚细胞成分大量降解的过程。据信，Atg5（参考文献4）和Atg7（参考文献5）是哺乳动物巨自噬的必需基因。然而，我们在此表明，缺乏Atg5或Atg7的小鼠细胞在受到某些应激源作用时，仍能形成自噬体/自溶酶体并进行自噬介导的蛋白质降解。尽管微管相关蛋白轻链3（LC3，也称为Map1lc3a）脂化形成LC3-II通常被认为是巨自噬的一个良好指标，但在不依赖Atg5/Atg7的巨自噬替代过程中并未发生。我们还发现，这种巨自噬替代过程受包括Unc-51样激酶1（Ulk1）和贝克林1在内的几种自噬蛋白调控。与传统巨自噬不同，自噬体似乎是以Rab9依赖的方式通过隔离膜与源自反式高尔基体和晚期内体的囊泡融合而产生的。在体内，在多个胚胎组织中检测到了不依赖Atg5的替代巨自噬。它在红细胞成熟过程中清除线粒体方面也有作用。这些结果表明，哺乳动物巨自噬至少可通过两种不同途径发生：一种是依赖Atg5/Atg7的传统途径，另一种是不依赖Atg5/Atg7的替代途径。
