Discovery of Atg5/Atg7-independent alternative macroautophagy

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Abstract
In a process known as macroautophagy, defective proteins and entire organelles are sequestered in membrane compartments called autophagosomes that ultimately fuse with lysososmes and undergo degradation. This pathway is activated in response to conditions such as starvation, allowing a cell to break up its own reserves to provide nutrients. At the molecular level, macroautophagy is regulated by Atg genes that are components of the ubiquitin-like conjugation system. Nishida et al. describe a second mode of autophagy that is independent of the Atg genes and is induced under certain stress conditions in vitro and in the clearance of organelles during erythroid maturation in vivo. Future studies will reveal the mechanistic basis for this pathway. Macroautophagy is the process by which defective proteins and entire organelles are sequestered in membrane compartments called autophagosomes, which ultimately fuse with lysosomes and undergo degradation. The genes Atg5 and Atg7 are believed to be essential for mammalian macroautophagy. Here it is shown, however, that under certain stress conditions mouse cells lacking Atg5 or Atg7 can still perform autophagy-mediated protein degradation through an alternative pathway. Macroautophagy is a process that leads to the bulk degradation of subcellular constituents by producing autophagosomes/autolysosomes1,2,3. 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 macroautophagy6, 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.