In autophagy, Atg proteins organize the pre-autophagosomal structure (PAS) to initiate autophagosome formation. Previous studies in yeast revealed that the autophagy-related E3 complex ATG12-Atg5-ATG16 is recruited to the PAS via ATG16 interaction with ATG21, which binds phosphatidylinositol 3-phosphate (PI3P) produced at the PAS, to stimulate conjugation of the ubiquitin-like protein ATG8 to phosphatidylethanolamine. Here, we discover a novel mechanism for the PAS targeting of ATG12-Atg5-ATG16, which is mediated by the interaction of ATG12 with the ATG1 kinase complex that serves as a scaffold for PAS organization. While autophagy is partially defective without one of these mechanisms, cells lacking both completely lose the PAS localization of ATG12-Atg5-ATG16 and show no autophagic activity. As with the PI3P-dependent mechanism, ATG12-Atg5-ATG16 recruited via the ATG12-dependent mechanism stimulates ATG8 lipidation, but also has the specific function of facilitating PAS scaffold assembly. Thus, this study significantly advances our understanding of the nucleation step in autophagosome formation.

• PMID: 30810528
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Journal Article | Research Support, Non-U.S. Gov't

Authors

Harada K, Kotani T, Kirisako H, Sakoh-Nakatogawa M, Oikawa Y, Kimura Y, Hirano H, Yamamoto H, Ohsumi Y, Nakatogawa H

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