Showed the DIRECT brake mTORC1 uses on autophagy: when nutrients are plentiful, mTORC1 physically joins the ULK1-Atg13-FIP200 complex (the autophagy-starter kinase) and phosphorylates ULK1 to keep it off. Starvation or rapamycin releases this brake and autophagy begins.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Molecular Biology of the Cell |
| Year | 2009 |
| Peer reviewed | Yes |
| Source | DOI 10.1091/mbc.e08-12-1248 · PMID 19211835 · Free full text (PMC2663915) |
Autophagy is an intracellular degradation system, by which cytoplasmic contents are degraded in lysosomes. Autophagy is dynamically induced by nutrient depletion to provide necessary amino acids within cells, thus helping them adapt to starvation. Although it has been suggested that mTOR is a major negative regulator of autophagy, how it controls autophagy has not yet been determined. Here, we report a novel mammalian autophagy factor, Atg13, which forms a stable approximately 3-MDa protein complex with ULK1 and FIP200. Atg13 localizes on the autophagic isolation membrane and is essential for autophagosome formation. In contrast to yeast counterparts, formation of the ULK1-Atg13-FIP200 complex is not altered by nutrient conditions. Importantly, mTORC1 is incorporated into the ULK1-Atg13-FIP200 complex through ULK1 in a nutrient-dependent manner and mTOR phosphorylates ULK1 and Atg13. ULK1 is dephosphorylated by rapamycin treatment or starvation. These data suggest that mTORC1 suppresses autophagy through direct regulation of the approximately 3-MDa ULK1-Atg13-FIP200 complex.
| Intervention | Genetic/biochemical (mTORC1/ULK1-Atg13-FIP200) |
| Target | mTORC1 / ULK1-Atg13-FIP200 |
| Model | Mammalian cells |
| Effect | Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex controls autophagy induction |