Nutrient-dependent mTORC1 Association with the ULK1–Atg13–FIP200 Complex Required for Autophagy
Open accessAbstract
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 ∼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 ∼3-MDa ULK1–Atg13–FIP200 complex.
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Initiation of autophagosome formation begins with dissociation of MTOR from the phagophore assembly site, cued by nutrient starvation or treatment with rapamycin or its derivatives.
“The initiation step begins with the dissociation of MTOR (mechanistic target of rapamycin kinase) from the PAS, cued by nutrient starvation or treatment with rapamycin or its various derivatives [36,37].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [37]
Under starvation, mTORC1 is suppressed and dissociates from the ULK1-ULK2 complex, allowing AMPK to activate ULK1 and induce autophagy.
“Under starvation, mTORC1 is suppressed and dissociates from the ULK1–ULK2 complex, allowing ULK1 to be activated by AMPK to induce autophagy”
From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [17]
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- Authors
- Hosokawa, N., Hara, T., Kaizuka, T., Kishi, C., Takamura, A., Miura, Y., Iemura, S.-I., Natsume, T., Takehana, K., Yamada, N., Guan, J.-L., Oshiro, N., & Mizushima, N.
- Affiliations
- Tokyo Medical and Dental University (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
- Exploratory Research, Pharmaceutical Research Laboratory, and
- Ajinomoto (Japan) (JP)
- University of Michigan (US)
- Biosignal Research Center, Kobe University (JP)
- Venue
- Molecular Biology of the Cell
- Published
- 2009-04
- Volume
- 20
- Issue
- 7
- Pages
- 1981-1991
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC2663915
- OpenAlex
- W2156144699
- Cited by
- 2,076
- References
- 54
- Citations by year
- 2026: 68 · 2025: 81 · 2024: 133 · 2023: 128 · 2022: 139 · 2021: 171 · 2020: 154 · 2019: 132 · 2018: 114 · 2017: 128 · 2016: 132 · 2015: 142 · 2014: 115 · 2013: 112 · 2012: 110
- FWCI
- 73.07
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Tokyo
- Tokyo Medical and Dental University
- Toray Science Foundation
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- autophagy, mTORC1, ULK1, ATG13, FIP200, autophagosome formation, nutrient signaling, mTOR phosphorylation, rapamycin, starvation, lysosomal degradation
- MeSH terms
- Autophagy-Related Proteins, Autophagy-Related Protein-1 Homolog, Mechanistic Target of Rapamycin Complex 1, Amino Acids, Animals, Autophagy, Cell Line, Cell Membrane, Humans, Molecular Weight, Phosphorylation, Protein Binding, Protein Kinases, Proteins, Transcription Factors, Protein Serine-Threonine Kinases, Protein Transport, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, TOR Serine-Threonine Kinases
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