CoChat
Sign Up
Cited by 5Autophagy in Disease and TherapyUbiquitin and proteasome pathwaysCalcium signaling and nucleotide metabolism

The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

The triad interaction of ULK1, ATG13, and FIP200 is required for ULK complex formation and autophagy

Open access
Hama, Yutaro, Fujioka, Yuko, Yamamoto, Hayashi, Mizushima, Noboru, Noda, Nobuo N·2025·eLife
DOI 10.7554/elife.101531.3

Published version of a preprint

Open this paper in CoChat — free account

Abstract

In mammals, autophagosome formation, a central event in autophagy, is initiated by the ULK complex comprising ULK1/2, FIP200, ATG13, and ATG101. However, the structural basis and mechanism underlying the ULK complex assembly have yet to be fully clarified. Here, we predicted the core interactions organizing the ULK complex using AlphaFold, which proposed that the intrinsically disordered region of ATG13 engages the bases of the two UBL domains in the FIP200 dimer via two phenylalanines and also binds the tandem microtubule-interacting and transport domain of ULK1, thereby yielding the 1:1:2 stoichiometry of the ULK1–ATG13–FIP200 complex. We validated the predicted interactions by point mutations and demonstrated direct triad interactions among ULK1, ATG13, and FIP200 in vitro and in cells, wherein each interaction was additively important for autophagic flux. These results indicate that the ULK1–ATG13–FIP200 triadic interaction is crucial for autophagosome formation and provides a structural basis and insights into the regulation mechanism of autophagy initiation in mammals.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.7554/elife.101531.3

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 50

  1. Alers, 2011, Atg13 and FIP200 act independently of Ulk1 and Ulk2 in autophagy induction, Autophagy, 7, 1423, 10.4161/auto.7.12.18027 · DOI · Paper page
  2. Alers, 2014, ATG13: just a companion, or an executor of the autophagic program?, Autophagy, 10, 944, 10.4161/auto.28987 · DOI
  3. Burki, 2020, The new tree of eukaryotes, Trends in Ecology & Evolution, 35, 43, 10.1016/j.tree.2019.08.008 · DOI · Paper page
  4. Chen, 2023, Structure and Activation of the Human Autophagy-Initiating ULK1C:PI3KC3-C1 Supercomplex, 10.1101/2023.06.01.543278 · DOI · Paper page
  5. Cheong, 2011, Ammonia-induced autophagy is independent of ULK1/ULK2 kinases, PNAS, 108, 11121, 10.1073/pnas.1107969108 · DOI
  6. Evans, 2021, Protein complex prediction with alphafold-multimer, 10.1101/2021.10.04.463034 · DOI · Paper page
  7. Fujioka, 2014, Structural basis of starvation-induced assembly of the autophagy initiation complex, Nature Structural & Molecular Biology, 21, 513, 10.1038/nsmb.2822 · DOI
  8. Fujioka, 2020, Phase separation organizes the site of autophagosome formation, Nature, 578, 301, 10.1038/s41586-020-1977-6 · DOI
  9. Ganley, 2009, ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy, The Journal of Biological Chemistry, 284, 12297, 10.1074/jbc.M900573200 · DOI · Paper page
  10. Hama, 2023, TAX1BP1 Recruits ATG9 Vesicles through SCAMP3 Binding, 10.1101/2023.08.18.553817 · DOI
  11. Hara, 2008, FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells, The Journal of Cell Biology, 181, 497, 10.1083/jcb.200712064 · DOI · Paper page
  12. Hieke, 2015, Expression of a ULK1/2 binding-deficient ATG13 variant can partially restore autophagic activity in ATG13-deficient cells, Autophagy, 11, 1471, 10.1080/15548627.2015.1068488 · DOI
  13. Holzer, 2024, The role of ATG9 vesicles in autophagosome biogenesis, Journal of Molecular Biology, 436, 10.1016/j.jmb.2024.168489 · DOI
  14. Hosokawa, 2009, Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy, Molecular Biology of the Cell, 20, 1981, 10.1091/mbc.e08-12-1248 · DOI · Paper page
  15. Itakura, 2012, Structures containing Atg9A and the ULK1 complex independently target depolarized mitochondria at initial stages of Parkin-mediated mitophagy, Journal of Cell Science, 125, 1488, 10.1242/jcs.094110 · DOI · Paper page
  16. Jung, 2009, ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery, Molecular Biology of the Cell, 20, 1992, 10.1091/mbc.e08-12-1249 · DOI · Paper page
  17. Kannangara, 2021, BioID reveals an ATG9A interaction with ATG13-ATG101 in the degradation of p62/SQSTM1-ubiquitin clusters, EMBO Reports, 22, 10.15252/embr.202051136 · DOI
  18. Kim, 2001, Cvt9/Gsa9 functions in sequestering selective cytosolic cargo destined for the vacuole, The Journal of Cell Biology, 153, 381, 10.1083/jcb.153.2.381 · DOI
  19. Kishi-Itakura, 2014, Ultrastructural analysis of autophagosome organization using mammalian autophagy-deficient cells, Journal of Cell Science, 127, 4089, 10.1242/jcs.156034 · DOI
  20. Kitamura, 2003, Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics, Experimental Hematology, 31, 1007, 10.1016/j.exphem.2003.07.005 · DOI
  21. Li, 2014, AUTOPHAGY-RELATED11 plays a critical role in general AUTOPHAGY- and senescence-induced mitophagy in Arabidopsis, The Plant Cell, 26, 788, 10.1105/tpc.113.120014 · DOI
  22. Lin, 2016, Structure and function of the ULK1 complex in autophagy, Current Opinion in Cell Biology, 39, 61, 10.1016/j.ceb.2016.02.010 · DOI
  23. Mirdita, 2019, MMseqs2 desktop and local web server app for fast, interactive sequence searches, Bioinformatics, 35, 2856, 10.1093/bioinformatics/bty1057 · DOI · Paper page
  24. Mirdita, 2022, ColabFold: making protein folding accessible to all, Nature Methods, 19, 679, 10.1038/s41592-022-01488-1 · DOI · Paper page
  25. Mizushima, 2011, Autophagy: renovation of cells and tissues, Cell, 147, 728, 10.1016/j.cell.2011.10.026 · DOI
  26. Mizushima, 2020, Autophagy in Human Diseases, The New England Journal of Medicine, 383, 1564, 10.1056/NEJMra2022774 · DOI · Paper page
  27. Nakatogawa, 2020, Mechanisms governing autophagosome biogenesis, Nature Reviews. Molecular Cell Biology, 21, 439, 10.1038/s41580-020-0241-0 · DOI
  28. Noda, 2024, Structural view on autophagosome formation, FEBS Letters, 598, 84, 10.1002/1873-3468.14742 · DOI
  29. Pan, 2020, Atg1 kinase in fission yeast is activated by Atg11-mediated dimerization and cis-autophosphorylation, eLife, 9, 10.7554/eLife.58073 · DOI
  30. Papinski, 2016, Regulation of autophagy by signaling through the Atg1/ULK1 complex, Journal of Molecular Biology, 428, 1725, 10.1016/j.jmb.2016.03.030 · DOI
  31. Park, 2016, The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14, Autophagy, 12, 547, 10.1080/15548627.2016.1140293 · DOI · Paper page
  32. Ragusa, 2012, Architecture of the Atg17 complex as a scaffold for autophagosome biogenesis, Cell, 151, 1501, 10.1016/j.cell.2012.11.028 · DOI · Paper page
  33. Ren, 2023, Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation, Science Advances, 9, 10.1126/sciadv.adg2997 · DOI · Paper page
  34. Rudinskiy, 2022, Quantitative and time-resolved monitoring of organelle and protein delivery to the lysosome with a tandem fluorescent Halo-GFP reporter, Molecular Biology of the Cell, 33, 10.1091/mbc.E21-10-0526 · DOI
  35. Saitoh, 2003, TWEAK induces NF-kappaB2 p100 processing and long lasting NF-kappaB activation, The Journal of Biological Chemistry, 278, 36005, 10.1074/jbc.M304266200 · DOI
  36. Schindelin, 2012, Fiji: an open-source platform for biological-image analysis, Nature Methods, 9, 676, 10.1038/nmeth.2019 · DOI · Paper page
  37. Shi, 2020, ULK complex organization in autophagy by a C-shaped FIP200 N-terminal domain dimer, The Journal of Cell Biology, 219, 10.1083/jcb.201911047 · DOI
  38. Sun, 2013, Global analysis of fission yeast mating genes reveals new autophagy factors, PLOS Genetics, 9, 10.1371/journal.pgen.1003715 · DOI
  39. Suzuki, 2001, The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation, The EMBO Journal, 20, 5971, 10.1093/emboj/20.21.5971 · DOI
  40. Suzuki, 2015, Structure of the Atg101-Atg13 complex reveals essential roles of Atg101 in autophagy initiation, Nature Structural & Molecular Biology, 22, 572, 10.1038/nsmb.3036 · DOI
  41. Wallot-Hieke, 2018, Systematic analysis of ATG13 domain requirements for autophagy induction, Autophagy, 14, 743, 10.1080/15548627.2017.1387342 · DOI
  42. Wold, 2016, ULK1-mediated phosphorylation of ATG14 promotes autophagy and is impaired in Huntington’s disease models, Molecular Neurodegeneration, 11, 10.1186/s13024-016-0141-0 · DOI · Paper page
  43. Wong, 2013, The ULK1 complex: sensing nutrient signals for autophagy activation, Autophagy, 9, 124, 10.4161/auto.23323 · DOI
  44. Yamamoto, 2012, Atg9 vesicles are an important membrane source during early steps of autophagosome formation, The Journal of Cell Biology, 198, 219, 10.1083/jcb.201202061 · DOI · Paper page
  45. Yamamoto, 2016, The intrinsically disordered protein Atg13 mediates supramolecular assembly of autophagy initiation complexes, Developmental Cell, 38, 86, 10.1016/j.devcel.2016.06.015 · DOI
  46. Yim, 2022, A pulse-chasable reporter processing assay for mammalian autophagic flux with HaloTag, eLife, 11, 10.7554/eLife.78923 · DOI
  47. Yorimitsu, 2005, Atg11 links cargo to the vesicle-forming machinery in the cytoplasm to vacuole targeting pathway, Molecular Biology of the Cell, 16, 1593, 10.1091/mbc.e04-11-1035 · DOI · Paper page
  48. Zheng, 2022, Calcium transients on the ER surface trigger liquid-liquid phase separation of FIP200 to specify autophagosome initiation sites, Cell, 185, 4082, 10.1016/j.cell.2022.09.001 · DOI
  49. Zhou, 2021, Phosphorylation regulates the binding of autophagy receptors to FIP200 Claw domain for selective autophagy initiation, Nature Communications, 12, 10.1038/s41467-021-21874-1 · DOI
  50. Noda NN. 2025. ULK1 complex. ModelArchive. https://modelarchive.org/doi/10.5452/ma-jz53c. ma-jz53c. · DOI

Metadata

Authors
Hama, Y., Fujioka, Y., Yamamoto, H., Mizushima, N., & Noda, N. N.
Affiliations
  • Hokkaido University (JP)
  • Institute for Genetic Medicine, Hokkaido University
  • The University of Tokyo (JP)
Corresponding author
Noda, Nobuo N
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2025-06-24
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.101531.3
OpenAlex
W4411609348
Cited by
5
References
2
Citations by year
2026: 4 · 2025: 1
FWCI
3.49
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
Funders
  • Japan Society for the Promotion of Science (JP19H05707, JP23K20044, JP23K06667, JP24H00060, JP25H00966, JP25H01320, JP25H01321, JP23K14140, JP22KJ0044, JP21H05731, JP23H02429, JP23K27122, JP23H04923, JP21H05256, JP22H04919)
  • Japan Science and Technology Agency (10.52926/jpmjcr20e3, 10.52926/jpmjer1702)
  • Japan Agency for Medical Research and Development (JP20gm6410009)
  • Takeda Science Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
ULK1, ATG13, FIP200, autophagy initiation, autophagosome formation, protein-protein interaction, intrinsically disordered regions, UBL domain, autophagic flux, protein complex formation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review