Evidence map›Paper›PMID 34121209›Full record

ArticleThe EMBO journal2021

Phosphoproteomic identification of ULK substrates reveals VPS15-dependent ULK/VPS34 interplay in the regulation of autophagy.

Thomas John Mercer, Yohei Ohashi, Stefan Boeing, Harold B J Jefferies, Stefano De Tito, Helen Flynn, Shirley Tremel, Wenxin Zhang, Martina Wirth, David Frith and 3 more

Open access · hybridAbstract read
In one paragraph

Article in The EMBO journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
44citing papers in PubMed, 1 pooled it
7.2field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

44 citing papers in PubMed, 1 synthesis or guideline pooled it, 60 citations in OpenAlex.

  1. Pooled it
  2. Regulation and roles of mammalian mitophagy.Nature reviews. Molecular cell biology · 2026
    Review
  3. Review
  4. Article
  5. Article
  6. Review
  7. The Human Autophagy Core Complexes.Annual review of biochemistry · 2026
    Review
  8. Article
  9. Article
  10. Review
  11. Review
  12. Article
  13. The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.Annual review of cell and developmental biology · 2025
    Review
  14. Article
  15. The human autophagy-initiating complexes ULK1C and PI3KC3-C1.The Journal of biological chemistry · 2025
    Review
  16. Review
  17. Article
  18. Review
  19. Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 3 institutions in 2 countries.

Thomas John MercerMolecular Cell Biology of Autophagy, The Francis Crick Institute, London, UK.
Yohei OhashiMRC Laboratory of Molecular Biology, Cambridge, UK.
Stefan BoeingBioinformatics and Biostatistics, The Francis Crick Institute, London, UK.
Harold B J JefferiesMolecular Cell Biology of Autophagy, The Francis Crick Institute, London, UK.
Stefano De TitoMolecular Cell Biology of Autophagy, The Francis Crick Institute, London, UK.
Helen FlynnInstitute of Experimental Endocrinology and Oncology (IEOS), National Research Council, Naples, Italy.ORCID 0000-0001-7002-9130
Shirley TremelMRC Laboratory of Molecular Biology, Cambridge, UK.
Wenxin ZhangMolecular Cell Biology of Autophagy, The Francis Crick Institute, London, UK.
Martina WirthMolecular Cell Biology of Autophagy, The Francis Crick Institute, London, UK.
David FrithProteomics, The Francis Crick Institute, London, UK.
Ambrosius P SnijdersProteomics, The Francis Crick Institute, London, UK.
Roger Lee WilliamsMRC Laboratory of Molecular Biology, Cambridge, UK.
Sharon A ToozeMolecular Cell Biology of Autophagy, The Francis Crick Institute, London, UK.ORCID 0000-0002-2182-3116
The Francis Crick Institute · GBMRC Laboratory of Molecular Biology · GBInstitute for Experimental Endocrinology and Oncology · IT

Funding

Cancer Research UK C14801/A21211Cancer Research UK FC001187Medical Research Council FC001187Medical Research Council FC001999Medical Research Council MC_U105184308Wellcome TrustWellcome Trust FC001187Wellcome Trust FC001999
6 · The paper itself

Abstract

Autophagy is a process through which intracellular cargoes are catabolised inside lysosomes. It involves the formation of autophagosomes initiated by the serine/threonine kinase ULK and class III PI3 kinase VPS34 complexes. Here, unbiased phosphoproteomics screens in mouse embryonic fibroblasts deleted for Ulk1/2 reveal that ULK loss significantly alters the phosphoproteome, with novel high confidence substrates identified including VPS34 complex member VPS15 and AMPK complex subunit PRKAG2. We identify six ULK-dependent phosphorylation sites on VPS15, mutation of which reduces autophagosome formation in cells and VPS34 activity in vitro. Mutation of serine 861, the major VPS15 phosphosite, decreases both autophagy initiation and autophagic flux. Analysis of VPS15 knockout cells reveals two novel ULK-dependent phenotypes downstream of VPS15 removal that can be partially recapitulated by chronic VPS34 inhibition, starvation-independent accumulation of ULK substrates and kinase activity-regulated recruitment of autophagy proteins to ubiquitin-positive structures.

Indexed as

AMP-Activated Protein KinasesAnimalsAutophagosomesAutophagyAutophagy-Related Protein-1 HomologAutophagy-Related ProteinsClass III Phosphatidylinositol 3-KinasesFibroblastsHEK293 CellsHumansMiceProteomicsVacuolar Sorting Protein VPS15AMP-Activated Protein KinasesAutophagy-Related Protein-1 HomologAutophagy-Related ProteinsClass III Phosphatidylinositol 3-KinasesPIK3R4 protein, humanVacuolar Sorting Protein VPS15p62PIK3R4PRKAG2ULK1VPS15

Identifiers

PMID34121209
PMCPMC8280838
OpenAlexW3168398752

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.