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Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1–phosphatidylinositol-3-kinase complex
Open accessAbstract
Beclin 1, a mammalian autophagy protein that has been implicated in development, tumour suppression, neurodegeneration and cell death, exists in a complex with Vps34, the class III phosphatidylinositol-3-kinase (PI(3)K) that mediates multiple vesicle-trafficking processes including endocytosis and autophagy. However, the precise role of the Beclin 1-Vps34 complex in autophagy regulation remains to be elucidated. Combining mouse genetics and biochemistry, we have identified a large in vivo Beclin 1 complex containing the known proteins Vps34, p150/Vps15 and UVRAG, as well as two newly identified proteins, Atg14L (yeast Atg14-like) and Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein). Characterization of the new proteins revealed that Atg14L enhances Vps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces Vps34 activity and downregulates autophagy. We show that Beclin 1 and Atg14L synergistically promote the formation of double-membraned organelles that are associated with Atg5 and Atg12, whereas forced expression of Rubicon results in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation. We hypothesize that by forming distinct protein complexes, Beclin 1 and its binding proteins orchestrate the precise function of the class III PI(3)K in regulating autophagy at multiple steps.
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In the citing paper
“Yeast Atg14 is the autophagy-specific subunit of the Vps34 complex I, 404 and a human homolog, named ATG14 (ATG14L/BARKOR), has been identified.[405][406][407][408]”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [406]
Experimental — accuracy not yet measuredIn the citing paper
“the class III phosphoinositide 3-kinase (PI3K) complex regulates vesicle nucleation and phagophore formation”
From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [10]
In the citing paper
“Defects in induction, maturation, or lysosomal clearance impair protein degradation (Zhong et al. 2009), (Pickford et al. 2008), (Ravikumar et al. 2005), (Webb et al. 2004), (Iwata et al. 2005), (Kimura et al. 2008), (Wong and Cuervo 2010), (Lee et al. 2010), and is assessable via LC3-II turnover or p62 degradation (Mizushima et al. 2010), (Ju et al. 2010), (Klionsky et al. 2008b), (Tanida et al.”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Zhong et al. 2009
In the citing paper
“Detection of endogenous phospho-ATG16L1 [823] has been demonstrated as a novel method to monitor autophagy induction.”
From Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1 (2021) · cites this paper as [823]
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Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
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Metadata
- Authors
- Zhong, Y., Wang, Q. J., Li, X., Yan, Y., Backer, J. M., Chait, B. T., Heintz, N., & Yue, Z.
- Affiliations
- Howard Hughes Medical Institute (US)
- Rockefeller University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Yue, Zhenyu
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2009-03-08
- Volume
- 11
- Issue
- 4
- Pages
- 468-476
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC2664389
- OpenAlex
- W1983831622
- Cited by
- 1,005
- References
- 35
- Citations by year
- 2026: 29 · 2025: 43 · 2024: 38 · 2023: 48 · 2022: 63 · 2021: 62 · 2020: 69 · 2019: 51 · 2018: 57 · 2017: 58 · 2016: 72 · 2015: 56 · 2014: 64 · 2013: 77 · 2012: 64
- FWCI
- 49.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (RNS055683A)
- National Institute of Neurological Disorders and Stroke (R21NS055683, R01NS060123)
- National Center for Research Resources (RR00862, P41RR000862, RR 022220, U54RR022220)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- autophagy regulation, Beclin-1, ATG14L, Rubicon, Vps34, class III phosphatidylinositol 3-kinase, UVRAG, autophagosome maturation, late endosomes, lysosomes, ATG5, ATG12, lipid kinase activity
- MeSH terms
- Beclin-1, Amino Acid Sequence, Animals, Autophagy, Cell Membrane, HeLa Cells, Humans, Lysosomes, Molecular Sequence Data, Protein Binding, Proteins, Endosomes, Phosphatidylinositol Phosphates, Phosphatidylinositol 3-Kinases, NIH 3T3 Cells, Adaptor Proteins, Signal Transducing, Green Fluorescent Proteins, Apoptosis Regulatory Proteins, Mice
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