Canonical autophagy captures within specialized double-membrane organelles, termed autophagosomes, an array of cytoplasmic components destined for lysosomal degradation. An autophagosome is completed when the growing phagophore undergoes ESCRT-dependent membrane closure, a prerequisite for its subsequent fusion with endolysosomal organelles and degradation of the sequestered cargo. ATG9A, a key integral membrane protein of the autophagy pathway, is best known for its role in the formation and expansion of phagophores. Here, we report a hitherto unappreciated function of mammalian ATG9A in directing autophagosome closure. ATG9A partners with IQGAP1 and key ESCRT-III component CHMP2A to facilitate this final stage in autophagosome formation. Thus, ATG9A is a central hub governing all major aspects of autophagosome membrane biogenesis, from phagophore formation to its closure, and is a unique ATG factor with progressive functionalities affecting the physiological outputs of autophagy.
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January 02 2025
ATG9A facilitates the closure of mammalian autophagosomes
Ruheena Javed
,
Ruheena Javed
(Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
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Muriel Mari
,
Muriel Mari
(Formal analysis, Investigation)
3Department of Biomedicine,
Aarhus University
, Aarhus, Denmark
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Einar Trosdal
,
Einar Trosdal
(Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Writing - review & editing)
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
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Thabata Duque
,
Thabata Duque
(Formal analysis)
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
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Masroor Ahmad Paddar
,
Masroor Ahmad Paddar
(Investigation, Validation)
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
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Lee Allers
,
Lee Allers
(Data curation, Software, Visualization)
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
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Michal H. Mudd
,
Michal H. Mudd
(Investigation, Resources)
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
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Aurore Claude-Taupin
,
Aurore Claude-Taupin
(Conceptualization, Methodology)
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
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Prithvi Reddy Akepati
,
Prithvi Reddy Akepati
(Investigation, Validation, Visualization)
4Gastroenterology Division, Department of Internal Medicine,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
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Emily Hendrix
,
Emily Hendrix
(Formal analysis, Investigation)
5Department of Chemistry and Chemical Biology,
The University of New Mexico
, Albuquerque, NM, USA
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Yi He
,
Yi He
(Formal analysis, Investigation, Methodology, Resources, Software)
5Department of Chemistry and Chemical Biology,
The University of New Mexico
, Albuquerque, NM, USA
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Michelle Salemi
,
Michelle Salemi
(Formal analysis)
6
Proteomics Core Facility, UC Davis Genome Center, University of California, Davis
, Davis, CA, USA
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Brett Phinney
,
Brett Phinney
(Data curation, Project administration, Resources, Software)
6
Proteomics Core Facility, UC Davis Genome Center, University of California, Davis
, Davis, CA, USA
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Yasuo Uchiyama
,
Yasuo Uchiyama
(Resources)
7Department of Cellular and Molecular Neuropathology,
Juntendo University Graduate School of Medicine
, Tokyo, Japan
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Fulvio Reggiori
,
Fulvio Reggiori
(Conceptualization, Funding acquisition, Writing - review & editing)
3Department of Biomedicine,
Aarhus University
, Aarhus, Denmark
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Vojo Deretic
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
Correspondence to Vojo Deretic: [email protected]
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Ruheena Javed
Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
Muriel Mari
Formal analysis, Investigation
3Department of Biomedicine,
Aarhus University
, Aarhus, Denmark
Einar Trosdal
Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Writing - review & editing
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
Thabata Duque
Formal analysis
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
Masroor Ahmad Paddar
Investigation, Validation
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
Lee Allers
Data curation, Software, Visualization
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
Michal H. Mudd
Investigation, Resources
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
Aurore Claude-Taupin
Conceptualization, Methodology
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
Prithvi Reddy Akepati
Investigation, Validation, Visualization
4Gastroenterology Division, Department of Internal Medicine,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
Emily Hendrix
Formal analysis, Investigation
5Department of Chemistry and Chemical Biology,
The University of New Mexico
, Albuquerque, NM, USA
Yi He
Formal analysis, Investigation, Methodology, Resources, Software
5Department of Chemistry and Chemical Biology,
The University of New Mexico
, Albuquerque, NM, USA
Michelle Salemi
Formal analysis
6
Proteomics Core Facility, UC Davis Genome Center, University of California, Davis
, Davis, CA, USA
Brett Phinney
Data curation, Project administration, Resources, Software
6
Proteomics Core Facility, UC Davis Genome Center, University of California, Davis
, Davis, CA, USA
Yasuo Uchiyama
Resources
7Department of Cellular and Molecular Neuropathology,
Juntendo University Graduate School of Medicine
, Tokyo, Japan
Fulvio Reggiori
Conceptualization, Funding acquisition, Writing - review & editing
3Department of Biomedicine,
Aarhus University
, Aarhus, Denmark
Vojo Deretic
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Autophagy, Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center
, Albuquerque, NM, USA
2Department of Molecular Genetics and Microbiology,
University of New Mexico School of Medicine
, Albuquerque, NM, USA
Correspondence to Vojo Deretic: [email protected]
Disclosures: The authors declare no competing interests exist.
A. Claude-Taupin’s current affiliation is Université Paris Cité, INSERM UMR-S1151, CNRS UMRS8253 Institut Necker Enfants Malades, Paris, France.
V. Deretic is a lead author.
Received:
April 17 2024
Revision Received:
August 29 2024
Accepted:
November 11 2024
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funder(s):
Swiss National Science Foundation
- Award Id(s): CRSII5_189952
Funder(s):
Novo Nordisk Foundation
- Award Id(s): 0066384
Funder(s):
Lundbeck Foundation
- Award Id(s): R383-2022-180
Funder(s):
National Institutes of Health
- Award Id(s): R37AI042999,R01AI111935,P20GM121176
© 2025 Javed et al.
2024
Javed et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
This work is licensed under a
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License
.
J Cell Biol (2025) 224 (2): e202404047.
Article history
Received:
April 17 2024
Revision Received:
August 29 2024
Accepted:
November 11 2024
Citation
Ruheena Javed, Muriel Mari, Einar Trosdal, Thabata Duque, Masroor Ahmad Paddar, Lee Allers, Michal H. Mudd, Aurore Claude-Taupin, Prithvi Reddy Akepati, Emily Hendrix, Yi He, Michelle Salemi, Brett Phinney, Yasuo Uchiyama, Fulvio Reggiori, Vojo Deretic; ATG9A facilitates the closure of mammalian autophagosomes. J Cell Biol 3 February 2025; 224 (2): e202404047. doi: https://doi.org/10.1083/jcb.202404047
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