The transmembrane autophagy protein ATG9 has multiple functions essential for autophagosome formation. Here, we uncovered a novel function of ATG-9 in regulating lysosome biogenesis and integrity in Caenorhabditis elegans. Through a genetic screen, we identified that mutations attenuating the lipid scrambling activity of ATG-9 suppress the autophagy defect in epg-5 mutants, in which non-degradative autolysosomes accumulate. The scramblase-attenuated ATG-9 mutants promote lysosome biogenesis and delivery of lysosome-localized hydrolases and also facilitate the maintenance of lysosome integrity. Through manipulation of phospholipid levels, we found that a reduction in phosphatidylethanolamine (PE) also suppresses the autophagy defects and lysosome damage associated with impaired lysosomal degradation. Our results reveal that modulation of phospholipid composition and distribution, e.g., by attenuating the scramblase activity of ATG-9 or reducing the PE level, regulates lysosome function and integrity.
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April 09 2025
The autophagy protein ATG-9 regulates lysosome function and integrity
Kangfu Peng
,
Kangfu Peng
(Data curation, Formal analysis, Investigation, Validation, Writing - original draft, Writing - review & editing)
1National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory,
Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
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Guoxiu Zhao
,
Guoxiu Zhao
(Investigation)
1National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory,
Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
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Hongyu Zhao
,
Hongyu Zhao
(Resources)
1National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory,
Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
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Nobuo N. Noda
,
Nobuo N. Noda
(Funding acquisition, Visualization, Writing - review & editing)
3
Institute for Genetic Medicine, Hokkaido University
, Sapporo, Japan
4
Institute of Microbial Chemistry (BIKAKEN)
, Tokyo, Japan
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Hong Zhang
(Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing)
1National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory,
Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
Correspondence to Hong Zhang: [email protected]
Search for other works by this author on:
Kangfu Peng
Data curation, Formal analysis, Investigation, Validation, Writing - original draft, Writing - review & editing
1National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory,
Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
Guoxiu Zhao
Investigation
1National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory,
Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
Hongyu Zhao
Resources
1National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory,
Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
Nobuo N. Noda
Funding acquisition, Visualization, Writing - review & editing
3
Institute for Genetic Medicine, Hokkaido University
, Sapporo, Japan
4
Institute of Microbial Chemistry (BIKAKEN)
, Tokyo, Japan
Hong Zhang
Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing
1National Laboratory of Biomacromolecules, New Cornerstone Science Laboratory,
Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
Correspondence to Hong Zhang: [email protected]
Disclosures: The authors declare no competing interests exist.
H. Zhang is the lead contact.
Received:
November 13 2024
Revision Received:
March 05 2025
Accepted:
March 11 2025
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 82188101
Funder(s):
New Cornerstone Science Foundation
Funder(s):
CREST, Japan Science and Technology Agency
- Award Id(s): JPMJCR20E3
© 2025 Peng et al.
2025
Peng et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (6): e202411092.
Article history
Received:
November 13 2024
Revision Received:
March 05 2025
Accepted:
March 11 2025
Citation
Kangfu Peng, Guoxiu Zhao, Hongyu Zhao, Nobuo N. Noda, Hong Zhang; The autophagy protein ATG-9 regulates lysosome function and integrity. J Cell Biol 2 June 2025; 224 (6): e202411092. doi: https://doi.org/10.1083/jcb.202411092
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