Selective autophagy plays a crucial role in maintaining cellular homeostasis by specifically targeting unwanted cargo labeled with “autophagy cues” signals for autophagic degradation. In this study, we identify Rab GTPases as a class of such autophagy cues signals involved in selective autophagy. Through biochemical and imaging screens, we reveal that human Rab GTPases are common autophagy substrates. Importantly, we confirm the conservation of Rab GTPase autophagic degradation in different model organisms. Rab GTPases translocate to damaged mitochondria, lipid droplets, and invading Salmonella-containing vacuoles (SCVs) to serve as degradation signals. Furthermore, they facilitate mitophagy, lipophagy, and xenophagy, respectively, by recruiting receptors. This interplay between Rab GTPases and receptors may ensure the de novo synthesis of isolation membranes around Rab-GTPase-labeled cargo, thereby mediating selective autophagy. These processes are further influenced by upstream regulators such as LRRK2, GDIs, and RabGGTase. In conclusion, this study unveils a conserved mechanism involving Rab GTPases as autophagy cues signals and proposes a model for the spatiotemporal control of selective autophagy.
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April 08 2025
Rab GTPases are evolutionarily conserved signals mediating selective autophagy
Pengwei Zhao
,
Pengwei Zhao
*
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft)
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
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Rui Tian
,
Rui Tian
*
(Data curation, Formal analysis, Investigation, Resources, Software)
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
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Dandan Song
,
Dandan Song
*
(Data curation, Formal analysis, Resources, Software)
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
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Qi Zhu
,
Qi Zhu
*
(Data curation, Formal analysis)
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
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Xianming Ding
,
Xianming Ding
*
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources)
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
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Jianqin Zhang
,
Jianqin Zhang
(Methodology, Resources)
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
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Beibei Cao
,
Beibei Cao
(Investigation, Methodology, Resources)
3
The Fourth Affiliated Hospital, Zhejiang University School of Medicine
, Yiwu, China
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Mengyuan Zhang
,
Mengyuan Zhang
(Resources, Software)
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
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Yilu Xu
,
Yilu Xu
(Software)
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
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Jie Fang
,
Jie Fang
(Investigation, Methodology, Resources, Validation, Visualization)
4
Institute of Translational Medicine, Zhejiang University
, Hangzhou, China
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Jieqiong Tan
,
Jieqiong Tan
(Resources)
5
Center for Medical Genetics, School of Life Sciences, Central South University
, Changsha, China
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Cong Yi
,
Cong Yi
(Data curation, Resources, Supervision)
6Department of Biochemistry, and Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital,
Zhejiang University School of Medicine
, Hangzhou, China
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Hongguang Xia
,
Hongguang Xia
(Writing - original draft)
6Department of Biochemistry, and Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital,
Zhejiang University School of Medicine
, Hangzhou, China
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Wei Liu
,
Wei Liu
(Supervision, Writing - review & editing)
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
2Department of Cardiology of Second Affiliated Hospital,
Zhejiang University School of Medicine
, Hangzhou, China
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Wei Zou
,
(Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing)
3
The Fourth Affiliated Hospital, Zhejiang University School of Medicine
, Yiwu, China
4
Institute of Translational Medicine, Zhejiang University
, Hangzhou, China
Wei Zou: [email protected]
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Qiming Sun
(Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing)
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
2Department of Cardiology of Second Affiliated Hospital,
Zhejiang University School of Medicine
, Hangzhou, China
3
The Fourth Affiliated Hospital, Zhejiang University School of Medicine
, Yiwu, China
7
Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorders
, Hangzhou, China
Correspondence to Qiming Sun: [email protected]
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Pengwei Zhao
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft
*
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
Rui Tian
Data curation, Formal analysis, Investigation, Resources, Software
*
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
Dandan Song
Data curation, Formal analysis, Resources, Software
*
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
Xianming Ding
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources
*
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
Jianqin Zhang
Methodology, Resources
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
Beibei Cao
Investigation, Methodology, Resources
3
The Fourth Affiliated Hospital, Zhejiang University School of Medicine
, Yiwu, China
Mengyuan Zhang
Resources, Software
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
Yilu Xu
Software
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
Jie Fang
Investigation, Methodology, Resources, Validation, Visualization
4
Institute of Translational Medicine, Zhejiang University
, Hangzhou, China
Jieqiong Tan
Resources
5
Center for Medical Genetics, School of Life Sciences, Central South University
, Changsha, China
Cong Yi
Data curation, Resources, Supervision
6Department of Biochemistry, and Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital,
Zhejiang University School of Medicine
, Hangzhou, China
Hongguang Xia
Writing - original draft
6Department of Biochemistry, and Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital,
Zhejiang University School of Medicine
, Hangzhou, China
Wei Liu
Supervision, Writing - review & editing
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
2Department of Cardiology of Second Affiliated Hospital,
Zhejiang University School of Medicine
, Hangzhou, China
Wei Zou
Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing
3
The Fourth Affiliated Hospital, Zhejiang University School of Medicine
, Yiwu, China
4
Institute of Translational Medicine, Zhejiang University
, Hangzhou, China
Qiming Sun
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - original draft, Writing - review & editing
1
Center for Metabolism Research, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University
, Yiwu, China
2Department of Cardiology of Second Affiliated Hospital,
Zhejiang University School of Medicine
, Hangzhou, China
3
The Fourth Affiliated Hospital, Zhejiang University School of Medicine
, Yiwu, China
7
Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorders
, Hangzhou, China
Correspondence to Qiming Sun: [email protected]
Wei Zou: [email protected]
*
P. Zhao, R. Tian, D. Song, Q. Zhu, and X. Ding contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
November 05 2024
Revision Received:
December 31 2024
Accepted:
January 21 2025
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 92254307,32025012,31970919,31900530
Funder(s):
Ministry of Science and Technology of the People’s Republic of China
- Award Id(s): 2024YFA1803003
© 2025 Zhao et al.
2025
Zhao et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (5): e202410150.
Article history
Received:
November 05 2024
Revision Received:
December 31 2024
Accepted:
January 21 2025
Connected Content
Citation
Pengwei Zhao, Rui Tian, Dandan Song, Qi Zhu, Xianming Ding, Jianqin Zhang, Beibei Cao, Mengyuan Zhang, Yilu Xu, Jie Fang, Jieqiong Tan, Cong Yi, Hongguang Xia, Wei Liu, Wei Zou, Qiming Sun; Rab GTPases are evolutionarily conserved signals mediating selective autophagy. J Cell Biol 5 May 2025; 224 (5): e202410150. doi: https://doi.org/10.1083/jcb.202410150
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