TBC1D20 deficiency causes Warburg Micro Syndrome in humans, characterized by multiple eye abnormalities, severe intellectual disability, and abnormal sexual development, but the molecular mechanisms remain unknown. Here, we identify TBC1D20 as a novel Rab11 GTPase-activating protein that coordinates vesicle transport and actin remodeling to regulate ciliogenesis. Depletion of TBC1D20 promotes Rab11 vesicle accumulation and actin deconstruction around the centrosome, facilitating the initiation of ciliogenesis even in cycling cells. Further investigations reveal enhanced Rab11–MICAL1 interaction upon TBC1D20 loss, activating the monooxygenase domain of MICAL1 and inducing F-actin depolymerization around the centrosome. This actin network reorganization facilitates vesicle trafficking and docking, ultimately promoting ciliogenesis. In summary, our work uncovers a coordinated ciliogenesis initiation mechanism via Rab11 activation. These findings underscore a pivotal role for TBC1D20 in early ciliogenesis, advancing our understanding of its spatiotemporal regulation and offering insights into the disease pathogenesis associated with TBC1D20 mutations.
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January 27 2025
TBC1D20 coordinates vesicle transport and actin remodeling to regulate ciliogenesis
Denghui Zhai
,
Denghui Zhai
*
(Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Lamei Li
,
Lamei Li
*
(Formal analysis, Investigation, Validation, Writing - original draft)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Difei Wang
,
Difei Wang
*
(Formal analysis, Investigation, Validation)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Weishu Wang
,
Weishu Wang
(Formal analysis, Investigation, Validation)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Siyang Zhao
,
Siyang Zhao
(Formal analysis, Investigation, Validation)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Xue Wang
,
Xue Wang
(Formal analysis, Methodology, Software)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Cheng Chen
,
Cheng Chen
(Formal analysis, Investigation, Validation)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Zixuan Zhu
,
Zixuan Zhu
(Formal analysis, Investigation, Validation)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Weiwen Bu
,
Weiwen Bu
(Formal analysis, Investigation, Validation)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Mulin Yang
,
Mulin Yang
(Formal analysis, Investigation, Validation)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Hanxiao Yin
,
Hanxiao Yin
(Formal analysis, Investigation, Validation)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Ying Shan
,
Ying Shan
(Formal analysis, Investigation, Validation)
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
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Huijie Zhao
,
Huijie Zhao
(Resources)
2
Center for Cell Structure and Function, College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Shandong Normal University
, Jinan, China
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Christopher J. Westlake
,
Christopher J. Westlake
(Methodology, Writing - review & editing)
3Laboratory of Cellular and Developmental Signaling,
Center for Cancer Research, National Cancer Institute, National Institutes of Health
, Frederick, MD, USA
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Quanlong Lu
,
(Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing)
3Laboratory of Cellular and Developmental Signaling,
Center for Cancer Research, National Cancer Institute, National Institutes of Health
, Frederick, MD, USA
Quanlong Lu: [email protected]
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Jun Zhou
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
2
Center for Cell Structure and Function, College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Shandong Normal University
, Jinan, China
Correspondence to Jun Zhou: [email protected]
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Denghui Zhai
Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
*
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Lamei Li
Formal analysis, Investigation, Validation, Writing - original draft
*
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Weishu Wang
Formal analysis, Investigation, Validation
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Siyang Zhao
Formal analysis, Investigation, Validation
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Xue Wang
Formal analysis, Methodology, Software
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Cheng Chen
Formal analysis, Investigation, Validation
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Zixuan Zhu
Formal analysis, Investigation, Validation
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Weiwen Bu
Formal analysis, Investigation, Validation
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Mulin Yang
Formal analysis, Investigation, Validation
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Hanxiao Yin
Formal analysis, Investigation, Validation
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Ying Shan
Formal analysis, Investigation, Validation
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
Huijie Zhao
Resources
2
Center for Cell Structure and Function, College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Shandong Normal University
, Jinan, China
Christopher J. Westlake
Methodology, Writing - review & editing
3Laboratory of Cellular and Developmental Signaling,
Center for Cancer Research, National Cancer Institute, National Institutes of Health
, Frederick, MD, USA
Quanlong Lu
Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing
3Laboratory of Cellular and Developmental Signaling,
Center for Cancer Research, National Cancer Institute, National Institutes of Health
, Frederick, MD, USA
1Department of Genetics and Cell Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology,
Nankai University
, Tianjin, China
2
Center for Cell Structure and Function, College of Life Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Shandong Normal University
, Jinan, China
Correspondence to Jun Zhou: [email protected]
Quanlong Lu: [email protected]
*
D. Zhai, L. Li, and D. Wang contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
June 25 2024
Revision Received:
November 30 2024
Accepted:
January 03 2025
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 32170695,31991193
© 2025 Zhai et al.
2025
Zhai et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (4): e202406139.
Article history
Received:
June 25 2024
Revision Received:
November 30 2024
Accepted:
January 03 2025
Citation
Denghui Zhai, Lamei Li, Difei Wang, Weishu Wang, Siyang Zhao, Xue Wang, Cheng Chen, Zixuan Zhu, Weiwen Bu, Mulin Yang, Hanxiao Yin, Ying Shan, Huijie Zhao, Christopher J. Westlake, Quanlong Lu, Jun Zhou; TBC1D20 coordinates vesicle transport and actin remodeling to regulate ciliogenesis. J Cell Biol 3 April 2025; 224 (4): e202406139. doi: https://doi.org/10.1083/jcb.202406139
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