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The TBCK-PPP1R21-FERRY3/C12orf4 complex: a RAB5-GAP brake essential for endo-lysosomal homeostasis
Yingji Chen1, Xiayun Xu1, Yi Zheng1
1Shanghai Pudong Hospital, Fudan University Pudong Medical Center, State Key Laboratory of Genetics and Development of Complex Phenotypes, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, P.R. China.
Autophagy
|March 6, 2026
Summary
TBCK syndrome is a neurodevelopmental disorder linked to faulty endosomal dynamics. Our study reveals TBCK acts as a RAB5 GTPase-activating protein, crucial for neuronal homeostasis.
Area of Science:
- Cell Biology
- Neuroscience
- Genetics
Background:
- TBCK syndrome is a severe neurodevelopmental disorder with unknown molecular mechanisms.
- The TBCK gene's role in MTOR signaling is debated.
- Previous research linked TBCK to MTOR signaling pathways.
Purpose of the Study:
- To elucidate the primary molecular function of the TBCK gene.
- To investigate the role of TBCK in endosomal trafficking and neurodegeneration.
- To define the molecular basis of TBCK syndrome.
Main Methods:
- Protein complex purification and characterization.
- GTPase-activating protein (GAP) assays.
- Analysis of TBCK mutations in cellular models.
- Endosomal trafficking and autophagy assays.
Main Results:
- TBCK forms a heterotrimeric complex with PPP1R21 and FERRY3, functioning as a RAB5 GAP.
- TBCK deficiency causes RAB5 hyperactivation, blocking endosome maturation.
- RAB5 hyperactivation leads to PIK3C3/VPS34 activation, impaired lysosomal delivery, and blocked autophagy.
Conclusions:
- TBCK syndrome is a primary disorder of endosomal dynamics.
- The TBCK-PPP1R21-FERRY3 complex is essential for regulating RAB5 activity.
- This complex acts as a critical brake for neuronal homeostasis, and its dysfunction causes TBCK syndrome.
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