The neuropathy-linked protein TECPR2 is a Rab5 effector that regulates cargo recycling from early endosomes

Sankalita Paul, Rajat Pant, Poonam Sharma, Kshitiz Walia, Suhasi Gupta, Adhil Aseem, Kamlesh Kumari Bajwa, Ruben George, Yudish Varma, Tripta Bhatia, Rajesh Ramachandran, Amit Tuli and Mahak Sharma ()
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Sankalita Paul: Indian Institute of Science Education and Research Mohali (IISERM), Department of Biological Sciences
Rajat Pant: Indian Institute of Science Education and Research Mohali (IISERM), Department of Biological Sciences
Poonam Sharma: Indian Institute of Science Education and Research Mohali (IISERM), Department of Biological Sciences
Kshitiz Walia: Academy of Scientific and Innovative Research (AcSIR)
Suhasi Gupta: Indian Institute of Science Education and Research Mohali (IISERM), Department of Physical Sciences
Adhil Aseem: Indian Institute of Science Education and Research Mohali (IISERM), Department of Biological Sciences
Kamlesh Kumari Bajwa: Indian Institute of Science Education and Research Mohali (IISERM), Department of Biological Sciences
Ruben George: Indian Institute of Science Education and Research Mohali (IISERM), Department of Biological Sciences
Yudish Varma: Indian Institute of Science Education and Research Mohali (IISERM), Department of Biological Sciences
Tripta Bhatia: Indian Institute of Science Education and Research Mohali (IISERM), Department of Physical Sciences
Rajesh Ramachandran: Indian Institute of Science Education and Research Mohali (IISERM), Department of Biological Sciences
Amit Tuli: Academy of Scientific and Innovative Research (AcSIR)
Mahak Sharma: Indian Institute of Science Education and Research Mohali (IISERM), Department of Biological Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-28

Abstract: Abstract Small GTP-binding proteins of the Rab, Arf, and Arf-like family mediate the recruitment of their effectors to subcellular membrane-bound compartments, which in turn mediate vesicle budding, motility, and tethering. Here, we report that Tectonin-β-propeller repeat containing protein 2 (TECPR2), a protein mutated in a form of hereditary sensory and autonomic neuropathy (HSAN), is an effector of early endosomal Rab protein, Rab5. We demonstrate that the HSAN-associated missense variants of TECPR2 are defective in Rab5 binding and, consequently, in membrane recruitment. Furthermore, our findings reveal that depletion of TECPR2 impairs recycling of a subset of cargo receptors, including α5β1 integrins, leading to their lysosomal degradation. TECPR2 interacts with SNX17 and subunits of the WASH complex, molecular players that regulate the formation of actin-dependent cargo retrieval subdomain on the early endosomes. Finally, we show that TECPR2 depletion in zebrafish embryos results in decreased survival, impaired movement and altered neuromuscular synaptic morphology. Our study suggests that TECPR2 functions as a linker between Rab5 and the actin-dependent cargo retrieval machinery, providing insights into how mutations in TECPR2 may result in a neurodegenerative disorder.

Date: 2025
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DOI: 10.1038/s41467-025-65568-4

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