creators_name: Paul, Sankalita creators_name: Pant, Rajat creators_name: Sharma, Poonam creators_name: Walia, Kshitiz creators_name: Gupta, Suhasi creators_name: Aseem, Adhil creators_name: Bajwa, Kamlesh Kumari creators_name: George, Ruben creators_name: Varma, Yudish creators_name: Bhatia, Tripta creators_name: Ramachandran, Rajesh creators_name: Tuli, Amit creators_name: Sharma, Mahak type: article datestamp: 2026-02-01 14:03:42 lastmod: 2026-02-01 14:03:42 metadata_visibility: show title: The neuropathy-linked protein TECPR2 is a Rab5 effector that regulates cargo recycling from early endosomes 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: 2025-11 publication: Nat. Commun. volume: 16 number: 1 publisher: Springer Science and Business Media LLC pagerange: 10537 citation: Paul, Sankalita and Pant, Rajat and Sharma, Poonam and Walia, Kshitiz and Gupta, Suhasi and Aseem, Adhil and Bajwa, Kamlesh Kumari and George, Ruben and Varma, Yudish and Bhatia, Tripta and Ramachandran, Rajesh and Tuli, Amit and Sharma, Mahak (2025) The neuropathy-linked protein TECPR2 is a Rab5 effector that regulates cargo recycling from early endosomes. Nat. Commun., 16 (1). p. 10537.