PUBLICATION
The neuropathy-linked protein TECPR2 is a Rab5 effector that regulates cargo recycling from early endosomes
- Authors
- Paul, S., Pant, R., Sharma, P., Walia, K., Gupta, S., Aseem, A., Bajwa, K.K., George, R., Varma, Y., Bhatia, T., Ramachandran, R., Tuli, A., Sharma, M.
- ID
- ZDB-PUB-251127-14
- Date
- 2025
- Source
- Nature communications 16: 1053710537 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Lysosomes/metabolism
- Microfilament Proteins/genetics
- Microfilament Proteins/metabolism
- Zebrafish/genetics
- Protein Binding
- rab5 GTP-Binding Proteins*/genetics
- rab5 GTP-Binding Proteins*/metabolism
- Hereditary Sensory and Autonomic Neuropathies*/genetics
- Hereditary Sensory and Autonomic Neuropathies*/metabolism
- HEK293 Cells
- Humans
- Endosomes*/metabolism
- Animals
- Protein Transport
- PubMed
- 41298403 Full text @ Nat. Commun.
Citation
Paul, S., Pant, R., Sharma, P., Walia, K., Gupta, S., Aseem, A., Bajwa, K.K., George, R., Varma, Y., Bhatia, T., Ramachandran, R., Tuli, A., Sharma, M. (2025) The neuropathy-linked protein TECPR2 is a Rab5 effector that regulates cargo recycling from early endosomes. Nature communications. 16:1053710537.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping