Autophagy , 3 April, 2025, DOI：https://doi.org/10.1080/15548627.2025.2485420

EPG-5 regulates TGFB/TGF-β and WNT signalling by modulating retrograde endocytic trafficking

Chongzhen Yuan, Huachuan Dong, Chunyan Wu, Jinyang Liu, Zheng Wang, Xingwei Wang, Haiyan Ren, Zhaoyu Wang & Qun Lu

Abstract

The Vici syndrome protein EPG5 acts as a tethering factor determining the fusion specificity of autophagosomes with late endosomes/lysosomes. Here we demonstrated that during C. elegans development, EPG-5 modulates SMA and MAB TGFB/TGF-β signaling in controlling body size and also WNT signaling in regulating cell migration. EPG-5 is required for retrograde trafficking of the TGFB receptor SMA-6 and WLS/Wntless homolog MIG-14. In epg-5 mutants, SMA-6 and MIG-14 are trapped within hybrid endosomal structures, which colocalize with SNX-1- and SNX-3-labeled vesicles, respectively. Basolateral recycling processes of transmembrane cargos H.s.TFR/hTfR and H.s.IL2RA/hTAC are also defective in epg-5 mutants. Depletion of EPG-5 causes defective RAB-5 and RAB-7, and RAB-5 and RAB-10 conversion, leading to the formation of these hybrid vesicles. The defects in endocytic trafficking and autophagy in epg-5 mutants are ameliorated by knocking down components of the HOPS complex. Our study demonstrates the intersection between the autophagy pathway and the endocytic pathway, providing insights into the pathogenesis of amyotrophic lateral sclerosis (ALS) and Vici syndrome.

文章链接：https://www.tandfonline.com/doi/full/10.1080/15548627.2025.2485420#abstract