Open AccessThe RBG-1/RBG-2 complex modulates autophagy activity by regulating lysosomal biogenesis and function
Author(s) -
Zhaoyu Wang,
Hongyu Zhao,
Chongzhen Yuan,
Dongfeng Zhao,
Yanan Sun,
Xiaochen Wang,
Hong Zhang
Publication year - 2019
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.234195
Subject(s) - biology , autophagy , biogenesis , microbiology and biotechnology , function (biology) , genetics , apoptosis , gene
Vici syndrome is a severe and progressive multisystem disease caused by mutations in the EPG5 gene. In patient tissues and animal models, loss of EPG5 function is associated with defective autophagy caused by accumulation of non-degradative autolysosomes, but very little is known about the mechanism underlying this cellular phenotype. Here we demonstrated that loss of function of the RBG-1/RBG-2 complex ameliorates the autophagy defect in epg-5 mutants. The suppression effect is independent of the complex's activity as a RAB-3 GAP and a RAB-18 GEF. Loss of rbg-1 activity promotes lysosomal biogenesis and function, and also suppresses the accumulation of non-functional autolysosomes in epg-5 mutants. The mobility of late endosome/lysosome-associated RAB-7 is reduced in epg-5 mutants, and this defect is rescued by simultaneous loss of function of rbg-1. Expression of the GDP-bound form of RAB-7 also promotes lysosomal biogenesis and suppresses the autophagy defect in epg-5 mutants. Our study reveals that the RBG-1/RBG-2 complex acts by modulating the dynamics of membrane-associated RAB-7 to regulate lysosomal biogenesis, and provides insights into the pathogenesis of Vici syndrome.