The RBG-1-RBG-2 complex modulates autophagy activity by regulating lysosomal biogenesis and function in C. elegans

Wang, Zhao, Yuan, Zhao, Sun, Wang, Zhang (2019) The RBG-1-RBG-2 complex modulates autophagy activity by regulating lysosomal biogenesis and function in C. elegans J Cell Sci (IF: 4) 132(19)

Abstract

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 demonstrate that loss of function of the RBG-1-RBG-2 complex ameliorates the autophagy defect in C. elegansepg-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- and 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.© 2019. Published by The Company of Biologists Ltd.

Links

http://www.ncbi.nlm.nih.gov/pubmed/31444285
http://dx.doi.org/10.1242/jcs.234195

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