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. elegans 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- 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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: H. Zhang, X.W.; Methodology: Z.W., C.Y., H. Zhao; Validation: Z.W., H. Zhao; Formal analysis: H. Zhang, Z.W.; Investigation: Z.W.; Resources: Z.W., C.Y., D.Z., Y.S., X.W.; Data curation: Z.W., H. Zhao; Writing - original draft: H. Zhang, Z.W.; Writing - review & editing: H. Zhang; Visualization: H. Zhang, Z.W., H. Zhao; Supervision: H. Zhang; Project administration: H. Zhang; Funding acquisition: H. Zhang.
Funding
This work was supported by the National Natural Science Foundation of China (NSFC) (31421002, 31561143001, 31630048 and 31790403), by Beijing Municipal Science and Technology Commission (Z181100001318003), by the National Chinese Ministry of Science and Technology (2017YFA0503401), by the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (grant XDB19000000) and Key Research Program of Frontier Sciences, CAS (grant QYZDY-SSW-SMC006) to H. Zhang. The research is also partly supported by University of Chinese Academy of Sciences Education Foundation Fountain-Valley Life Sciences Fund.
Supplementary information
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.234195.supplemental
- Received May 12, 2019.
- Accepted August 19, 2019.
- © 2019. Published by The Company of Biologists Ltd
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