The Vici Syndrome Protein EPG5 Is a Rab7 Effector that Determines the Fusion Specificity of Autophagosomes with Late Endosomes/Lysosomes

Wang Z, Miao G, Xue X, Guo X, Yuan C, Wang Z, Zhang G, Chen Y, Feng D, Hu J, Zhang H

Molecular Cell, 63(5), 2016

Speaker: Hsi-Yu, Liu (劉席羽)                                     Time: 15:00~16:00, May 24, 2017

Commentator: Dr. Pin Ling (凌斌老師)                       Place: Room 601

Abstract:

Autophagy is an evolutionarily conserved lysosome-mediated degradation process. In higher eukaryotes, nascent autophagosomes fuse with endocytic vesicles to form amphisomes which further fuse with lysosomes to form autolysosomes. Fusion of autophagosomes with late endosomes/lysosomes is mediated by the SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor) complex consisting of autophagosome Syntaxin 17, SNAP29, and endosomal/lysosomal VAMP7/8. A large family of small GTPases associate with distinct membrane organelles, which control membrane identity, vesicle budding, uncoating, motility and fusion through the recruitment of specific effector proteins. EPG5(Ectopic P-Granules Autophagy Protein 5 Homolog) is one of the tethering factors, which are generally recruited to the cognate membranes by Rab GTPases. Tethering factors are responsible for the initial attachment of transport vesicles to their target membranes for fusion. The metazoan-specific autophagy gene EPG5 was identified by genetic screening in Caenorhabditis elegans (C. elegans). Loss of epg-5 function in C. eleganscauses defective autophagic degradation of a variety of protein aggregates during development. Mammalian homologs of EPG-5/mEPG5 are essential for starvation-induced autophagy. Furthermore, mEPG5 are required for formation of degradative autolysosomes¹. Loss of Epg5 activity also impairs endosomal trafficking, slows endocytic degradation and delays endocytic recycling. However, recessive mutations of human EPG5 gene cause Vici syndrome, a multisystem disorder with a wide range of clinical manifestations, including agenesis of the corpus callosum, myopathy, and combined immunodeficiency. In this paper, the authors reveal that EPG5 directly interacts with Rab7 and VAMP7/8 on late endosomes/lysosomes, followed by binding with LC3/LGG-1 and the assembled STX17-SNAP29 complex on the autophagosomes. EPG5 specifically promotes fusion of the autophagosomes with the late endosomes/lysosomes. Aberration of EPG5 function causes non-specific fusion of the autophagosomes with other endocytic vesicles, resulting in formation of nondegradable enlarged vesicles.

Reference:

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