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

Mol Cell. 2016 Sep 1;63(5):781-95. doi: 10.1016/j.molcel.2016.08.021.

Abstract

Mutations in the human autophagy gene EPG5 cause the multisystem disorder Vici syndrome. Here we demonstrated that EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. EPG5 is recruited to late endosomes/lysosomes by direct interaction with Rab7 and the late endosomal/lysosomal R-SNARE VAMP7/8. EPG5 also binds to LC3/LGG-1 (mammalian and C. elegans Atg8 homolog, respectively) and to assembled STX17-SNAP29 Qabc SNARE complexes on autophagosomes. EPG5 stabilizes and facilitates the assembly of STX17-SNAP29-VAMP7/8 trans-SNARE complexes, and promotes STX17-SNAP29-VAMP7-mediated fusion of reconstituted proteoliposomes. Loss of EPG5 activity causes abnormal fusion of autophagosomes with various endocytic vesicles, in part due to elevated assembly of STX17-SNAP25-VAMP8 complexes. SNAP25 knockdown partially suppresses the autophagy defect caused by EPG5 depletion. Our study reveals that EPG5 is a Rab7 effector involved in autophagosome maturation, providing insight into the molecular mechanism underlying Vici syndrome.

Keywords: LC3; RAB effector; SNARE; autophagosome maturation; epg-5.

MeSH terms

  • Agenesis of Corpus Callosum / genetics*
  • Agenesis of Corpus Callosum / metabolism
  • Agenesis of Corpus Callosum / pathology
  • Amino Acid Sequence
  • Animals
  • Autophagosomes / metabolism*
  • Autophagosomes / ultrastructure
  • Autophagy / genetics
  • Autophagy-Related Proteins
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cataract / genetics*
  • Cataract / metabolism
  • Cataract / pathology
  • Endosomes / metabolism*
  • Endosomes / ultrastructure
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Lysosome-Associated Membrane Glycoproteins
  • Lysosomes / metabolism*
  • Lysosomes / ultrastructure
  • Membrane Fusion
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Protein Binding
  • Proteins / genetics*
  • Proteins / metabolism
  • Qa-SNARE Proteins / genetics
  • Qa-SNARE Proteins / metabolism
  • Qb-SNARE Proteins / genetics
  • Qb-SNARE Proteins / metabolism
  • Qc-SNARE Proteins / genetics
  • Qc-SNARE Proteins / metabolism
  • R-SNARE Proteins / genetics
  • R-SNARE Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Synaptosomal-Associated Protein 25 / genetics
  • Synaptosomal-Associated Protein 25 / metabolism
  • Vesicular Transport Proteins
  • rab GTP-Binding Proteins / genetics*
  • rab GTP-Binding Proteins / metabolism

Substances

  • Autophagy-Related Proteins
  • Caenorhabditis elegans Proteins
  • EPG5 protein, human
  • LGG-1 protein, C elegans
  • Lysosome-Associated Membrane Glycoproteins
  • Microtubule-Associated Proteins
  • Proteins
  • Qa-SNARE Proteins
  • Qb-SNARE Proteins
  • Qc-SNARE Proteins
  • R-SNARE Proteins
  • SNAP25 protein, human
  • SNAP29 protein, human
  • STX17 protein, human
  • Synaptosomal-Associated Protein 25
  • VAMP7 protein, human
  • VAMP8 protein, human
  • Vesicular Transport Proteins
  • light chain 3, human
  • rab7 protein
  • rab GTP-Binding Proteins

Supplementary concepts

  • Absent corpus callosum cataract immunodeficiency