title: Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila.
abstract: During autophagy, phagophores capture portions of cytoplasm and form double-membrane autophagosomes to deliver cargo for lysosomal degradation. How autophagosomes gain competence to fuse with late endosomes and lysosomes is not known. In this paper, we show that Syntaxin17 is recruited to the outer membrane of autophagosomes to mediate fusion through its interactions with ubisnap (SNAP-29) and VAMP7 in Drosophila melanogaster. Loss of these genes results in accumulation of autophagosomes and a block of autolysosomal degradation during basal, starvation-induced, and developmental autophagy. Viable Syntaxin17 mutant adults show large-scale accumulation of autophagosomes in neurons, severe locomotion defects, and premature death. These mutant phenotypes cannot be rescued by neuron-specific inhibition of caspases, suggesting that caspase activation and cell death do not play a major role in brain dysfunction. Our findings reveal the molecular mechanism underlying autophagosomal fusion events and show that lysosomal degradation and recycling of sequestered autophagosome content is crucial to maintain proper functioning of the nervous system.
authors.affiliation: Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, H-1117 Budapest, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Takáts
authors.forename: Péter
authors.initials: P
authors.lastname: Nagy
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Varga
authors.forename: Karolina
authors.initials: K
authors.lastname: Pircs
authors.forename: Manuéla
authors.initials: M
authors.lastname: Kárpáti
authors.forename: Kata
authors.initials: K
authors.lastname: Varga
authors.forename: Attila L
authors.initials: AL
authors.lastname: Kovács
authors.forename: Krisztina
authors.initials: K
authors.lastname: Hegedűs
authors.forename: Gábor
authors.initials: G
authors.lastname: Juhász
mesh_terms: D000818:Animals; D001343:Autophagy; D003593:Cytoplasm / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology*; D011992:Endosomes / Q000378:metabolism; D005786:Gene Expression Regulation; D008247:Lysosomes / Q000378:metabolism*; D008854:Microscopy, Electron; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D010588:Phagosomes / Q000502:physiology*; D050765:Qa-SNARE Proteins / Q000378:metabolism*; D050683:R-SNARE Proteins / Q000378:metabolism*; D034622:RNA Interference; D050600:SNARE Proteins / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; D050600:SNARE Proteins; C582206:Snap29 protein, Drosophila; C582207:VAMP7 protein, Drosophila