A dual function of V0-ATPase a1 provides an endolysosomal degradation mechanism in Drosophila melanogaster photoreceptors.
The vesicular adenosine triphosphatase (v-ATPase) is a proton pump that acidifies intracellular compartments. In addition, mutations in components of the membrane-bound v-ATPase V0 sector cause acidification-independent defects in yeast, worm, fly, zebrafish, and mouse. In this study, we present a dual function for the neuron-specific V0 subunit a1 orthologue v100 in Drosophila melanogaster. A v100 mutant that selectively disrupts proton translocation rescues a previously characterized synaptic vesicle fusion defect and vesicle fusion with early endosomes. Correspondingly, V100 selectively interacts with syntaxins on the respective target membranes, and neither synaptic vesicles nor early endosomes require v100 for their acidification. In contrast, V100 is required for acidification once endosomes mature into degradative compartments. As a consequence of the complete loss of this neuronal degradation mechanism, photoreceptors undergo slow neurodegeneration, whereas selective rescue of the acidification-independent function accelerates cell death by increasing accumulations in degradation-incompetent compartments. We propose that V100 exerts a temporally integrated dual function that increases neuronal degradative capacity.
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
W Ryan
WR
Williamson
Dong
D
Wang
Adam S
AS
Haberman
P Robin
PR
Hiesinger
D000251:Adenosine Triphosphatases; D000818:Animals; D001343:Autophagy / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D004596:Electroretinography; D011992:Endosomes / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008564:Membrane Potentials / Q000235:genetics; D008959:Models, Neurological; D009154:Mutation / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics / Q000503:physiopathology; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D013574:Synaptosomes / Q000378:metabolism; D051438:Syntaxin 16 / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D018942:Macrolides; D008562:Membrane Glycoproteins; D050765:Qa-SNARE Proteins; D011994:Recombinant Proteins; D051438:Syntaxin 16; C055093:chp protein, Drosophila; C496133:syntaxin 16, Drosophila; C040929:bafilomycin A1; D000251:Adenosine Triphosphatases; D025262:Vacuolar Proton-Translocating ATPases; C550849:Vha100-1 protein, Drosophila