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Interaction of the HOPS complex with Syntaxin 17 mediates autophagosome clearance in Drosophila

Takáts, Szabolcs; Pircs, Karolina LU ; Nagy, Péter; Varga, Ágnes; Kárpáti, Manuéla; Hegedűs, Krisztina; Kramer, Helmut; Kovács, Attila L; Sass, Miklós and Juhász, Gábor (2014) In Molecular Biology of the Cell 25(8). p.54-1338
Abstract

Homotypic fusion and vacuole protein sorting (HOPS) is a tethering complex required for trafficking to the vacuole/lysosome in yeast. Specific interaction of HOPS with certain SNARE (soluble NSF attachment protein receptor) proteins ensures the fusion of appropriate vesicles. HOPS function is less well characterized in metazoans. We show that all six HOPS subunits (Vps11 [vacuolar protein sorting 11]/CG32350, Vps18/Dor, Vps16A, Vps33A/Car, Vps39/CG7146, and Vps41/Lt) are required for fusion of autophagosomes with lysosomes in Drosophila. Loss of these genes results in large-scale accumulation of autophagosomes and blocks autophagic degradation under basal, starvation-induced, and developmental conditions. We find that HOPS colocalizes... (More)

Homotypic fusion and vacuole protein sorting (HOPS) is a tethering complex required for trafficking to the vacuole/lysosome in yeast. Specific interaction of HOPS with certain SNARE (soluble NSF attachment protein receptor) proteins ensures the fusion of appropriate vesicles. HOPS function is less well characterized in metazoans. We show that all six HOPS subunits (Vps11 [vacuolar protein sorting 11]/CG32350, Vps18/Dor, Vps16A, Vps33A/Car, Vps39/CG7146, and Vps41/Lt) are required for fusion of autophagosomes with lysosomes in Drosophila. Loss of these genes results in large-scale accumulation of autophagosomes and blocks autophagic degradation under basal, starvation-induced, and developmental conditions. We find that HOPS colocalizes and interacts with Syntaxin 17 (Syx17), the recently identified autophagosomal SNARE required for fusion in Drosophila and mammals, suggesting their association is critical during tethering and fusion of autophagosomes with lysosomes. HOPS, but not Syx17, is also required for endocytic down-regulation of Notch and Boss in developing eyes and for proper trafficking to lysosomes and eye pigment granules. We also show that the formation of autophagosomes and their fusion with lysosomes is largely unaffected in null mutants of Vps38/UVRAG (UV radiation resistance associated), a suggested binding partner of HOPS in mammals, while endocytic breakdown and lysosome biogenesis is perturbed. Our results establish the role of HOPS and its likely mechanism of action during autophagy in metazoans.

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publishing date
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Contribution to journal
publication status
published
keywords
Animals, Autophagy, Cell Line, Down-Regulation, Drosophila, Drosophila Proteins, Eye, Eye Proteins, Lysosomal-Associated Membrane Protein 1, Lysosomes, Membrane Fusion, Membrane Glycoproteins, Mutation, Phagosomes, Pigment Epithelium of Eye, Qa-SNARE Proteins, R-SNARE Proteins, RNA Interference, RNA, Small Interfering, Receptors, Notch, Receptors, Peptide, Tumor Suppressor Proteins, Vesicular Transport Proteins, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
in
Molecular Biology of the Cell
volume
25
issue
8
pages
17 pages
publisher
American Society for Cell Biology
external identifiers
  • scopus:84901308155
ISSN
1939-4586
DOI
10.1091/mbc.E13-08-0449
language
English
LU publication?
no
id
7185df88-52ba-4276-88be-8f31025ecf8e
date added to LUP
2017-03-16 15:25:52
date last changed
2017-11-05 05:15:24
@article{7185df88-52ba-4276-88be-8f31025ecf8e,
  abstract     = {<p>Homotypic fusion and vacuole protein sorting (HOPS) is a tethering complex required for trafficking to the vacuole/lysosome in yeast. Specific interaction of HOPS with certain SNARE (soluble NSF attachment protein receptor) proteins ensures the fusion of appropriate vesicles. HOPS function is less well characterized in metazoans. We show that all six HOPS subunits (Vps11 [vacuolar protein sorting 11]/CG32350, Vps18/Dor, Vps16A, Vps33A/Car, Vps39/CG7146, and Vps41/Lt) are required for fusion of autophagosomes with lysosomes in Drosophila. Loss of these genes results in large-scale accumulation of autophagosomes and blocks autophagic degradation under basal, starvation-induced, and developmental conditions. We find that HOPS colocalizes and interacts with Syntaxin 17 (Syx17), the recently identified autophagosomal SNARE required for fusion in Drosophila and mammals, suggesting their association is critical during tethering and fusion of autophagosomes with lysosomes. HOPS, but not Syx17, is also required for endocytic down-regulation of Notch and Boss in developing eyes and for proper trafficking to lysosomes and eye pigment granules. We also show that the formation of autophagosomes and their fusion with lysosomes is largely unaffected in null mutants of Vps38/UVRAG (UV radiation resistance associated), a suggested binding partner of HOPS in mammals, while endocytic breakdown and lysosome biogenesis is perturbed. Our results establish the role of HOPS and its likely mechanism of action during autophagy in metazoans.</p>},
  author       = {Takáts, Szabolcs and Pircs, Karolina and Nagy, Péter and Varga, Ágnes and Kárpáti, Manuéla and Hegedűs, Krisztina and Kramer, Helmut and Kovács, Attila L and Sass, Miklós and Juhász, Gábor},
  issn         = {1939-4586},
  keyword      = {Animals,Autophagy,Cell Line,Down-Regulation,Drosophila,Drosophila Proteins,Eye,Eye Proteins,Lysosomal-Associated Membrane Protein 1,Lysosomes,Membrane Fusion,Membrane Glycoproteins,Mutation,Phagosomes,Pigment Epithelium of Eye,Qa-SNARE Proteins,R-SNARE Proteins,RNA Interference,RNA, Small Interfering,Receptors, Notch,Receptors, Peptide,Tumor Suppressor Proteins,Vesicular Transport Proteins,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {8},
  pages        = {54--1338},
  publisher    = {American Society for Cell Biology},
  series       = {Molecular Biology of the Cell},
  title        = {Interaction of the HOPS complex with Syntaxin 17 mediates autophagosome clearance in Drosophila},
  url          = {http://dx.doi.org/10.1091/mbc.E13-08-0449},
  volume       = {25},
  year         = {2014},
}