Syntaxin 13, a Genetic Modifier of Mutant CHMP2B in Frontotemporal Dementia, Is Required for Autophagosome Maturation
Copyright policy )Syntaxin 13, a Genetic Modifier of Mutant CHMP2B in Frontotemporal Dementia, Is Required for Autophagosome Maturation
Phagophore maturation is a key step in the macroautophagy pathway, which is critical in many important physiological and pathological processes. Here we identified Drosophila N-ethylmaleimide-sensitive fusion protein 2 (dNSF2) and soluble NSF attachment protein (Snap) as strong genetic modifiers of mutant CHMP2B, an ESCRT-III component that causes frontotemporal dementia and autophagosome accumulation. Among several SNAP receptor (SNARE) genes, Drosophila syntaxin 13 (syx13) exhibited a strong genetic interaction with mutant CHMP2B. Knockdown of syntaxin 13 (STX13) or its binding partner Vti1a in mammalian cells caused LC3-positive puncta to accumulate and blocks autophagic flux. STX13 was present on LC3-positive phagophores induced by rapamycin and was highly enriched on multilamellar structures induced by dysfunctional ESCRT-III. Loss of STX13 also caused the accumulation of Atg5-positive puncta and the formation of multilamellar structures. These results suggest that STX13 is a genetic modifier of ESCRT-III dysfunction and participates in the maturation of phagophores into closed autophagosomes.
- University of Massachusetts Medical School United States
- University of York United Kingdom
Blotting, Western, Vesicular Transport Proteins, Cell and Developmental Biology, Phagosomes, Autophagy, Animals, Drosophila Proteins, Humans, Eye Abnormalities, Microscopy, Immunoelectron, Molecular Biology, N-Ethylmaleimide-Sensitive Proteins, Immunoelectron, Microscopy, *Autophagy, Microscopy, Confocal, Neuroscience and Neurobiology, Endosomal Sorting Complexes Required for Transport, Blotting, Qa-SNARE Proteins, Genetics and Genomics, Cell Biology, Cellular and Molecular Physiology, Luminescent Proteins, Drosophila melanogaster, HEK293 Cells, Phenotype, Neurology, Confocal, Frontotemporal Dementia, Mutation, RNA Interference, Western, Microtubule-Associated Proteins, HeLa Cells
Blotting, Western, Vesicular Transport Proteins, Cell and Developmental Biology, Phagosomes, Autophagy, Animals, Drosophila Proteins, Humans, Eye Abnormalities, Microscopy, Immunoelectron, Molecular Biology, N-Ethylmaleimide-Sensitive Proteins, Immunoelectron, Microscopy, *Autophagy, Microscopy, Confocal, Neuroscience and Neurobiology, Endosomal Sorting Complexes Required for Transport, Blotting, Qa-SNARE Proteins, Genetics and Genomics, Cell Biology, Cellular and Molecular Physiology, Luminescent Proteins, Drosophila melanogaster, HEK293 Cells, Phenotype, Neurology, Confocal, Frontotemporal Dementia, Mutation, RNA Interference, Western, Microtubule-Associated Proteins, HeLa Cells
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