Syntaxin 13, a genetic modifier of mutant CHMP2B in frontotemporal dementia, is required for autophagosome maturation
Department of Neurology
Animals; *Autophagy; Blotting, Western; Drosophila Proteins; Drosophila melanogaster; Endosomal Sorting Complexes Required for Transport; Eye Abnormalities; Frontotemporal Dementia; HEK293 Cells; HeLa Cells; Humans; Luminescent Proteins; Microscopy, Confocal; Microscopy, Immunoelectron; Microtubule-Associated Proteins; Mutation; N-Ethylmaleimide-Sensitive Proteins; Phagosomes; Phenotype; Qa-SNARE Proteins; RNA Interference; Vesicular Transport Proteins
Cell and Developmental Biology | Cellular and Molecular Physiology | Genetics and Genomics | Molecular Biology | Neurology | Neuroscience and Neurobiology
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.
DOI of Published Version
Mol Cell. 2013 Oct 24;52(2):264-71. doi: 10.1016/j.molcel.2013.08.041. Epub 2013 Oct 3. Link to article on publisher's site
Lu Y, Zhang Z, Sun D, Sweeney ST, Gao F. (2013). Syntaxin 13, a genetic modifier of mutant CHMP2B in frontotemporal dementia, is required for autophagosome maturation. UMass Chan Medical School Faculty Publications. https://doi.org/10.1016/j.molcel.2013.08.041. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/774