Syntaxin 13, a genetic modifier of mutant CHMP2B in frontotemporal dementia, is required for autophagosome maturation

Mol Cell. 2013 Oct 24;52(2):264-71. doi: 10.1016/j.molcel.2013.08.041. Epub 2013 Oct 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Blotting, Western
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Eye Abnormalities / genetics
  • Eye Abnormalities / metabolism
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Microscopy, Confocal
  • Microscopy, Immunoelectron
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mutation
  • N-Ethylmaleimide-Sensitive Proteins / genetics
  • N-Ethylmaleimide-Sensitive Proteins / metabolism
  • Phagosomes / metabolism*
  • Phagosomes / ultrastructure
  • Phenotype
  • Qa-SNARE Proteins / genetics
  • Qa-SNARE Proteins / metabolism*
  • RNA Interference
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • CHMP2B protein, Drosophila
  • CHMP2B protein, human
  • Drosophila Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Luminescent Proteins
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • Nsf2 protein, Drosophila
  • Qa-SNARE Proteins
  • Vesicular Transport Proteins
  • N-Ethylmaleimide-Sensitive Proteins