O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation

Nat Cell Biol. 2014 Dec;16(12):1215-26. doi: 10.1038/ncb3066. Epub 2014 Nov 24.

Abstract

The mechanism by which nutrient status regulates the fusion of autophagosomes with endosomes/lysosomes is poorly understood. Here, we report that O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) mediates O-GlcNAcylation of the SNARE protein SNAP-29 and regulates autophagy in a nutrient-dependent manner. In mammalian cells, OGT knockdown, or mutating the O-GlcNAc sites in SNAP-29, promotes the formation of a SNAP-29-containing SNARE complex, increases fusion between autophagosomes and endosomes/lysosomes, and promotes autophagic flux. In Caenorhabditis elegans, depletion of ogt-1 has a similar effect on autophagy; moreover, expression of an O-GlcNAc-defective SNAP-29 mutant facilitates autophagic degradation of protein aggregates. O-GlcNAcylated SNAP-29 levels are reduced during starvation in mammalian cells and in C. elegans. Our study reveals a mechanism by which O-GlcNAc-modification integrates nutrient status with autophagosome maturation.

Publication types

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

MeSH terms

  • Acetylglucosamine / metabolism*
  • Animals
  • Autophagy / physiology*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Endosomes / physiology*
  • Green Fluorescent Proteins / genetics
  • HeLa Cells
  • Humans
  • Lysosome-Associated Membrane Glycoproteins
  • Lysosomes / physiology*
  • Membrane Fusion*
  • Mutation
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism*
  • Phagosomes / physiology*
  • Protein Binding
  • Proteins / genetics
  • Q-SNARE Proteins / genetics
  • Q-SNARE Proteins / metabolism
  • Qa-SNARE Proteins / genetics
  • Qb-SNARE Proteins / genetics
  • Qb-SNARE Proteins / metabolism*
  • Qc-SNARE Proteins / genetics
  • Qc-SNARE Proteins / metabolism*
  • R-SNARE Proteins / genetics
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction / genetics
  • Vesicular Transport Proteins

Substances

  • Caenorhabditis elegans Proteins
  • EPG5 protein, human
  • Lysosome-Associated Membrane Glycoproteins
  • Proteins
  • Q-SNARE Proteins
  • Qa-SNARE Proteins
  • Qb-SNARE Proteins
  • Qc-SNARE Proteins
  • R-SNARE Proteins
  • RNA, Small Interfering
  • SNAP-29 protein, C elegans
  • SNAP29 protein, human
  • STX17 protein, human
  • VAMP8 protein, human
  • Vesicular Transport Proteins
  • Green Fluorescent Proteins
  • N-Acetylglucosaminyltransferases
  • UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase
  • Acetylglucosamine