Increased O-GlcNAcylation of SNAP29 drives arsenicinduced autophagic dysfunction

Matthew Dodson, Pengfei Liu, Tao Jiang, Andrew J. Ambrose, Gang Luo, Montserrat Rojo de la Vega, Aram B. Cholanians, Pak Kin Wong, Eli Chapman, Donna D. Zhang

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Environmental exposure to arsenic is linked to adverse health effects, including cancer and diabetes. Pleiotropic cellular effects are observed with arsenic exposure. Previously, we demonstrated that arsenic dysregulated the autophagy pathway at low, environmentally relevant concentrations. Here we show that arsenic blocks autophagy by preventing autophagosome-lysosome fusion. Specifically, arsenic disrupts formation of the STX17-SNAP29-VAMP8 SNARE complex, where SNAP29 mediates vesicle fusion through bridging STX17-containing autophagosomes to VAMP8- bearing lysosomes. Mechanistically, arsenic inhibits SNARE complex formation, at least in part, by enhancing O-GlcNAcylation of SNAP29. Transfection of O-GlcNAcylation- defective, but not wild-type, SNAP29 into clustered regularly interspaced short palindromic repeat (CRISPR)-mediated SNAP29 knockout cells abolishes arsenicmediated autophagy inhibition. These findings reveal a mechanism by which low levels of arsenic perturb proteostasis through inhibition of SNARE complex formation, providing a possible therapeutic target for disease intervention in the more than 200 million people exposed to unsafe levels of arsenic.

Original languageEnglish (US)
Article numbere00595-17
JournalMolecular and cellular biology
Issue number11
StatePublished - Jun 1 2018


  • Arsenic
  • Autophagy
  • O-GlcNAc
  • SNAP29
  • SNARE complex
  • STX17
  • VAMP8

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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