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  • Increased O-GlcNAcylation of SNAP29 Drives Arsenic-Induced Autophagic Dysfunction.

Increased O-GlcNAcylation of SNAP29 Drives Arsenic-Induced Autophagic Dysfunction.

Molecular and cellular biology (2018-03-07)
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
ABSTRACT

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 arsenic-mediated 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.

MATERIALS
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Product Description

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