Increased O-GlcNAcylation of SNAP29 Drives Arsenic-Induced Autophagic Dysfunction
Ambrose, Andrew J.
Rojo de la Vega, Montserrat
Cholanians, Aram B.
Wong, Pak Kin
Zhang, Donna D.
AffiliationUniv Arizona, Coll Pharm, Dept Pharmacol & Toxicol
Univ Arizona, Arizona Canc Ctr
MetadataShow full item record
PublisherAMER SOC MICROBIOLOGY
CitationDodson M, Liu P, Jiang T, Ambrose AJ, Luo G, Rojo de la Vega M, Cholanians AB, Wong PK, Chapman E, Zhang DD. 2018. Increased O-GlcNAcylation of SNAP29 drives arsenic-induced autophagic dysfunction. Mol Cell Biol 38:e00595-17. https://doi.org/10.1128/MCB.00595-17.
JournalMOLECULAR AND CELLULAR BIOLOGY
RightsCopyright © 2018 American Society for Microbiology.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractEnvironmental 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.
Note6 month embargo; published online: 5 March 2018
VersionFinal published version
SponsorsNational Institutes of Health [ES015010, DK109555, ES023758, GM008804, ES006694]