Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.

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Glucose analog 2-deoxyglucose (2DG) inhibits growth of yeast and human tumor cells, but its modes of action have not been fully elucidated. Yeast cells lacking Snf1 (AMP-activated protein kinase) are hypersensitive to 2DG. Overexpression of either Hxt1 or Hxt3, low-affinity high-capacity glucose transporters, suppresses the 2DG hypersensitivity of snf1Δ cells. Addition of 2DG or loss of Snf1 reduce HXT1 and HXT3 expression and stimulate transporter endocytosis and degradation in the vacuole. 2DG-stimulated trafficking of Hxt1 and Hxt3 requires Rod1/Art4 and Rog3/Art7, two members of the α-arrestin trafficking adaptor family. Mutations in ROD1 and ROG3 that block binding to the ubiquitin ligase Rsp5 eliminate Rod1- and Rog3-mediated trafficking of Hxt1 and Hxt3. Genetic analysis suggests that Snf1 negatively regulates both Rod1 and Rog3, but via different mechanisms. Snf1 activated by 2DG phosphorylates Rod1, but fails to phosphorylate other known targets such as the transcriptional repressor Mig1. We propose a novel mechanism for 2DG-induced toxicity whereby 2DG stimulates modification of α-arrestins, which promote glucose transporter internalization and degradation, causing glucose starvation, even when cells are in a glucose-rich environment.