Abstract #74

Activity of the arsenic-responsive transcription factor Yap8p is controlled by the ubiquitin-proteasome pathway. Yujun Di, Markus J. Tamás. Cell and Molecular Biology, Göteborg University, Göteborg, Sweden.
   Toxic metals are an integral part of the environment and all organisms possess systems to evade toxicity and acquire tolerance. The Saccharomyces cerevisiae AP-1-like protein Yap8p (Acr1p/Arr1p) confers arsenic tolerance by activating transcription of the arsenic-specific detoxification genes ACR2 and ACR3. However, the mechanism(s) by which arsenic controls Yap8p activity is unknown. Here, we report that Yap8p is stabilized in arsenite-exposed cells in a time- and dose-dependent manner. We also find that mutants with defective proteasome activity or that lack the ubiquitin-conjugating enzymes Ubc4p and Ubc5p, display increased Yap8p levels and elevated expression of the Yap8p gene-target ACR3. Yap8p forms homodimers in vivo but dimerization is not regulated by arsenic. Instead, arsenite-stimulated Yap8p stabilization and transcriptional activation of ACR3 requires critical cysteine residues within Yap8p. Collectively, our data is consistent with a model where Yap8p is degraded by the ubiquitin-proteasome pathway in the absence of arsenite whereas exposure results in Yap8p stabilization and gene activation. Control of Yap8p activity by stabilization provides an effective mechanism for the cell to fine-tune ACR3 expression depending on cytosolic arsenite concentrations. Hence, Yap8p cysteines may function as highly sensitive arsenite sensors that control the Yap8p response to a broad range of metal concentrations.

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