Accumulation of a Threonine Biosynthetic Intermediate Attenuates General Amino Acid Control by Accelerating Degradation of Gcn4 via Pho85 and Cdk8

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Transcriptional activator Gcn4 maintains amino acid homeostasis in budding yeast by inducing multiple amino acid biosynthetic pathways in response to starvation for any amino acid—the general amino acid control. Gcn4 abundance is tightly regulated by the interplay between an intricate translational control mechanism, which induces Gcn4 synthesis in starved cells, and a pathway of phosphorylation and ubiquitylation that mediates its rapid degradation by the proteasome. Here, we discovered that accumulation of a threonine biosynthetic pathway intermediate, β-aspartate semialdehyde (ASA), in hom6Δ mutant cells impairs general amino acid control in cells starved for isoleucine and valine by accelerating the already rapid degradation of Gcn4, in a manner requiring its phosphorylation by cyclin-dependent kinases Cdk8/Srb10 and Pho85. Interestingly, our results unveil a division of labor between these two kinases wherein Srb10 primarily targets inactive Gcn4 molecules—presumably damaged under conditions of ASA excess—while Pho85 clears a greater proportion of functional Gcn4 species from the cell. The ability of ASA to inhibit transcriptional induction of threonine pathway enzymes by Gcn4, dampening ASA accumulation and its toxic effects on cell physiology, should be adaptive in the wild when yeast encounters natural antibiotics that target Hom6 enzymatic activity.

Vyšlo v časopise: Accumulation of a Threonine Biosynthetic Intermediate Attenuates General Amino Acid Control by Accelerating Degradation of Gcn4 via Pho85 and Cdk8. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004534
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004534

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