Elucidating the mysterious regulation of Snf1/AMPK by glucose in yeast
Glucose functions both as a nutrient and as a signaling molecule. In budding yeast, its presence steers metabolism toward fermentation by repressing genes required for the utilization of alternative carbon sources and for respiratory metabolism. This regulation, known as glucose repression, depends on Snf1, the yeast orthologue of 5′-AMP-activated protein kinase (AMPK). During glucose deprivation, Snf1 is phosphorylated and active, allowing derepression of glucose-repressed genes. Conversely, glucose addition restores glucose repression by rapidly triggering Snf1 dephosphorylation and inactivation by Protein Phosphatase 1 (PP1), through its regulatory subunit Reg1. Yet, how glucose promotes PP1 activity toward Snf1 remains unclear.
To investigate this mechanism, we performed a genetic screen to identify new regulators of glucose signaling. The screen uncovered point mutations in BMH1, which encodes the major isoform of the yeast 14-3-3 phospho-binding proteins, potentially implicating Bmh1 in PP1-mediated Snf1 inhibition. We identify a previously uncharacterized interface in Reg1 that mediates its interaction with 14-3-3 proteins independently of its phosphorylation, potentially through metabolite binding. We further uncover a role for this interaction in glucose-dependent signaling. This metabolite-binding motif is present in various proteins in fungi, animals and plants, suggesting a previously unrecognized regulation of 14-3-3 interactions by metabolism. These findings provide new insight into how metabolic signals may be integrated into nutrient signaling pathways.
