The Std1 Activator of the Snf1/AMPK Kinase Controls Glucose Response in Yeast by a Regulated Protein Aggregation

The ability to respond to available nutrients is critical for all living cells. The AMP-activated protein kinase (SNF1 in yeast) is a central regulator of metabolism that is activated when energy is depleted. We found that SNF1 activity in the nucleus is regulated by controlled relocalization of the SNF1 activator Std1 into puncta. This process is regulated by glucose through the activity of the previously uncharacterized protein kinase Vhs1 and its substrate Sip5, a protein of hitherto unknown function. Phosphorylation of Sip5 prevents its association with Std1 and triggers Std1 accretion. Reversible Std1 puncta formation occurs under non-stressful, ambient conditions, creating non-amyloid inclusion bodies at the nuclear-vacuolar junction, and it utilizes cellular chaperones similarly to the aggregation of toxic or misfolded proteins such as those associated with Parkinson's, Alzheimer's, and CJD diseases. Our results reveal a controlled, non-pathological, physiological role of protein aggregation in the regulation of a major metabolic cellular pathway. SNF1/AMPK is a key regulator of the switch from fermentation to respiration upon glucose withdrawal in S. cerevisiae and other organisms. Simpson-Lavy et al. have analyzed a signaling pathway comprised of the Vhs1 kinase and Sip5, which regulates SNF1 by controlling Std1 localization to reversible, non-amyloid aggregates, with the help of several chaperones.