A regulated protein aggregation controls glucose response in S. cerevisiae

The ability to respond to available nutrients is critical for all living cells. The AMP-activated protein kinase (SNF1 in S. cerevisiae) 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 relocalisation of the SNF1 activator Std1 into puncta at the NVJ. 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. Unphosphorylated Sip5 associates with Std1 and prevents its accretion. Reversible Std1 puncta formation occurs under non-stressful, ambient conditions, creating inclusion bodies in the form of a liquid drop, and utilizes the Hsp40, Hsp70 and Hsp104 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.