ATP hydrolysis by yeast Hsp104 determines protein aggregate dissolution and size in vivo

Udhayabhaskar Sathyanarayanan,Peter Bou Dib,Anita Krisko,Marina Musa,Nuno Raimundo,Ira Milosevic

doi:10.1038/s41467-020-19104-1

Abstract

Signs of proteostasis failure often entwine with those of metabolic stress at the cellular level. Here, we study protein sequestration during glucose deprivation-induced ATP decline in Saccharomyces cerevisiae. Using live-cell imaging, we find that sequestration of misfolded proteins and nascent polypeptides into two distinct compartments, stress granules, and Q-bodies, is triggered by the exhaustion of ATP. Both compartments readily dissolve in a PKA-dependent manner within minutes of glucose reintroduction and ATP level restoration. We identify the ATP hydrolase activity of Hsp104 disaggregase as the critical ATP-consuming process determining compartments abundance and size, even in optimal conditions. Sequestration of proteins into distinct compartments during acute metabolic stress and their retrieval during the recovery phase provide a competitive fitness advantage, likely promoting cell survival during stress.

Highlights

Signs of proteostasis failure often entwine with those of metabolic stress at the cellular level
In optimal conditions, budding yeast grows in 2% glucose, which they mainly consume during their exponential growth stage[25]
There is a growing body of evidence supporting the concept of protein sequestration into various types of cellular aggregates being an adaptive mechanism helping cells to overcome stressful conditions[18,42]

Summary

Introduction

Signs of proteostasis failure often entwine with those of metabolic stress at the cellular level. Using live-cell imaging, we find that sequestration of misfolded proteins and nascent polypeptides into two distinct compartments, stress granules, and Qbodies, is triggered by the exhaustion of ATP. Sequestering misfolded proteins into insoluble aggregates is a part of the cellular attempts to remain functional even in the conditions of proteotoxic stress Their formation is proposed to be beneficial during heat shock for multiple reasons, the dominant one being the removal of toxic protein conformers from the soluble phase[4,5]. Depositing proteins into aggregates and their timely dissolution during recovery from the starvation stress provide a significant fitness advantage during glucose deprivation, which offers new perspectives on the role of protein sequestration into isolated deposits in cell adaptation to stress. Understanding the interplay between protein disaggregation and metabolic activity of the cell is of universal importance due to the association of protein aggregation with aging and many medical conditions

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Conclusion