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

Abstract

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.

The sequestration of misfolded protein into insoluble aggregates occurs under conditions of proteotoxic stress. Here the authors observe that a reduction in cellular ATP promotes protein sequestration into two separate compartments: Q-bodies and stress granules; and identify Hsp104 as a critical ATP-consuming process that determines those compartments abundance and size.