Misfolding-prone proteins are reversibly sequestered to an Hsp42-associated granule upon chronological aging.

Alteration of protein localization is an important strategy for cells to regulate protein homeostasis upon environmental stresses. In the budding yeast , many proteins relocalize and form cytosolic granules during chronological aging. However, the functions and exact components of these protein granules remain uncharacterized in most cases. In this study, we performed a genome-wide analysis of protein localization in stationary phase cells, leading to the discovery of 307 granule-forming proteins and the identification of new components in the Hsp42-stationary phase granule (Hsp42-SPG), P-bodies, Ret2 granules and actin bodies. We further characterized the Hsp42-SPG, which contains the largest number of protein components, including many molecular chaperones, metabolic enzymes and regulatory proteins. Formation of the Hsp42-SPG efficiently downregulates the activities of sequestered components, which can be differentially released from the granule based on environmental cues. We found a similar structure in the pre-whole genome duplication yeast species, , suggesting that the Hsp42-SPG is a common machinery allowing chronologically aged cells to contend with changing environments when available energy is limited. This article has an associated First Person interview with the first author of the paper.