Kang, P. J.; Mazak, H.; Lee, S. S.; Park, H.-O.

The small GTPase Cdc42 is a central regulator of cell polarity, but it is often hyperactivated in aged cells, contributing to senescence and aging in both yeast and animal cells. Yet, the mechanisms underlying its age-related upregulation remain poorly understood. Here, we examine how Cdc42 levels change over successive divisions in budding yeast, which undergoes asymmetric cell division, leading to aging predominantly in mother cells. Using microfluidics-based live-cell imaging and genetic analyses, we find that Cdc42 protein is unevenly distributed between mother and daughter cells during division. Notably, daughter cells inherit lower levels of Cdc42, which helps them rejuvenate. This asymmetry depends on Cdc42s association with endomembranes and requires the presence of farnesylated Ydj1, an Hsp40/DnaJ chaperone tethered to the endoplasmic reticulum. Furthermore, maintaining proper Cdc42 levels relies on its interaction with Ydj1. These findings reveal a chaperone-mediated mechanism that controls Cdc42 partitioning during asymmetric division, linking it to cellular aging--a process that may be conserved in other asymmetrically dividing cells.