Cdc42 interacts with chaperone Ydj1 to enhance its stability and partitioning during asymmetric cell division and aging in yeast.

Cdc42, a small GTPase essential for cell polarity, often becomes hyperactive with age and promotes senescence in yeast and animal cells. Yet, the mechanisms driving its age-related upregulation remain unclear. Here, we show that in budding yeast, Cdc42 accumulates over successive cell divisions and that reducing its levels extends life span. Using microfluidics-assisted live-cell imaging and genetic analysis, we found that Cdc42 is distributed unevenly between mother and daughter cells during division. Daughter cells inherit lower Cdc42 levels, which likely help them remain young. This asymmetric distribution depends on Cdc42's association with and/or release from endomembranes and likely involves Ydj1, a farnesylated Hsp40/DnaJ chaperone anchored to the endoplasmic reticulum. Ydj1 interacts with Cdc42, promoting its stability and proper partitioning during cell division. We propose that ER-bound Ydj1 facilitates the asymmetric distribution of Cdc42, thereby restricting aging to mother cells.