Cdc42 Partitioning by Chaperone Ydj1 During Asymmetric Division and Aging in Yeast

Cdc42, a small GTPase crucial for cell polarity, often becomes hyperactive with age and contributes to senescence and aging in yeast and animal cells. However, the mechanisms underlying its age-related upregulation are not well understood. Here, we report that in budding yeast, Cdc42 accumulates over successive divisions and that lowering its levels can extend lifespan. 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 levels of Cdc42, which likely helps them remain young. This asymmetric distribution depends on Cdc42’s localization to endomembranes and involves Ydj1, a farnesylated Hsp40/DnaJ chaperone anchored to the endoplasmic reticulum ( ER ). Ydj1 interacts with Cdc42, enhancing its stability and proper partitioning during cell division. We thus propose that ER-bound Ydj1 facilitates the asymmetric distribution of Cdc42, limiting aging to mother cells. We thus propose that ER-bound Ydj1 facilitates the asymmetric distribution of Cdc42, limiting aging to mother cells.