Kang Pil Jung, Mazak Hana, Lee Sung Sik, Park Hay-Oak
Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA.
Scientific Center of Optical and Electron Microscopy, Institute of Biochemistry, ETH Zurich, Zurich, Switzerland.
bioRxiv. 2025 Jul 15:2025.07.10.664052. doi: 10.1101/2025.07.10.664052.
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 Cdc42's 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.
小GTP酶Cdc42是细胞极性的核心调节因子，但它在衰老细胞中常常过度激活，导致酵母和动物细胞的衰老。然而，其与年龄相关的上调背后的机制仍知之甚少。在这里，我们研究了在进行不对称细胞分裂、主要导致母细胞衰老的芽殖酵母中，Cdc42水平在连续分裂过程中是如何变化的。通过基于微流控的活细胞成像和基因分析，我们发现Cdc42蛋白在分裂过程中在母细胞和子细胞之间分布不均。值得注意的是，子细胞继承的Cdc42水平较低，这有助于它们恢复活力。这种不对称性取决于Cdc42与内膜的结合，并且需要法尼基化的Ydj1的存在，Ydj1是一种与内质网相连的Hsp40/DnaJ伴侣蛋白。此外，维持适当的Cdc42水平依赖于它与Ydj1的相互作用。这些发现揭示了一种伴侣蛋白介导的机制，该机制在不对称分裂过程中控制Cdc42的分配，将其与细胞衰老联系起来——这一过程可能在其他不对称分裂细胞中是保守的。
