Doyle Laura P, Chen Jun-Song, Gould Kathleen L, McCollum Dannel, Verde Fulvia
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.
iScience. 2025 Aug 5;28(9):113298. doi: 10.1016/j.isci.2025.113298. eCollection 2025 Sep 19.
Cdc42 is a Rho-family GTPase that controls cell polarization from yeast to human cells. In fission yeast, under normal growth conditions, Cdc42-GTP oscillates between cell tips to promote polarized growth. However, when exposed to environmental stressors, Cdc42 adopts an "exploratory" pattern of Cdc42 activation along the cell membrane. This pattern also occurs when the NDR kinase Orb6 is downregulated. Here, we describe the molecular mechanism behind the emergence of exploratory Cdc42 dynamics and identify a substrate of Orb6 kinase, the Cdc42 GAP Rga3. Additionally, we show that MAP kinase Sty1, known for linking stress signals to the Cdc42 polarity module, negatively regulates Orb6 kinase. During nutritional stress, activation of Sty1 and inactivation of Orb6 are associated with chronological lifespan extension. Our findings reveal a mechanism controlling cell morphology during stress, with important implications for cell survival.
Cdc42是一种Rho家族的GTP酶，它控制从酵母到人类细胞的细胞极化。在裂殖酵母中，在正常生长条件下，Cdc42-GTP在细胞尖端之间振荡以促进极化生长。然而，当暴露于环境应激源时，Cdc42会沿着细胞膜采用一种“探索性”的Cdc42激活模式。当NDR激酶Orb6下调时也会出现这种模式。在这里，我们描述了探索性Cdc42动力学出现背后的分子机制，并鉴定了Orb6激酶的一个底物，即Cdc42 GAP Rga3。此外，我们表明，以将应激信号与Cdc42极性模块联系起来而闻名的丝裂原活化蛋白激酶Sty1负向调节Orb6激酶。在营养应激期间，Sty1的激活和Orb6的失活与按时间顺序延长的寿命相关。我们的发现揭示了一种在应激期间控制细胞形态的机制，对细胞存活具有重要意义。
