Cho Yena, Hwang Jee Won, Bedford Mark T, Song Dae-Geun, Kim Su-Nam, Kim Yong Kee
Muscle Physiome Research Center and Research Institute of Pharmaceutical Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
Cell Commun Signal. 2025 Mar 5;23(1):120. doi: 10.1186/s12964-025-02124-z.
Tubulin is crucial in several cellular processes, including intracellular organization, organelle transport, motility, and chromosome segregation. Intracellular tubulin concentration is tightly regulated by an autoregulation mechanism, in which excess free tubulin promotes tubulin mRNA degradation. However, the details of how changes in free tubulin levels initiate this autoregulation remain unclear. In this study, we identified coactivator-associated arginine methyltransferase 1 (CARM1)-phosphatidylinositol 3-kinase class 2α (PI3KC2α) axis as a novel regulator of tubulin autoregulation. CARM1 stabilizes PI3KC2α by methylating its R175 residue. Once PI3KC2α is not methylated, it becomes unstable, leading to decreased cellular levels. Loss of PI3KC2α results in the release of tetratricopeptide repeat domain 5 (TTC5), which initiates tubulin autoregulation. Thus, PI3KC2α, along with its CARM1-mediated arginine methylation, regulates the initiation of tubulin autoregulation. Additionally, disruption of the CARM1-PI3KC2α axis decreases intracellular tubulin levels, leading to a synergistic increase in the cytotoxicity of microtubule-targeting agents (MTAs). Taken together, our study demonstrates that the CARM1-PI3KC2α axis is a key regulator of TTC5-mediated tubulin autoregulation and that disrupting this axis enhances the anti-cancer activity of MTAs.
微管蛋白在多个细胞过程中至关重要，包括细胞内组织、细胞器运输、运动以及染色体分离。细胞内微管蛋白浓度受一种自动调节机制严格调控，在该机制中，过量的游离微管蛋白会促进微管蛋白mRNA降解。然而，游离微管蛋白水平的变化如何启动这种自动调节的具体细节仍不清楚。在本研究中，我们确定了共激活因子相关精氨酸甲基转移酶1（CARM1）-磷脂酰肌醇3-激酶2α类（PI3KC2α）轴是微管蛋白自动调节的一种新型调节因子。CARM1通过甲基化PI3KC2α的R175残基来使其稳定。一旦PI3KC2α未被甲基化，它就会变得不稳定，导致细胞内水平降低。PI3KC2α的缺失会导致四肽重复结构域5（TTC5）的释放，从而启动微管蛋白的自动调节。因此，PI3KC2α及其CARM1介导的精氨酸甲基化调节微管蛋白自动调节的启动。此外，CARM1-PI3KC2α轴的破坏会降低细胞内微管蛋白水平，导致靶向微管的药物（MTA）的细胞毒性协同增加。综上所述，我们的研究表明CARM1-PI3KC2α轴是TTC5介导的微管蛋白自动调节的关键调节因子，破坏该轴可增强MTA的抗癌活性。
