Unit of Cell Biology and Imaging Study of Pathogen Host Interaction, The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China.
Guangzhou National Laboratory, Guangzhou 510005, China.
J Mol Cell Biol. 2024 Aug 26;16(3). doi: 10.1093/jmcb/mjae009.
The dynamic remodeling of the cytoskeletal network of vimentin intermediate filaments supports various cellular functions, including cell morphology, elasticity, migration, organelle localization, and resistance against mechanical or pathological stress. Currently available chemicals targeting vimentin predominantly induce network reorganization and shrinkage around the nucleus. Effective tools for long-term manipulation of vimentin network dispersion in living cells are still lacking, limiting in-depth studies on vimentin function and potential therapeutic applications. Here, we verified that a commercially available small molecule, trametinib, is capable of inducing spatial spreading of the cellular vimentin network without affecting its transcriptional or Translational regulation. Further evidence confirmed its low cytotoxicity and similar effects on different cell types. Importantly, Trametinib has no impact on the other two cytoskeletal systems, actin filaments and the microtubule network. Moreover, Trametinib regulates vimentin network dispersion rapidly and efficiently, with effects persisting for up to 48 h after drug withdrawal. We also ruled out the possibility that Trametinib directly affects the phosphorylation level of vimentin. In summary, we identified an unprecedented regulator Trametinib, which is capable of spreading the vimentin network toward the cell periphery, and thus complemented the existing repertoire of vimentin remodeling drugs in the field of cytoskeletal research.
波形蛋白中间丝细胞骨架网络的动态重塑支持多种细胞功能，包括细胞形态、弹性、迁移、细胞器定位以及抵抗机械或病理应激。目前可用的针对波形蛋白的化学物质主要诱导核周围的网络重组和收缩。缺乏用于在活细胞中长期操纵波形蛋白网络分散的有效工具，限制了对波形蛋白功能和潜在治疗应用的深入研究。在这里，我们验证了一种商业上可用的小分子，曲美替尼，能够诱导细胞波形蛋白网络的空间扩散，而不影响其转录或翻译调节。进一步的证据证实了它的低细胞毒性和对不同细胞类型的相似作用。重要的是，曲美替尼对另外两个细胞骨架系统，肌动蛋白丝和微管网络没有影响。此外，曲美替尼能够快速有效地调节波形蛋白网络的分散，并且在停药后长达 48 小时内效果持续。我们还排除了曲美替尼直接影响波形蛋白磷酸化水平的可能性。总之，我们鉴定了一种前所未有的调节剂曲美替尼，它能够将波形蛋白网络向细胞外周扩散，从而补充了细胞骨架研究领域中现有的波形蛋白重塑药物库。
