中国科学院上海免疫与感染研究所酒亚明，广州国家实验室曹小宝，上海科技大学范高峰研究组近日取得一项新成果。经过不懈努力，他们发现了曲美替尼作为细胞骨架波形蛋白重塑的调控者。这一研究成果发表在2024年3月1日出版的《分子细胞生物学报》上。

研究团队证实了一种市售的小分子，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，曲美替尼对其他两个细胞骨架系统，肌动蛋白微丝和微管网络没有影响。

此外，曲美替尼快速有效地调节波形蛋白网络分散，其作用在停药后持续48小时。该研究组也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，该研究组发现了一种前所未有的调节剂，曲美替尼，能够将波形蛋白网络向细胞周围扩散，并且它们补充了细胞骨架研究领域现有的波形蛋白重塑药物库。

据了解，波形蛋白中间微丝网络的细胞骨架网络的动态重塑支持各种细胞功能，包括细胞形态、弹性、迁移、细胞器定位以及对机械或病理应激的抵抗力。目前可用的靶向波形蛋白的化学物主要诱导细胞核周围的网络重组和收缩。目前尚缺乏长期调控活细胞中波形蛋白网络分散的有效工具，这限制了对波形蛋白功能和潜在治疗应用的深入研究。

附：英文原文

Title: Discovery of Trametinib as an orchestrator for cytoskeletal vimentin remodeling

Author: Zhao, Shuangshuang, Li, Zhifang, Zhang, Qian, Zhang, Yue, Zhang, Jiali, Fan, Gaofeng, Cao, Xiaobao, Jiu, Yaming

Issue&Volume: 2024-03-01

Abstract: The dynamic remodeling of the cytoskeletal network of vimentin intermediate filaments network 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, 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.

DOI: 10.1093/jmcb/mjae009

Source: https://dx.doi.org/10.1093/jmcb/mjae009