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Discovery of Trametinib as an orchestrator for cytoskeletal vimentin remodeling
Shuangshuang Zhao1,†,* , Zhifang Li2,† , Qian Zhang1 , Yue Zhang1,3 , Jiali Zhang4 , Gaofeng Fan4,* , Xiaobao Cao2,* , Yaming Jiu1,4,*
1Unit 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
2Guangzhou National Laboratory, Guangzhou 510005, China
3University of Chinese Academy of Sciences, Beijing 100049, China
4School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
These authors contributed equally to this work
*Correspondence to:Yaming Jiu , Email:ymjiu@siii.cas.cn Xiaobao Cao , Email:cao_xiaobao@gzlab.ac.cn Gaofeng Fan , Email:fangf@shanghaitech.edu.cn Shuangshuang Zhao , Email:sszhao2@siii.cas.cn
J Mol Cell Biol, Volume 16, Issue 3, March 2024, mjae009,  https://doi.org/10.1093/jmcb/mjae009
Keyword: vimentin, intermediate filaments, cytoskeleton, small molecule, network reorganization

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.