Discovery of Trametinib as an orchestrator for cytoskeletal vimentin remodeling  

作　　者：Shuangshuang Zhao Zhifang Li Qian Zhang Yue Zhang Jiali Zhang Gaofeng Fan Xiaobao Cao Yaming Jiu 

机构地区：[1]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 [2]Guangzhou National Laboratory,Guangzhou 510005,China [3]University of Chinese Academy of Sciences,Beijing 100049,China [4]School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China

出　　处：《Journal of Molecular Cell Biology》2024年第3期24-34,共11页分子细胞生物学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(92354301,32222022,32300569,and 92054104);R&D Program of Guangzhou National Laboratory(GZNL2023A03004);Key Research and Development Program,the Ministry of Science and Technology of China(2022YFC2303502 and 2021YFC2300204);the Natural Science Foundation of Shanghai(23ZR1470900);Youth Innovation Promotion Association,Chinese Academy of Sciences.

摘　　要：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.

关 键 词：VIMENTIN intermediate filaments CYTOSKELETON small molecule network reorganization 

分 类 号：Q51[生物学—生物化学]