Calumenin prevents fibroblast senescence and lung aging by promoting vimentin proteostasis
Abstract
Progressive lung fibrosis is linked to aging-related dysfunction in fibroblasts, which remains poorly understood. To investigate the alterations in fibroblasts, particularly the molecular programs driving this profibrotic evolution in the aging lung, we isolated senescent lung fibroblasts from aged mice. We observed aberrant vimentin aggregates, which correlate with accelerated fibroblast senescence. CRISPR-based screening identified calumenin as a chaperone protein essential for vimentin proteostasis. A fibroblast-specific knockout of calumenin promotes the accumulation of vimentin aggregates and profibrotic factors migracytosis, exacerbating fibroblast senescence and lung aging. Mechanistically, calumenin collaborates with the TRiC complex to facilitate proper vimentin folding and recruits the chaperonin subunit Chaperonin Containing TCP1 Subunit 2 (CCT2) to degrade misfolded vimentin aggregates. Pathologically, external profibrotic stimuli trigger calcium transients and induce calumenin degradation, resulting in fibroblast senescence and the initiation of fibrosis. The natural product 9-85, derived from high-content screening, specifically targets and disrupts vimentin aggregates upon stimulation, alleviating aging-related lung fibrosis. Our findings reveal that calumenin coordinates vimentin quality control to shape cell structure and suppress the secretome of senescent fibroblasts, providing a promising therapeutic strategy for aging-related organ fibrosis.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (23)
Ting Dong
Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education) and State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong University
Xue Jiao
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University
Huirui Wang
Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education) and State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong University
Yinghui Gao
Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education) and State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong University
Yuliang Xu
Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education) and State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong University
Hui Li
Senbiao Fang
Marine Biomedical Research institute of Qingdao, Ocean University of China
Xinyi Chen
Mengmeng Wang
Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China
Hanbing Zhu
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University
Nianyu Li
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University
Bo Han
Electron Microscopy Laboratory, School of Physics
Mei Qi
Department of Pathology, Shandong University Qilu hospital
Kaige Lyu
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
Kaicheng Ma
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
Ke Li
Haigen Fu
State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Medicinal Biotechnology
Bowen Gu
Department of Stem Cell and Regenerative Biology, Harvard University
Wenfei Li
Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University
Yingying Qin
Zi-Jiang Chen
State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University
Xiaohui Liu
Hydrogen Energy Industry Institute of Jilin Province
Hongxiang Lou
Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Shandong University