Nuclear envelope budding inhibition slows down progerin- induced aging process

• 成果类型: Article
• 署名作者: Wang, Xiangyang; Ma, Lin; Lu, Di; Zhao, Gan; Ren, He; Lin, Qiaoyu; Jia, Mingkang; Huang, Fan; Wang, Shan; Xu, Zhe; Yang, Zhou; Chu, Yan; Xu, Zigang; Li, Wei; Yu, Li; Jiang, Qing; Zhang, Chuanmao
• 署名单位: Peking University; Kunming University of Science & Technology; Capital Medical University; Tsinghua University; Capital Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12776
• DOI: 10.1073/pnas.2321378121
• 发表日期: 2024-10-08
• 关键词: encoding lamin a/c; disease phenotypes; dusp6 mkp3; mice; phosphatase; mutations; farnesylation; fibroblasts; proteins; promises

摘要

Progerin causes Hutchinson-Gilford progeria syndrome (HGPS), but how progerin accelerates aging is still an interesting question. Here, we provide evidence linking nuclear envelope (NE) budding and accelerated aging. Mechanistically, progerin disrupts nuclear lamina to induce NE budding in concert with lamin A/C, resulting in transport of chromatin into the cytoplasm where it is removed via autophagy, whereas emerin antagonizes this process. Primary cells from both HGPS patients and mouse models express progerin and display NE budding and chromatin loss, and ectopically expressing progerin in cells can mimic this process. More excitingly, we screen a NE budding inhibitor chaetocin by high- throughput screening, which can dramatically sequester progerin from the NE and prevent this NE budding through sustaining ERK1/2 activation. Chaetocin alleviates NE budding- induced chromatin loss and ameliorates HGPS defects in cells and mice and significantly extends lifespan of HGPS mice. Collectively, we propose that progerin- induced NE budding participates in the induction of progeria, highlight the roles of chaetocin and sustained ERK1/2 activation in anti- aging, and provide a distinct avenue for treating HGPS.