细胞外 HSP90α 通过调节 TGF-β 信号通路促进肺纤维化中的细胞衰老。
Extracellular HSP90α promotes cellular senescence by modulating TGF-β signaling in pulmonary fibrosis.
机构信息
Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Dermatology, The USC-Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, California, USA.
出版信息
FASEB J. 2022 Aug;36(8):e22475. doi: 10.1096/fj.202200406RR.
Recent findings suggest that extracellular heat shock protein 90α (eHSP90α) promotes pulmonary fibrosis, but the underlying mechanisms are not well understood. Aging, especially cellular senescence, is a critical risk factor for idiopathic pulmonary fibrosis (IPF). Here, we aim to investigate the role of eHSP90α on cellular senescence in IPF. Our results found that eHSP90α was upregulated in bleomycin (BLM)-induced mice, which correlated with the expression of senescence markers. This increase in eHSP90α mediated fibroblast senescence and facilitated mitochondrial dysfunction. eHSP90α activated TGF-β signaling through the phosphorylation of the SMAD complex. The SMAD complex binding to p53 and p21 promoters triggered their transcription. In vivo, the blockade of eHSP90α with 1G6-D7, a specific eHSP90α antibody, in old mice attenuated the BLM-induced lung fibrosis. Our findings elucidate a crucial mechanism underlying eHSP90α-induced cellular senescence, providing a framework for aging-related fibrosis interventions.
最近的研究结果表明，细胞外热休克蛋白 90α（eHSP90α）促进肺纤维化，但潜在机制尚不清楚。衰老，特别是细胞衰老，是特发性肺纤维化（IPF）的一个关键危险因素。在这里，我们旨在研究 eHSP90α 在 IPF 中对细胞衰老的作用。我们的研究结果发现，博来霉素（BLM）诱导的小鼠中 eHSP90α 上调，与衰老标志物的表达相关。这种 eHSP90α 的增加介导成纤维细胞衰老并促进线粒体功能障碍。eHSP90α 通过磷酸化 SMAD 复合物激活 TGF-β 信号通路。SMAD 复合物与 p53 和 p21 启动子结合触发它们的转录。在体内，用 1G6-D7（一种特异性 eHSP90α 抗体）阻断老年小鼠中的 eHSP90α 可减轻 BLM 诱导的肺纤维化。我们的研究结果阐明了 eHSP90α 诱导细胞衰老的关键机制，为与衰老相关的纤维化干预提供了框架。
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