Extracellular HSP90α promotes cellular senescence by modulating TGF-β signaling in pulmonary fibrosis

作者：Zhong, Wenshan; Chen, Weimou; Liu, Yuanyuan; Zhang, Jinming; Lu, Ye; Wan, Xuan; Qiao, Yujie; Huang, Haohua; Zeng, Zhaojin; Li, Wei; Meng, Xiaojing; Zhao, Haijin; Zou, Mengchen; Cai, Shaoxi^*; Dong, Hangming^*

来源：FASEB Journal, 2022, 36(8): e22475.

DOI：10.1096/fj.202200406RR

• cellular senescence
• HSP90 heat-shock proteins
• mitochondria
• pulmonary fibrosis
• reactive oxygen species
• transforming growth factor beta

Recent findings suggest that extracellular heat shock protein 90 alpha (eHSP90 alpha) 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 eHSP90 alpha on cellular senescence in IPF. Our results found that eHSP90 alpha was upregulated in bleomycin (BLM)-induced mice, which correlated with the expression of senescence markers. This increase in eHSP90 alpha mediated fibroblast senescence and facilitated mitochondrial dysfunction. eHSP90 alpha activated TGF-beta 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 eHSP90 alpha with 1G6-D7, a specific eHSP90 alpha antibody, in old mice attenuated the BLM-induced lung fibrosis. Our findings elucidate a crucial mechanism underlying eHSP90 alpha-induced cellular senescence, providing a framework for aging-related fibrosis interventions.

• 单位
  南方医科大学