2. Academic Validation
  3. PKM2 promotes pulmonary fibrosis by stabilizing TGF-β1 receptor I and enhancing TGF-β1 signaling

PKM2 promotes pulmonary fibrosis by stabilizing TGF-β1 receptor I and enhancing TGF-β1 signaling

  • Sci Adv. 2022 Sep 23;8(38):eabo0987. doi: 10.1126/sciadv.abo0987.
Shaoyan Gao 1,  Xiaohe Li 1 2,  Qiuyan Jiang 1,  Qing Liang 1,  Fangxia Zhang 1 2,  Shuangling Li 1 2,  Ruiqin Zhang 1 2,  Jiaoyan Luan 1 2,  Jingyan Zhu 1 2,  Xiaoting Gu 1,  Ting Xiao 1,  Hui Huang 3,  Shanshan Chen 4,  Wen Ning 5,  Guang Yang 1,  Cheng Yang 1 2,  Honggang Zhou 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, 300000 Tianjin, China.
  • 2 High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, 300070 Tianjin, China.
  • 3 Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 100730 Beijing, China.
  • 4 Respiratory department, The First Affiliated Hospital of Zhengzhou University, 450003 Zhangzhou, China.
  • 5 State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
PMID: 36129984 DOI: 10.1126/sciadv.abo0987
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease, and the molecular mechanisms remain poorly understood. Our findings demonstrated that Pyruvate Kinase M2 (PKM2) promoted fibrosis progression by directly interacting with Smad7 and reinforcing transforming growth factor-β1 (TGF-β1) signaling. Total PKM2 expression and the portion of the tetrameric form elevated in lungs and fibroblasts were derived from mice with bleomycin (BLM)-induced pulmonary fibrosis. Pkm2 deletion markedly alleviated BLM-induced fibrosis progression, myofibroblast differentiation, and TGF-β1 signaling activation. Further study showed that PKM2 tetramer enhanced TGF-β1 signaling by directly binding with Smad7 on its MH2 domain, and thus interfered with the interaction between Smad7 and TGF-β type I receptor (TβR1), decreased TβR1 ubiquitination, and stabilized TβR1. Pharmacologically enhanced PKM2 tetramer by TEPP-46 promoted BLM-induced pulmonary fibrosis, while tetramer disruption by compound 3k alleviated fibrosis progression. Our results demonstrate how PKM2 regulates TGF-β1 signaling and is a key factor in fibrosis progression.

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