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.
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DOI：
10.1126/sciadv.abo0987
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发表时间：
2022-09-23
期刊：
影响因子：
13.6
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中科院分区：
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特发性肺纤维化(IPF)是一种进行性间质性肺疾病，其分子机制尚不清楚。我们的研究结果表明，丙酮酸激酶M2通过直接与Smad7相互作用，增强转化生长因子-β1(TGFR-β1)信号通路，从而促进纤维化的进展。博莱霉素(BLM)诱导的肺纤维化小鼠肺和成纤维细胞中PKM2的总表达和部分四聚体表达升高。PKM2缺失显著减缓博莱曼诱导的纤维化进程、肌成纤维细胞分化和转化生长因子-β1信号的激活。进一步研究表明，PKM2四聚体通过与Smad7在其MH2型结构域上直接结合而增强了转化生长因子-β1信号，从而干扰了Smad7与转化生长因子-βI型受体(TβR1)的相互作用，降低了TβR1的泛素化，稳定了TβR1。Tepp-46药物增强的PKM2四聚体可促进博莱曼诱导的肺纤维化，而化合物3k阻断四聚体可减缓纤维化进展。我们的结果表明，PKM2是如何调节转化生长因子-β-1信号转导的，并且是纤维化进展的关键因素。PKM2四聚体与Smad7相互作用，增强转化生长因子-β-1信号转导和肺纤维化。
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. PKM2 tetramer interacts with Smad7 and reinforces TGF-β1 signaling and pulmonary fibrosis.
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