The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis
The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis
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DOI：
10.1038/s41467-020-18621-3
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发表时间：
2019-01-02
影响因子：
16.6
通讯作者：
Chambers, Rachel C.
中科院分区：
文献类型：
--
作者：
Woodcock, Hannah V.;Eley, Jessica D.;Chambers, Rachel C.
Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluation in IPF. Here we demonstrate that rapamycin-insensitive mTORC1 signaling via 4E-BP1 is a critical pathway for TGF-beta(1) stimulated collagen synthesis in human lung fibroblasts, whereas canonical PI3K/Akt signaling is not required. The importance of mTORC1 signaling was confirmed by CRISPR-Cas9 gene editing in normal and IPF fibroblasts, as well as in lung cancer-associated fibroblasts, dermal fibroblasts and hepatic stellate cells. The inhibitory effect of ATP-competitive mTOR inhibition extended to other matrisome proteins implicated in the development of fibrosis and human disease relevance was demonstrated in live precision-cut IPF lung slices. Our data demonstrate that the mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies.
