The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis.
Hannah V WoodcockJessica D EleyDelphine GuillotinManuela PlatéCarmel B NanthakumarMatteo MartufiSimon PeaceGerard JobertyDaniel PoeckelRobert B GoodAdam R TaylorNico ZinnMatthew ReddingEllen J FortyRobert Edward HyndsCharles SwantonMorten KarsdalToby M MaherAndrew FisherGiovanna BergaminiRichard P MarshallAndy D BlanchardPaul F MercerRachel Clare ChambersPublished in: Nature communications (2019)
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-β1 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.
Keyphrases
- idiopathic pulmonary fibrosis
- extracellular matrix
- cell cycle arrest
- pi k akt
- crispr cas
- interstitial lung disease
- induced apoptosis
- cell proliferation
- signaling pathway
- lymph node
- clinical evaluation
- endothelial cells
- cell death
- systemic sclerosis
- endoplasmic reticulum stress
- oxidative stress
- epithelial mesenchymal transition
- risk assessment
- regulatory t cells
- data analysis
- type iii