TGF-β Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation.

American Journal of Respiratory Cell and Molecular Biology
Erin M O'LearyRobert B Hamanaka

Abstract

Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by the TGF-β (transforming growth factor-β)-dependent differentiation of lung fibroblasts into myofibroblasts, which leads to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by myofibroblasts requires de novo synthesis of glycine, the most abundant amino acid found in collagen protein. TGF-β upregulates the expression of the enzymes of the de novo serine-glycine synthesis pathway in lung fibroblasts; however, the transcriptional and signaling regulators of this pathway remain incompletely understood. Here, we demonstrate that TGF-β promotes accumulation of ATF4 (activating transcription factor 4), which is required for increased expression of the serine-glycine synthesis pathway enzymes in response to TGF-β. We found that induction of the integrated stress response (ISR) contributes to TGF-β-induced ATF4 activity; however, the primary driver of ATF4 downstream of TGF-β is activation of mTORC1 (mTOR Complex 1). TGF-β activates the PI3K-Akt-mTOR pathway, and inhibition of PI3K prevents activation of downstream signaling and induction of ATF4. Using a panel of mTOR inhibitors, we ...Continue Reading

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Citations

Sep 29, 2020·Expert Review of Respiratory Medicine·Dingyuan JiangGang Liu
Jan 5, 2021·The FEBS Journal·Robert B Hamanaka, Gökhan M Mutlu
Jan 18, 2021·Matrix Biology : Journal of the International Society for Matrix Biology·Francis Migneault, Marie-Josée Hébert
Mar 7, 2021·International Journal of Molecular Sciences·Aleksandra BabichevaJason X-J Yuan
Apr 10, 2021·American Journal of Respiratory and Critical Care Medicine·Anna J PodolanczukOliver Eickelberg
Aug 26, 2021·Science Signaling·Brintha SelvarajahRachel C Chambers
Aug 27, 2021·Cellular Signalling·Alexis Paulina Jiménez-UribeJosé Pedraza-Chaverri

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Methods Mentioned

BETA
electrophoresis
PCR

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ImageJ
GraphPad
Prism

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