Research ArticleFibrosis

mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-β1–induced collagen biosynthesis

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Science Signaling  21 May 2019:
Vol. 12, Issue 582, eaav3048
DOI: 10.1126/scisignal.aav3048

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Glucose supports fibrosis

Transforming growth factor–β (TGF-β) stimulates fibrosis by promoting the differentiation of fibroblasts into collagen-secreting myofibroblasts, a process associated with alterations in cellular metabolism. Selvarajah et al. found that TGF-β1 promoted the expression of glycine biosynthesis genes in primary human lung fibroblasts, which depended on Smad3 signaling and mTORC1-dependent generation of the transcription factor ATF4. ATF4 stimulated the expression of genes encoding the glucose transporter GLUT1 and enzymes for the biosynthesis of glycine from glucose. Interfering with the mTOR-ATF4 axis reduced the incorporation of glucose-derived glycine into collagen in TGF-β1 stimulated fibroblasts. The mTORC1-ATF4 axis therefore enhances the de novo glycine pathway to meet the biosynthetic requirements associated with TGF-β1–induced collagen production and could potentially be therapeutically targeted as an anti-fibrotic strategy.

Abstract

The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)–producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue repair is complete, lead to pathological fibrosis and are also features of the stromal response in cancer. Myofibroblast differentiation is accompanied by changes in cellular metabolism, including increased glycolysis, to meet the biosynthetic demands of enhanced ECM production. Here, we showed that transforming growth factor–β1 (TGF-β1), the key pro-fibrotic cytokine implicated in multiple fibrotic conditions, increased the production of activating transcription factor 4 (ATF4), the transcriptional master regulator of amino acid metabolism, to supply glucose-derived glycine to meet the amino acid requirements associated with enhanced collagen production in response to myofibroblast differentiation. We further delineated the signaling pathways involved and showed that TGF-β1–induced ATF4 production depended on cooperation between canonical TGF-β1 signaling through Smad3 and activation of mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). ATF4, in turn, promoted the transcription of genes encoding enzymes of the de novo serine-glycine biosynthetic pathway and glucose transporter 1 (GLUT1). Our findings suggest that targeting the TGF-β1–mTORC1–ATF4 axis may represent a novel therapeutic strategy for interfering with myofibroblast function in fibrosis and potentially in other conditions, including cancer.

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