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

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.

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