Transforming Growth Factor (TGF)-β promotes de novo serine synthesis for collagen production

Recep Nigdelioglu, Robert B. Hamanaka, Angelo Y. Meliton, Erin O'Leary, Leah J. Witt, Takugo Cho, Kaitlyn Sun, Catherine Bonham, David Wu, Parker S. Woods, Aliya N. Husain, Don Wolfgeher, Nickolai O. Dulin, Navdeep S. Chandel, Gökhan M. Mutlu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

TGF-β promotes excessive collagen deposition in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). The amino acid composition of collagen is unique due to its high (33%) glycine content. Here, we report that TGF-β induces expression of glycolytic genes and increases glycolytic flux. TGF-β also induces the expression of the enzymes of the de novo serine synthesis pathway (phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH)) and de novo glycine synthesis (serine hydroxymethyltransferase 2 (SHMT2)). Studies in fibroblasts with genetic attenuation of PHGDH or SHMT2 and pharmacologic inhibition of PHGDH showed that these enzymes are required for collagen synthesis. Furthermore, metabolic labeling experiments demonstrated carbon from glucose incorporated into collagen. Lungs from humans with IPF demonstrated increased expression of PHGDH and SHMT2. These results indicate that the de novo serine synthesis pathway is necessary for TGF-β-induced collagen production and suggest that this pathway may be a therapeutic target for treatment of fibrotic diseases including IPF.

Original languageEnglish (US)
Pages (from-to)27239-27251
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number53
DOIs
StatePublished - Dec 30 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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