Enhanced vulnerability to oxidative stress and induction of inflammatory gene expression in 3‐phosphoglycerate dehydrogenase‐deficient fibroblasts

• Published in: FEBS open bio 2018-06, Vol.8 (6), p.914-922
• Main Authors: Hamano, Momoko, Haraguchi, Yurina, Sayano, Tomoko, Zyao, Chong, Arimoto, Yashiho, Kawano, Yui, Moriyasu, Kazuki, Udono, Miyako, Katakura, Yoshinori, Ogawa, Takuya, Kato, Hisanori, Furuya, Shigeki
• Format: Article
• Language: English
• Subjects: Amino acids; Biosynthesis; Cell death; Cellular stress response; Cysteine; D-Serine; Dehydrogenases; Embryo fibroblasts; Embryos; Fibroblasts; Gene expression; Glutathione; Glycine; Hydrogen peroxide; Inflammation; Intracellular; Kinases; L-Serine; Laboratories; Lipid metabolism; l‐serine deficiency; Metabolites; Molecular modelling; Oxidative stress; Phgdh; Phosphoglycerate dehydrogenase; Proteins; Ptgs2; Software; Tetrahydrofolic acid; Thioredoxin; Transcription factors; Txnip
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12429

l‐Serine (l‐Ser) is a necessary precursor for the synthesis of proteins, lipids, glycine, cysteine, d‐serine, and tetrahydrofolate metabolites. Low l‐Ser availability activates stress responses and cell death; however, the underlying molecular mechanisms remain unclear. l‐Ser is synthesized de novo from 3‐phosphoglycerate with 3‐phosphoglycerate dehydrogenase (Phgdh) catalyzing the first reaction step. Here, we show that l‐Ser depletion raises intracellular H2O2 levels and enhances vulnerability to oxidative stress in Phgdh‐deficient mouse embryonic fibroblasts. These changes were associated with reduced total glutathione levels. Moreover, levels of the inflammatory markers thioredoxin‐interacting protein and prostaglandin‐endoperoxide synthase 2 were upregulated under l‐Ser‐depleted conditions; this was suppressed by the addition of N‐acetyl‐l‐cysteine. Thus, intracellular l‐Ser deficiency triggers an inflammatory response via increased oxidative stress, and de novo l‐Ser synthesis suppresses oxidative stress damage and inflammation when the external l‐Ser supply is restricted. l‐Serine (l‐Ser) is a necessary precursor for the synthesis of a variety of biological molecules, and reduced availability of l‐Ser causes increased vulnerability to oxidative stress and inflammation. In this study, we found that l‐Ser depletion leads to enhanced reactive oxygen species generation and subsequent induction of the inflammatory markers thioredoxin‐interacting protein and prostaglandin‐endoperoxide synthase 2 in Phgdh‐deleted embryonic fibroblast cells.