The alternative activity of nuclear PHGDH contributes to tumor growth under nutrient stress

Here we show under glucose deficiency PHGDH is phosphorylated by p38 at Ser371, which promotes the cytosol-localized PHGDH translocation into the nucleus. Meanwhile, AMPK concurrently phosphorylates PHGDH-Ser55 and selectively increases PHGDH catalytic activity against malate oxidation, thus pushing the reduction of NAD+ towards NADH generation. In the nucleus, the altered PHGDH activity positively regulates NADH/NAD+ ratio and thus restricts NAD+ level, and thereby leads to repression of NAD+-dependent PARP1 activity. Moreover, PHGDH is found to be associated with Ser73-phosphorylated c-Jun and specifically inhibits PARP1-mediated c-Jun poly(ADP-ribosyl)ation, which accordingly led to the impaired c-Jun transcriptional activity against genes expression linking to cell growth inhibition. Transcriptome profile analysis in WT rPHGDH and rPHGDH S371A or rPHGDH S55A SW1990 cells under glucose deprivation