RNA-binding protein AUF1 suppresses cellular senescence and glycolysis by targeting PDP2 and PGAM1 mRNAs

Signaling pathways and transcriptional regulation during cellular senescence have been investigated; however, energy metabolism is one of the understudied areas. Senescent cells secrete pro-inflammatory cytokines and release proteins and RNAs via exosomes that contribute to organismal aging. Although senescent fibroblasts in solid organs are in a low oxygen environment, these fibroblasts have more active glucose metabolism and consume more oxygen than proliferating ones. A critical gap in our knowledge is how senescent fibroblasts facilitate glucose metabolism and organismal aging by creating a distinct microenvironment. Our high throughput profiling of mRNAs and proteins from Human Diploid Fibroblasts (HDFs) revealed that the expression of pyruvate metabolic enzymes is inhibited by the anti-senescent RNA-binding protein (RBP) AUF1 (AU-binding Factor 1). Our studies revealed that AUF1 promotes the decay of mRNAs encoding two enzymes: PGAM1 (phosphoglycerate mutase 1), a glycolytic enzyme involved in the pyruvate synthetic pathway, and PDP2 (Pyruvate Dehydrogenase Phosphatase 2), which activates Pyruvate Dehydrogenase. We also demonstrated that AUF1 is phosphorylated by a Serine/Threonine kinase, MST1 (Mammalian Ste20-like kinase 1; encoded by STK4), resulting in the inactivation of AUF1, which leads to target mRNA stabilization and senescence. Overexpression of PGAM1 and PDP2 predicts an acceleration of pyruvate production and subsequent citrate metabolism, leading to cellular senescence and aging. Thus, our studies revealed regulatory mechanisms of glycolysis-driven cellular senescence by AUF1-mediated decay of <i>PGAM1</i> and <i>PDP2</i> mRNAs.