p53 enables phospholipid headgroup scavenging

Abstract Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here, we show that the transcription factor p53 enables recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases supply of phosphoethanolamine (PEtn), an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine (PE), by transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of PEtn conversion to PE is well-tolerated in the absence of p53 but results in dramatic organelle remodeling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR-Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state specific metabolic vulnerability.