Activated PKR inhibits pancreatic β-cell proliferation through sumoylation-dependent stabilization of P53

•Activation of PKR by low-dosage of BEPP inhibited proliferation in PKR-overexpressing β-cells.•Activated PKR interacts with sumo-conjugating enzyme Ubc9 to promote P53 sumoylation.•This stabilizes P53 and stimulates transcriptional activity.•The second messenger ceramide translates extracellular stress into PKR activation.•Glucolipotoxicity- and TNFα-induced stabilization of P53 is ceramide-dependent.