Cyclin Y Overexpression Drives a Fatal Metabolic Syndrome via Defective Glucose Homeostasis

Cyclin Y (CCNY) is a membrane-associated, non-canonical cyclin best known for regulating WNT/beta-catenin signaling via the recruitment of CDK14/16 protein kinases. Whereas its role in the activation of members of the atypical CDK14-18 subfamily is established, its function in systemic metabolism remains poorly defined. Here, we report that CCNY overexpression drives a fatal metabolic syndrome. Using a novel inducible knock-in mouse model, we demonstrate that CCNY overexpression causes severe cachexia and profound hypoglycemia, resulting in death of adult mice independent of tumor burden. While these mutant mice maintain normal food intake and hepatic synthetic function, they succumb to metabolic starving state. Proteomics reveals that CCNY interacts with and stabilizes Pyruvate Dehydrogenase Kinase 4 (PDK4), in agreement with defective pyruvate use at mitochondria and enforcing a Warburg-like shift to aerobic glycolysis. Phosphoproteomic analysis indicates activation of apoptotic pathways and defective phosphorylation of several enzymes critical for glycolysis and gluconeogenesis as well as amino acid metabolism in addition to other metabolic routes. Altogether, these data suggest that CCNY overexpression uncouples nutrient sensing from utilization, a finding with possible therapeutic implications in CCNY-high cancers with similar changes in metabolic pathways.