We previously reported that glucokinase is ubiquitinated and degraded by cereblon with an unknown endogenous glucokinase protein degrader. Here, we show that UDP-glucose is a glucokinase protein degrader. We identified that both glucose and UDP-glucose bind to glucokinase and that both uridine and UDP-glucose bind to cereblon in a similar way to thalidomide. From these results, UDP-glucose was identified as a molecular glue between cereblon and glucokinase. Glucokinase produces glucose-6-phosphate in the pancreas and liver. Especially in β-cells, glucokinase is the main target of glucose for glucose-induced insulin secretion. UDP-glucose administration ubiquitinated and degraded glucokinase, lowered glucose-6-phosphate production, and then reduced insulin secretion in β-cell lines and mice. Maturity-onset diabetes of the young type 2 (MODY2) glucokinaseE256K mutant protein was resistant to UDP-glucose induced ubiquitination and degradation. Taken together, glucokinase ubiquitination and degradation signaling might be impaired in MODY2 patients.
Keywords: MODY; PROTACs; UDP-glucose; diabetes; glucokinase; glucose; insulin; protein degrader.