UDP-Glucose: A Cereblon-Dependent Glucokinase Protein Degrader

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 U...

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Veröffentlicht in:International journal of molecular sciences 2022-08, Vol.23 (16), p.9094
Hauptverfasser: Cho, Jaeyong, Miyagawa, Atsushi, Yamaguchi, Kazuki, Abe, Wakana, Tsugawa, Yoji, Yamamura, Hatsuo, Imai, Takeshi
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Sprache:eng
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Zusammenfassung: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23169094