Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis

Le résumé fourni par la source

The bi-functional enzyme FicD catalyzes AMPylation and deAMPylation of the endoplasmic reticulum chaperone BiP to modulate ER homeostasis and the unfolded protein response (UPR). Human hFicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the m FicD R371S mutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas of m FicD R371S mice appeared normal at birth, adult mFicD R371S mice displayed disturbed pancreatic islet organization that progressed with age. mFicD R371S mice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience. • FicD R371S mutation recessively alters global AMPylation of BiP • Loss of BiP deAMPylation alters UPR signaling in the pancreas resulting in neonatal diabetes • FicD R371S mutation leads to disruption of pancreatic islet organization and function • FicD R371S mutation leads to disruption of pancreatic islets that progresses with age after birth • FicD R371S mice provide a preclinical mouse model for UPR associated diabetes

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