Bernard, HugoTeijeiro, AnaChaves-Pérez, AlmudenaPerna, CristianSatish, BasanthiNovials, AnnaWang, Jennifer PDjouder, Nabil2024-02-082024-02-082020-10-20Cell Rep Med . 2020;1(7):100125.http://hdl.handle.net/20.500.12105/17556Enteroviruses are suspected to contribute to insulin-producing β cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting β cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in β cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in β cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter hypermethylation and silencing. Consequently, demethylating agent procainamide-mediated DNMT1 inhibition reinstates PDX1 expression and protects against diabetes in pancreatic URI-depleted mice . Finally, the β cells of human diabetes patients show correlations between viral protein 1 and URI, PDX1, and DNMT1 levels. URI and DNMT1 expression and PDX1 silencing provide a causal link between enterovirus infection and diabetes.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/AnimalsCapsid ProteinsCoxsackievirus InfectionsDNA (Cytosine-5-)-Methyltransferase 1Diabetes Mellitus, Type 2Disease Models, AnimalEnterovirus B, HumanFemaleGene Expression RegulationGlucoseHomeodomain ProteinsHumansInsulin-Secreting CellsMaleMiceMice, TransgenicProcainamideRatsRepressor ProteinsSignal TransductionTrans-ActivatorsTransplantation, HeterologousAttribution-NonCommercial-NoDerivatives 4.0 Internacional332050751710012510.1016/j.xcrm.2020.1001252666-3791Cell reports. Medicineopen access