Coxsackievirus B Type 4 Infection in ? Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing.

ABSTRACT: Enteroviruses are suspected to contribute to insulin-producing ? 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 ? cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in ? cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in ? 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 ? 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.

SUBMITTER: Bernard H 

PROVIDER: S-EPMC7659558 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature