Bernard, HugoTeijeiro, AnaChaves-Perez, AlmudenaPerna, CristianSatish, BasanthiNovials, AnnaWang, Jennifer P.Djouder, Nabil2022-08-232022-08-232020-10-202021-01-06<p>Bernard H, Teijeiro A, Chaves-Pérez A, Perna C, Satish B, Novials A, Wang JP, Djouder N. Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via <em>Pdx1</em> Silencing. Cell Rep Med. 2020 Oct 20;1(7):100125. doi: 10.1016/j.xcrm.2020.100125. PMID: 33205075; PMCID: PMC7659558. <a href="https://doi.org/10.1016/j.xcrm.2020.100125">Link to article on publisher's site</a></p>2666-3791 (Linking)10.1016/j.xcrm.2020.10012533205075https://hdl.handle.net/20.500.14038/29639Enteroviruses are suspected to contribute to insulin-producing beta 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 beta cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in beta cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in beta 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 beta 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.en-USCopyright 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).http://creativecommons.org/licenses/by-nc-nd/4.0/DNMT1PDX1beta cellscoxsackievirus B Type 4diabetesenterovirusesestrogen receptorhypermethylationprefoldin URItransdifferentiationCellular and Molecular PhysiologyEndocrine System DiseasesEndocrinologyHormones, Hormone Substitutes, and Hormone AntagonistsNutritional and Metabolic DiseasesVirusesJournal Articlehttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2873&amp;context=faculty_pubs&amp;unstamped=1https://escholarship.umassmed.edu/faculty_pubs/185520950821faculty_pubs/1855