Department of Medicine
Cellular and Molecular Physiology | Endocrine System Diseases | Endocrinology | Hormones, Hormone Substitutes, and Hormone Antagonists | Nutritional and Metabolic Diseases | Viruses
Enteroviruses 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.
DNMT1, PDX1, beta cells, coxsackievirus B Type 4, diabetes, enteroviruses, estrogen receptor, hypermethylation, prefoldin URI, transdifferentiation
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Copyright 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/).
DOI of Published Version
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 Pdx1 Silencing. Cell Rep Med. 2020 Oct 20;1(7):100125. doi: 10.1016/j.xcrm.2020.100125. PMID: 33205075; PMCID: PMC7659558. Link to article on publisher's site
Cell reports. Medicine
Bernard H, Teijeiro A, Chaves-Perez A, Perna C, Satish B, Novials A, Wang JP, Djouder N. (2020). Coxsackievirus B Type 4 Infection in beta Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1016/j.xcrm.2020.100125. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1855
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Cellular and Molecular Physiology Commons, Endocrine System Diseases Commons, Endocrinology Commons, Hormones, Hormone Substitutes, and Hormone Antagonists Commons, Nutritional and Metabolic Diseases Commons, Viruses Commons