University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Medicine

Publication Date

2020-10-20

Document Type

Article

Disciplines

Cellular and Molecular Physiology | Endocrine System Diseases | Endocrinology | Hormones, Hormone Substitutes, and Hormone Antagonists | Nutritional and Metabolic Diseases | Viruses

Abstract

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.

Keywords

DNMT1, PDX1, beta cells, coxsackievirus B Type 4, diabetes, enteroviruses, estrogen receptor, hypermethylation, prefoldin URI, transdifferentiation

Rights and Permissions

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

10.1016/j.xcrm.2020.100125

Source

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

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Cell reports. Medicine

PubMed ID

33205075

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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