Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing
Summary: Enteroviruses 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 un...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-10-01
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| Series: | Cell Reports Medicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666379120301671 |
| _version_ | 1828783782337970176 |
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| author | Hugo Bernard Ana Teijeiro Almudena Chaves-Pérez Cristian Perna Basanthi Satish Anna Novials Jennifer P. Wang Nabil Djouder |
| author_facet | Hugo Bernard Ana Teijeiro Almudena Chaves-Pérez Cristian Perna Basanthi Satish Anna Novials Jennifer P. Wang Nabil Djouder |
| author_sort | Hugo Bernard |
| collection | DOAJ |
| description | Summary: Enteroviruses 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. |
| first_indexed | 2024-12-11T23:18:29Z |
| format | Article |
| id | doaj.art-55310db7154f4a68aeaf05ccd000dc1b |
| institution | Directory Open Access Journal |
| issn | 2666-3791 |
| language | English |
| last_indexed | 2024-12-11T23:18:29Z |
| publishDate | 2020-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports Medicine |
| spelling | doaj.art-55310db7154f4a68aeaf05ccd000dc1b2022-12-22T00:46:25ZengElsevierCell Reports Medicine2666-37912020-10-0117100125Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 SilencingHugo Bernard0Ana Teijeiro1Almudena Chaves-Pérez2Cristian Perna3Basanthi Satish4Anna Novials5Jennifer P. Wang6Nabil Djouder7Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, SpainMolecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, SpainMolecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, SpainDepartment of Pathology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid 28034, SpainDepartment of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USAIDIBAPS, August Pi i Sunyer Biomedical Research Institute and, CIBERDEM, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, Barcelona, SpainDepartment of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USAMolecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain; Corresponding authorSummary: Enteroviruses 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.http://www.sciencedirect.com/science/article/pii/S2666379120301671enterovirusescoxsackievirus B Type 4diabetestransdifferentiationbeta cellsprefoldin URI |
| spellingShingle | Hugo Bernard Ana Teijeiro Almudena Chaves-Pérez Cristian Perna Basanthi Satish Anna Novials Jennifer P. Wang Nabil Djouder Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing Cell Reports Medicine enteroviruses coxsackievirus B Type 4 diabetes transdifferentiation beta cells prefoldin URI |
| title | Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing |
| title_full | Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing |
| title_fullStr | Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing |
| title_full_unstemmed | Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing |
| title_short | Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing |
| title_sort | coxsackievirus b type 4 infection in β cells downregulates the chaperone prefoldin uri to induce a mody4 like diabetes via pdx1 silencing |
| topic | enteroviruses coxsackievirus B Type 4 diabetes transdifferentiation beta cells prefoldin URI |
| url | http://www.sciencedirect.com/science/article/pii/S2666379120301671 |
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