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.

Abstract

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.

Keywords: DNMT1; PDX1; beta cells; coxsackievirus B Type 4; diabetes; enteroviruses; estrogen receptor; hypermethylation; prefoldin URI; transdifferentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capsid Proteins / genetics*
  • Capsid Proteins / metabolism
  • Coxsackievirus Infections / genetics*
  • Coxsackievirus Infections / metabolism
  • Coxsackievirus Infections / pathology
  • Coxsackievirus Infections / virology
  • DNA (Cytosine-5-)-Methyltransferase 1 / antagonists & inhibitors
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics*
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / virology
  • Disease Models, Animal
  • Enterovirus B, Human / genetics*
  • Enterovirus B, Human / metabolism
  • Enterovirus B, Human / pathogenicity
  • Female
  • Gene Expression Regulation
  • Glucose / metabolism
  • Glucose / pharmacology
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Insulin-Secreting Cells / transplantation
  • Male
  • Mice
  • Mice, Transgenic
  • Procainamide / pharmacology
  • Rats
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transplantation, Heterologous

Substances

  • Capsid Proteins
  • Homeodomain Proteins
  • Repressor Proteins
  • Trans-Activators
  • Uri1 protein, mouse
  • VP1 protein, enterovirus B
  • pancreatic and duodenal homeobox 1 protein
  • DNA (Cytosine-5-)-Methyltransferase 1
  • Dnmt1 protein, mouse
  • Glucose
  • Procainamide

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 4