USP18 is a key regulator of the interferon-driven gene network modulating pancreatic beta cell inflammation and apoptosis

I Santin,D L Eizirik,F A Grieco,C Brancolini,F Moore,P Marchetti

doi:10.1038/cddis.2012.158

Abstract

Type 1 diabetes (T1D) is an autoimmune disease targeting pancreatic beta cells. Genome-wide association studies and gene expression analysis identified interferon (IFN)-driven gene networks as crucial pathways in the pathogenesis of T1D. IFNs are linked to the response to viral infections and might contribute to the initiation of the autoimmune process in T1D. We presently analyzed the role of ubiquitin-specific peptidase 18 (USP18), an interferon-stimulated gene 15-specific protease, on IFN-induced pancreatic beta cell inflammation and apoptosis. Our findings indicate that USP18 inhibition induces inflammation by increasing the STAT signaling and exacerbates IFN-induced beta cell apoptosis by the mitochondrial pathway of cell death. USP18 regulates activation of three BH3-only proteins, namely, DP5, Bim and PUMA in pancreatic beta cells, suggesting a direct link between regulators of the type I IFN signaling pathway and members of the BCL-2 family. USP18 depletion increases the expression of the T1D candidate gene MDA5, leading to an upregulation of double-stranded RNA-induced chemokine production. These data suggest a cross talk between the type I IFN signaling pathway and a candidate gene for T1D to increase pro-inflammatory responses in beta cells. The present study shows that USP18 is a key regulator of IFN signaling in beta cells and underlines the importance of this pathway in beta cell inflammation and death.

Highlights

Integration of genome-wide association studies (GWAS) with global gene expression analysis have identified interferon (IFN)-driven gene networks, potentially linked to the response to viral infections, as crucial regulating pathways in the pathogenesis of Type 1 diabetes (T1D).2 Several of the genes present in these networks are expressed in pancreatic beta cells,[3] reinforcing the concept of a ‘dialog’ between these cells and the immune system in the early stages of T1D.4
We have previously shown that polyinosinic: polycytidylic acid (PIC; a synthetic viral double-stranded RNA analog)-induced beta cell death is partially mediated by type I IFNs released by the beta cells
The current study shows that ubiquitin-specific peptidase 18 (USP18) is a key regulator of type I IFN signaling pathway in pancreatic beta cells and its inhibition contributes to IFN-induced beta cell apoptosis and inflammation (Figure 8)

Summary

Introduction

Integration of genome-wide association studies (GWAS) with global gene expression analysis have identified interferon (IFN)-driven gene networks, potentially linked to the response to viral infections, as crucial regulating pathways in the pathogenesis of T1D.2 Several of the genes present in these networks are expressed in pancreatic beta cells,[3] reinforcing the concept of a ‘dialog’ between these cells and the immune system in the early stages of T1D.4. Type I IFNs are important mediators of antiviral responses and their implication in the pathogenesis of T1D is supported by human data.[5] IFNs might contribute to the initiation and acceleration of the autoimmune process in T1D by inducing activation of dendritic cells, proliferation of T cells and direct beta cell apoptosis.[4,6] There is a positive correlation between elevated levels of IFNa in blood and T1D associated with enterovirus infections,[7] and histological studies indicate that pancreatic beta cells express IFNa in almost all cases of new onset T1D.8. Knockout of STAT1 gene suppresses development of diabetes in the nonobese diabetic mice[13] and protects against streptozotocin-induced diabetes.[14] These data suggest that regulators of type I IFN signaling pathways may be potential therapeutic targets for the prevention of T1D. Received 26.6.12; revised 31.8.12; accepted 24.9.12; Edited by M Federici level; (2) how can this regulation modulate beta cell death and the generation of signals that contribute to trigger and amplify the local inflammation (insulitis); and (3) how can this regulation cross talk with relevant candidate genes for T1D

Methods

Results

Conclusion