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

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.

SUBMITTER: Santin I

PROVIDER: S-EPMC3542594 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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

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

Cell death & disease 20121115

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-ind ...[more]

PMID: 23152055

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Project description:Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-? (IFN-? knockout [IFN-?-KO] mice or mice treated with an IFN-?-blocking antibody) or IFN-? (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-?-blocking antibody). Mice lacking either IFN-? or IFN-? developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-? sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-?-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-? had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-?-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-? limiting early viral replication and dissemination and IFN-? modulating neutrophil-mediated inflammation.IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-? and IFN-? both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-? limits CHIKV replication and dissemination, whereas IFN-? protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response.

Dataset Information

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

Publications

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

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