Figure 1 Regulation of key antiviral responses in pancreatic β cells Figure 1 | Regulation of key antiviral responses in pancreatic β cells. Following infection, replicating coxsackievirus subtype B (CVB) produce cytosolic double-stranded RNA (dsRNA), a nonphysiological form of mRNA recognized by the cytoplasmic receptor MDA5. Binding of MDA5 to the dsRNA activates the transcription factors NF-κB, IRFs and STATs, triggering production of type I interferons and chemokines, thus contributing to local inflammation (insulitis). Type I interferons (IFN-α and IFN-β), type II interferon (IFN-γ) and the cytokines TNF and IL-1β contribute to β-cell destruction among genetically susceptible individuals. Type I interferons bound to the IFN-α/β receptor (IFNAR) signal via TYK2 and JAK1 and induce activation of STATs and expression of interferon-stimulated genes (ISGs) with antiviral properties. Proinflammatory cytokines promote the activation of JNK1, which induces the intrinsic (mitochondrial) apoptotic pathway through the proapoptotic protein BIM and its phosphorylated form (P-BIM). PTPN2 modulates β-cell death induced by interferons by regulating activation of P-BIM via JNK1. BIM and/or JNK1 are downregulated by BACH2, GLIS3 and CTSH. PTPN2 also functions as a negative regulator of the STAT signalling pathway, whereas USP18 exerts negative feedback on interferon-induced STAT signalling and mitochondrial apoptotic pathways in β cells. Candidate-gene regulated factors implicated in type 1 diabetes mellitus are framed in red and the consequences of their modulated expression and/or activity on biological function or type 1 diabetes mellitus risk indicated. Kinases and phosphatases are indicated by green ovals and transcription factors by grey ovals. Beeck, A. O. d. & Eizirik, D. L. (2016) Viral infections in type 1 diabetes mellitus — why the β cells? Nat. Rev. Neurol. doi:10.1038/nrendo.2016.30