Fig. 1

A schematic representation of interferon signalling with display of current genetic findings. The left section of the figure points out the three major cytosolic pattern recognition receptor (PRR) signalling pathways that recognize viruses and culminate in the production of defensive type I and III interferons (IFNs). These routes consist of Toll-like receptor (TLR), RIG-I-like receptor (RLR) and cGAS-STING signalling pathways that utilize distinct adaptor complexes with associating kinases and ubiquitin ligases for their signal transduction. These TASL, MyD88, TRIF and MAVS complexes subsequently lead to the phosphorylation of interferon regulatory factors (IRFs) that initiate transcription of IFNs. Furthermore, the production of the type II IFN interferon gamma (IFNγ) is induced through TLR7-IRF7-dependent signalling. The right section shows autocrine and paracrine signalling of type I and III IFNs through the respective IFNAR1/2 and IFNLR1/IL10RB receptors. This activation leads to the formation of either STAT1 homo- or STAT1/2 heterodimers that recruit IRF9 to induce transcription of IFNs and a plethora of interferon-stimulated genes (ISGs). Several inhibitory proteins are highlighted in pink to illustrate a selection of the negatively regulating feedback loops in this highly regulated pathways. Lastly, symbols above selected proteins indicate whether rare or common variants have been identified in the genes from which these proteins are encoded. P, phosphatase; STAT, signal transducer and activator of transcription; IFITM, interferon-induced transmembrane protein; OAS, oligoadenylate synthase; MX1, interferon-induced GTP-binding protein; GBP, guanylate-binding protein; TRIM, tripartite motif protein; ISRE, interferon-stimulated response element; GAS, gamma-activated sequence