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. 2012 Dec 14;13(1):46–57. doi: 10.1038/nri3344

Figure 1. Detection of pathogen RNA and DNA in the cytoplasm and activation of IFNB and ISGs.

Figure 1

IFN-induced protein with tetratricopeptide repeats (IFIT) genes and IFN-induced transmembrane protein (IFITM) genes are induced by host innate immune defences after pathogen infection. The figure shows a scheme of innate immune signalling triggered by viral infection. Viral RNA and DNA is detected by: cytosolic RIG-I-like receptors (RLRs), such as melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I); cytosolic DNA sensors, such as DNA-dependent activator of IRFs (DAI), IFNγ-inducible protein 16 (IFI16), DEAH box protein 9 (DHX9) and DHX36; and endosomal Toll-like receptors (TLRs), including TLR3, TLR7 and TLR9. Infection by RNA viruses produces RNA intermediates that are recognized as non-self by RIG-I and MDA5 in the cytosol and by TLR3 and TLR7 in endosomes. The RLRs interact with mitochondrial antiviral signalling protein (MAVS), leading to the recruitment of TNFR-associated factor 3 (TRAF3), TANK-binding kinase 1 (TBK1) and IκB kinase-ε (IKKε), or of IKKγ (also known as NEMO), IKKα and IKKβ, which results in the activation and nuclear translocation of IFN-regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB), respectively. TLRs interact with the adaptor proteins TRIF and MYD88, leading to the activation of IRF3 or IRF7. IRF3, IRF7 and NF-κB bind to the interferon-β (IFNB) gene promoter and induce transcription. Secretion of IFNβ by the infected cells results in paracrine type I IFN signalling through the IFNα/β receptor, which induces hundreds of IFN-stimulated genes (ISGs). Phosphorylated IRF3 also can activate the expression of ISGs (such as IFIT and IFITM genes) independently of IFN signalling. DNA can be present in the cytoplasm and in endosomes during viral or bacterial infection and following the phagocytosis of dead cells. TLR9 recognizes CpG DNA in endosomes and activates MYD88. The binding of DNA by DAI or IFI16 results in stimulator of IFN genes (STING)-dependent activation of IRF3 and NF-κB. RNA polymerase III transcribes this DNA to produce short RNAs containing a 5′-ppp motif, which are ligands for RIG-I. DHX9 and DHX36 bind to DNA ligands (such as CpG-A and CpG-B DNA) in the cytosol and induce MYD88- and IRF7-dependent responses. ER, endoplasmic reticulum; IκB, NF-κB inhibitor.