Fig. 2.

Nucleic acid-sensing innate immune signaling

The nucleic acid sensing system plays a fundamental role in anti-viral immunity. A cytosolic DNA sensor cGAS recognizes DNA from DNA viruses and generate the second messenger cGAMP, which activates STING located on the endoplasmic reticulum. TLR9 in the endosome also recognizes virus-derived DNA and transmits the downstream signal through the adaptor MyD88. Notably, DNA released from dying tumor cells is also incorporated into intratumoral DCs and activates them through STING and TLR9. TLR7 and TLR8 in the endosome recognize single-stranded RNA (ssRNA) from RNA virus and transmits the downstream signal through the adaptor MyD88, whereas TLR3 in the endosome recognizes double-stranded RNA (dsRNA) from RNA viruses and transmits the downstream signal through a different adaptor, TRIF/TICAM-1. Cytosolic RNA sensors, RIG-I-like receptors (RIG-I and MDA5), also recognize dsRNA and transmit the downstream signal though the adaptor IPS-1/MAVS. Engagement of all these nucleic acid sensors leads to the final common pathways: the TBK1-IRF3/7 pathway to the production of type I IFN (IFN-α/β) and the IKK-NF-κB pathway to the production of inflammatory cytokines such as TNF and IL-6. Whereas the cytosolic nucleic acid sensors are expressed broadly in numerous tissue types of both immune and non-immune origin, expression of the endosomal TLRs is largely restricted to antigen-presenting cells including monocytes, macrophages, DCs, and B cells. MyD88, myeloid differentiation primary response 88; TRIF, Toll-interleukin-1 receptor domain-containing adapter inducing interferon-β; TICAM-1, Toll-like receptor adaptor molecule 1; IPS-1, interferon-β promoter stimulator 1; MAVS, mitochondrial antiviral signaling; TBK1, TNAK-binding kinase 1; IRF, interferon regulatory factor; IKK, IκB kinase; NF-κB, nuclear factor-κB.