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. Author manuscript; available in PMC: 2018 Jan 31.
Published in final edited form as: Nat Immunol. 2017 Jun 20;18(7):716–724. doi: 10.1038/ni.3731

Figure 2. Engagement of endosomal or cytosolic nucleic acid sensors as central events in inflammatory responses.

Figure 2

Nucleic acid sensors are critical innate immune receptors that reside either in endolysosomes or the cytosol. Upon recognition of specific ligands, they initiate a signaling cascade resulting in the activation of several transcription factors that promote cell activation and production of type I interferons (IFN-I) and inflammatory cytokines. Two ER molecules, GRP94 and PRAT4A, act in concert to ensure proper folding of TLRs 3, 7, 8 and 9 and exit from the ER, while UNC93B1 mediates TLR transport to endolysosomes, where ligand recognition takes place. Other proteins participating in TLR trafficking and/or function are the adaptor protein 3 (AP-3), the biogenesis of lysosome organelle complex 1 and 2 (BLOC1/2), and the solute carrier 15A4 (SLC15A4), a molecule known to transport protons (H+), histidine (His) and selected peptides from endosomes to the cytosol. In the cytosol, RNA is sensed by the helicases RIG-I and MDA5, while DNA is primarily sensed by the cyclic GMP-AMP synthase (cGAS). Engagement of cGAS leads to synthesis of the second messenger cGAMP that interacts with the stimulator of interferon genes (STING) to promote inflammatory responses.