Figure 4.

Innate immune signaling from endosomes. (a) NOD receptors associate with endosomal membranes, where they are positioned to encounter PAMPs, as microbes escape from endosomes or as they are pumped out by transporters such as SLC15A3. NOD signaling activates RIPK2, which triggers proinflammatory cytokine production through NF-κB and MAPK activation. (b) TLR3 responds to double-stranded RNA and triggers an enzymatic signaling cascade through the adaptor protein TRIF. Unlike TLR4, TLR3 does not require the adaptor TRAM, but it can similarly activate IRF3 to produce type I IFN and ISGs, as well as NF-κB, to produce proinflammatory cytokines. (c) Other endosomal TLRs principally activate NF-κB through the adaptors MyD88 and TIRAP. In pDCs, TLR7 and -9 trigger IFN and ISG production through the activation of IRF7. (Abbreviations: IFN, interferon; IRAK, interleukin-1 receptor-associated kinase; IRF, IFN regulatory factor; ISG, IFN-stimulated gene; MAPK, mitogen-activated protein kinase; MDP, muramyl dipeptide; NOD, nucleotide-binding oligomerization domain; PAMP, pathogen-associated molecular pattern; pDC, plasmacytoid dendritic cell; RIPK2, RIP2 kinase; TIRAP, TIR-containing adaptor protein; TRAF, TNF receptor–associated factor; TRIF, TIR domain–containing adaptor-inducing IFN-β.)