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. 2020 Apr 28;21(9):3124. doi: 10.3390/ijms21093124

Figure 1.

Figure 1

Intracellular TLR3 signaling pathways. Double stranded-RNA (dsRNA) derived from virus, mRNA liberated from necrotic cells and synthetic polyinosinic:polycytidylic acid are recognized by endosomal toll-like receptor, TLR3. TLR3 is located in acidic endosomes formed during clathrin-dependent endocytosis. TLR3 signaling occurs via TRIF, an adaptor that can also be recruited by TLR4. TRIF activates NF-κB and AP1 to induce transcription of type I interferon and pro-inflammatory cytokines. Apoptosis and proliferation can be induced by TRIF-independent TLR3 signaling via BAX and c-SRC respectively. Cytosolic receptors can respond to dsRNA independently of TLR3 or in a synergistic manner and these include retinoic acid inducible gene-I (RIG-I) and melanoma differentiation antigen 5 (MDA-5). These signal via the mitochondrial anti-viral signaling protein (MAVS) to activate interferon regulatory factor 3 (IRF3). RNA can also suppress translation via activation of protein kinase R (PKR), which in turn phosphorylates eukaryotic initiation factor 2-alpha (EIF2α). Abbreviations: TRIF, TIR-domain-containing adapter-inducing interferon-β (TRIF); TRAF6, Tumor necrosis factor receptor (TNFR)-associated factor 6; MAPK, mitogen-activated protein kinase; RIP-1, receptor-interacting protein 1; AP-1, Activator protein 1; BAX, BCL2 Associated X Protein; TBK1, TANK-binding kinase; IKK, inhibitor of nuclear factor-κB (IκB) kinase. Created with BioRender (Toronto, ON, Canada).