Sensing of Viral Infection and Activation of Innate Immunity by Toll-Like Receptor 3
Elisabeth Vercammen, Jens Staal, and Rudi Beyaert





TLR3 signaling pathways. Binding of dsRNA to the TLR3-CD14 complex induces the activation of several intracellular signaling pathways. The activation of NF-B and IRF3 is achieved by two different signaling branches emanating from the TLR3 adaptor molecule TRIF, which binds to the BB loop of the TLR3 TIR domain. Distinct regions of TRIF bind the ubiquitin ligase TRAF6 and the kinase RIP1. Analogously with the ubiquitin ligase activity of TRAF2 in the TNF receptor pathway, the activity of TRIF-associated TRAF6 might be responsible for the Ub of RIP1 in the TLR3 pathway. RIP1 ubiquitination is recognized by the ubiquitin receptor proteins TAB2 and TAB3, leading to the activation of the kinase TAK1, which is part of the same complex. TAK1 phosphorylates and activates IKK and IKKβ, which are part of a bigger IKK complex with the IKK adaptor protein IKK. IKKβ is known to be the crucial IKK in TLR signaling and phosphorylates IB, which binds and keeps NF-B (here depicted as a p65/p50 dimer) in an inactive state in the cytoplasm. IB phosphorylation leads to its recognition and degradation by the proteasome, thus allowing NF-B to translocate to the nucleus, where it binds and activates specific gene promoters (e.g., A20). TRIF also binds TRAF3 and NAP1. Whereas the role of TRAF3 is still largely unclear, NAP1 functions as an adaptor for the IKK-related kinases IKK and TBK1, which have largely redundant functions. Both kinases phosphorylate IRF3, leading to its dimerization and translocation to the nucleus, where it binds and activates specific gene promoters (e.g., IFN-β). Whereas these TRIF-mediated signaling pathways result in the activation of NF-B and IRF3, the phosphorylation of NF-B and IRF3 is involved in acquiring the fully activated status of both transcription factors (see the text for more details). Signaling leading to these events is still largely unclear, but IRF3 phosphorylation is dependent on the kinase Akt, which is activated by the lipid kinase PI3K, which binds phospho-Tyr759 of TLR3. Interestingly, PI3K also seems to have an inhibitory function on NF-B activation, whereas the phosphorylation of TLR3 on Tyr858 enhances NF-B activation by an unknown mechanism. TLR3 also induces apoptosis via a TRIF- and RIP1-dependent mechanism. The binding of RIP1 to TRIF not only activates NF-B but also recruits the DD-containing adaptor protein FADD via a homotypic DD-DD interaction. FADD in turn interacts with the cysteine protease procaspase-8 through the death effector domain (DED) present in both proteins. This is believed to result in the proteolytic auto-activation of procaspase-8 and the initiation of cell death. CYT, cytoplasmic linker.

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