Signaling to NF-κB by Toll-like receptors Taro Kawai, Shizuo Akira  Trends in Molecular Medicine  Volume 13, Issue 11, Pages 460-469 (November 2007) DOI: 10.1016/j.molmed.2007.09.002 Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 1 TLRs, TLR ligands and TIR-domain-containing adaptor proteins. TLR2 recognizes various PAMPs, including peptidoglycan from Gram-positive bacteria, lipoarabinomannan from mycobacteria, hemagglutinin protein from measles virus and tGPI-mutin from Trypanosoma. TLR2/1 and TLR2/6 discriminate the lipid structures between triacyl- and diacyl-lipopeptide, respectively. TLR2/6 also recognizes zymosan from Saccharomyces cerevisiae (S. cerevisiae). TLR4 recognizes bacterial LPS and synthetic MPLA as well as envelope proteins from respiratory syncytial virus (RSV) and mouse mammary tumor virus (MMTV). TLR5 detects bacterial flagellin expressed in intestinal epithelial cells as well as CD11c-positive lamina propria in DCs. In mice, TLR11 recognizes as yet unknown components of uropathogenic bacteria, and a profilin-like molecule of Toxoplasma gondii. TLR3, 7, 8 and 9, which are localized to endosomes, detect nucleic acids derived from viruses and bacteria. TLR3 recognizes dsRNA, which is produced by many viruses during replication, and poly IC. TLR7 recognizes ssRNA derived from various viruses and synthetic imidazoquinolines with antitumor properties. Human TLR8 also participates in the recognition of ssRNA and imidazoquinolines, whereas the function of mouse TLR8 remains unclear. TLR9 recognizes CpG DNA motifs present in bacterial and viral genomes as well as non-nucleic acids such as hemozoin from Plasmodium. TLR1, 2 and 6 utilize MyD88 and TIRAP as adaptors while TLR5, 7, 9 and 11 utilize MyD88. TLR4 uses four adaptors, MyD88, TIRAP, TRIF and TRAM. TLR3 uses TRIF as the sole adaptor. Trends in Molecular Medicine 2007 13, 460-469DOI: (10.1016/j.molmed.2007.09.002) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 2 Structures of NF-κB, IκB and IKK proteins. (a) RelA, RelB and c-Rel contain the Rel homology domain (RHD) and the transcriptional activation domain (TAD), whereas (b) p105 and p100 contain the RHD and ankyrin repeats (ANK). (c) IκB proteins (IκBα, IκBβ, IκBγ, IκBɛ, Bcl3, IκBζ and IκBNS) contain ANK. (d) IKKα and IKKβ are composed of the kinase domain, a leucine zipper domain (LZ), a helix–loop–helix structure (HLH) and a NEMO-binding domain (NBD). (e) TBK1 and IKKi contain the kinase domain, LZ and HLH. Trends in Molecular Medicine 2007 13, 460-469DOI: (10.1016/j.molmed.2007.09.002) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 3 TLR2-, TLR3- and TLR4-mediated signaling. TLR4 activates both the MyD88- and the TRIF-dependent pathways. TIRAP and TRAM are required for the activation of the MyD88- and the TRIF-dependent pathways, respectively. MyD88 recruits TRAF6 and members of the IRAK family. TRAF6, together with Ubc13 and Uev1A, activates the TAK1 complex via K63-linked ubiquitination (Ub). The activated TAK1 complex then activates the IKK complex consisting of IKKα, IKKβ and NEMO, which catalyzes the phosphorylation of IκB proteins (P). IκBs are destroyed by the proteasome-dependent pathway, allowing NF-κB (RelA–p50 heterodimer) to translocate into the nucleus (canonical pathway). Simultaneously, the TAK1 complex activates the MAPK pathway, which results in the phosphorylation (P) and activation of AP-1. NF-κB and AP-1 control inflammatory responses through the induction of inflammatory cytokines. TRIF recruits TRAF3, which then interacts with TBK1 and IKKi. These kinases mediate phosphorylation of IRF3 (P). Phosphorylated IRF3 dimerizes and translocates into the nucleus to regulate transcription. TRIF also interacts with TRAF6 and RIP1, which mediate NF-κB activation. Activation of the IRF3, NF-κB and MAPK pathways is required for induction of type I IFN, particularly IFN-β. There are two types of NF-κB activation in TLR4 signaling: the MyD88-dependent pathway, which mediates early phase activation of NF-κB and the TRIF-dependent pathway, which mediates the late phase activation of NF-κB. TLR3, which resides in endosomal vesicles, utilizes TRIF, whereas TLR2 utilizes TIRAP and MyD88. Trends in Molecular Medicine 2007 13, 460-469DOI: (10.1016/j.molmed.2007.09.002) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure 4 TLR7- and TLR9-mediated signaling. TLR7 and TLR9 are expressed in endosomal compartments. These TLRs elicit the MyD88-dependent pathway to regulate inflammatory responses through activation of the TAK1-mediated NF-κB and MAPK pathways. In pDCs, IRF7 forms a signaling complex with MyD88, IRAK4, TRAF6, IRAK1 and IKKα. In response to ligand stimulation, IRF7 is phosphorylated by IRAK1 and IKKα, dimerizes and is then translocated into the nucleus. IRF7 regulates the expression of type I IFNs, including IFN-α and IFN-β. Trends in Molecular Medicine 2007 13, 460-469DOI: (10.1016/j.molmed.2007.09.002) Copyright © 2007 Elsevier Ltd Terms and Conditions

Figure I Antiviral signaling pathways mediated by IKK-related kinases. Cells express cytoplasmic RNA helicases (RIG-I and Mda5) that recognize RNA derived from actively replicating RNA viruses. RIG-I and Mda5 contain CARD-like structures that mediate interaction with the adaptor IPS-1. IPS-1 localizes to mitochondria and initiates signaling pathways leading to NF-κB and IRF3 via IKKα/ IKKβ and TBK1/IKKi, respectively. IPS-1 recruits FADD and Caspase-10/8 for NF-κB activation as well as TRAF3 for TBK1/IKKi activation. NEMO is involved in both NF-κB and IRF3 activation. Cells express DAI that detects dsDNA derived from DNA viruses or bacteria and this in turn results in the induction of type I IFN through TBK1/IKKi. Signaling pathways of DAI-mediated NF-κB activation are unclear. Trends in Molecular Medicine 2007 13, 460-469DOI: (10.1016/j.molmed.2007.09.002) Copyright © 2007 Elsevier Ltd Terms and Conditions