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• W2020996714 abstract "The complexity of the immune system mirrors its manifold mechanisms of host-microbe interactions. A relatively simplified view was posited after the identification of host innate immune receptors that their distinct mechanisms of sensing “microbial signatures” create unique molecular switches to trigger the immune system. Recently, more sophisticated and cooperative strategies for these receptors have been revealed during receptor-ligand interactions, trafficking, and intra- and intercellular signaling, in order to deal with a diverse range of microbes. Continued mapping of the complex networks of host-microbe interactions may improve our understanding of self/non-self discrimination in immunity and its intervention. The complexity of the immune system mirrors its manifold mechanisms of host-microbe interactions. A relatively simplified view was posited after the identification of host innate immune receptors that their distinct mechanisms of sensing “microbial signatures” create unique molecular switches to trigger the immune system. Recently, more sophisticated and cooperative strategies for these receptors have been revealed during receptor-ligand interactions, trafficking, and intra- and intercellular signaling, in order to deal with a diverse range of microbes. Continued mapping of the complex networks of host-microbe interactions may improve our understanding of self/non-self discrimination in immunity and its intervention. Host-microbe interactions are essential for many aspects of the normal physiologies of both types of organisms, ranging from metabolic activities to immune homeostasis (Dethlefsen et al., 2007Dethlefsen L. McFall-Ngai M. Relman D.A. An ecological and evolutionary perspective on human-microbe mutualism and disease.Nature. 2007; 449: 811-818Crossref PubMed Scopus (409) Google Scholar). Despite this mutual relationship after long-term coevolution, infectious diseases and their secondary effects have always been one of the biggest threats to humans and are still the second major cause of death (Fauci, 2006Fauci A.S. Emerging and re-emerging infectious diseases: Influenza as a prototype of the host-pathogen balancing act.Cell. 2006; 124: 665-670Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Moreover, economic and environmental changes in human lifestyles have significantly influenced host-microbe interactions in many ways, driving us to face more than 30 emerging pathogens during the past 30 years. Therefore, we urgently need to devise novel strategies for intervening in such pathogen emergence through better understanding of the manifold mechanisms of host immune responses to, and manipulation by, microbial infections. Over the past decade, a large number of studies in immunology and microbiology have revealed pivotal roles of the host innate immune system in sensing microbial infections via specific innate immune receptors, which are germline encoded and consist of a “recognition” domain and a protein-protein-interacting region for downstream signaling. These receptors act as a molecular switch to trigger innate immune activation and tightly regulate the subsequent adaptive immune responses to microbial infections (Medzhitov, 2007Medzhitov R. Recognition of microorganisms and activation of the immune response.Nature. 2007; 449: 819-826Crossref PubMed Scopus (825) Google Scholar). In mammals, Toll-like receptors (TLRs) are the best characterized examples (Takeda et al., 2003Takeda K. Kaisho T. Akira S. Toll-like receptors.Annu. Rev. Immunol. 2003; 21: 335-376Crossref PubMed Scopus (3200) Google Scholar, Beutler, 2004Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling.Nature. 2004; 430: 257-263Crossref PubMed Scopus (827) Google Scholar). In addition, nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) (Inohara et al., 2005Inohara Chamaillard McDonald C. Nunez G. NOD-LRR proteins: Role in host-microbial interactions and inflammatory disease.Annu. Rev. Biochem. 2005; 74: 355-383Crossref PubMed Scopus (544) Google Scholar, Fritz et al., 2006Fritz J.H. Ferrero R.L. Philpott D.J. Girardin S.E. Nod-like proteins in immunity, inflammation and disease.Nat. Immunol. 2006; 7: 1250-1257Crossref PubMed Scopus (426) Google Scholar, Martinon and Tschopp, 2007Martinon F. Tschopp J. Inflammatory caspases and inflammasomes: Master switches of inflammation.Cell Death Differ. 2007; 14: 10-22Crossref PubMed Scopus (333) Google Scholar), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) (Yoneyama et al., 2007Yoneyama M. Onomoto K. Fujita T. Cytoplasmic recognition of RNA.Adv. Drug Deliv. Rev. 2007; 60: 841-846Crossref PubMed Scopus (35) Google Scholar), and some C-type lectin receptors (CLRs) (Geijtenbeek et al., 2004Geijtenbeek T.B. van Vliet S.J. Engering A. 't Hart B.A. van Kooyk Y. Self- and nonself-recognition by C-type lectins on dendritic cells.Annu. Rev. Immunol. 2004; 22: 33-54Crossref PubMed Scopus (274) Google Scholar, Robinson et al., 2006Robinson M.J. Sancho D. Slack E.C. LeibundGut-Landmann S. Reis e Sousa C. Myeloid C-type lectins in innate immunity.Nat. Immunol. 2006; 7: 1258-1265Crossref PubMed Scopus (243) Google Scholar, Willment and Brown, 2008Willment J.A. Brown G.D. C-type lectin receptors in antifungal immunity.Trends Microbiol. 2008; 16: 27-32Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar) recognize specific components of microbes and are therefore included among the innate immune receptors (Figure 1). The innate immune receptors are widely distributed in or on a variety of cell types and can detect a wide range of ligands derived from either pathogenic or nonpathogenic microbial infections. In particular, TLRs are localized at the plasma membrane and can sense microbial products such as bacterial cell wall components or viral proteins at the level of the cell surface or microbial nucleic acids exposed within “vesicular” compartments such as endosomes and/or phagosomes. On the other hand, RLRs and NLRs reside in the cytoplasm, probably in the cytosol, and serve as sensors for intracellular microbial invasion. Interestingly, ligands for RLRs and NLRs are often shared with TLRs (Table 1), although the molecular bases of their receptor-ligand interactions and outcomes are quite different. Although CLRs comprise a large family of proteins containing one or more C-type lectin domains with quite diverse functions, some of them are directly involved in innate immune recognition of microbial products for the innate immune system (reviewed in Geijtenbeek et al., 2004Geijtenbeek T.B. van Vliet S.J. Engering A. 't Hart B.A. van Kooyk Y. Self- and nonself-recognition by C-type lectins on dendritic cells.Annu. Rev. Immunol. 2004; 22: 33-54Crossref PubMed Scopus (274) Google Scholar, Robinson et al., 2006Robinson M.J. Sancho D. Slack E.C. LeibundGut-Landmann S. Reis e Sousa C. Myeloid C-type lectins in innate immunity.Nat. Immunol. 2006; 7: 1258-1265Crossref PubMed Scopus (243) Google Scholar, Willment and Brown, 2008Willment J.A. Brown G.D. C-type lectin receptors in antifungal immunity.Trends Microbiol. 2008; 16: 27-32Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). As more evidence accumulates, we continue to learn that receptor-mediated recognition of microbes can cooperate at the level of ligand recognition and the intracellular and intercellular signaling pathways (Table 1). Here, we review recent progress in research on host-microbe interactions through the relatively simplified, yet manifold, recognition machinery of host innate immune receptors.Table 1Host Innate Immune Receptors of Microbial SignaturesMicrobial SignatureTLRs (Transmembrane)RLRs (Cytoplasm)NLRs (Cytoplasm)CLRs (Membrane-Bound)Virusesstructural proteins (i.e., capsid, envelope proteins)TLR2, TLR4N.D.N.D.N.D.DNATLR9DAI?NALP3? (through ASC)FcγRRNATLR3, TLR7, TLR8RIG-I, MDA5, LGP2NALP3FcγRBacteriacell wall components (LPS, peptidoglycan, lipoteichoic acid, lipoproteins)TLR2/1, TLR2/6, TLR4N.D.NOD1, NOD2, NALP1, NALP3collectins (MBL)flagellinTLR5N.D.IPAF, NAIP5N.D.perotoxinsN.D.N.D.NALP3N.D.DNATLR9N.D.ASCN.D.RNAN.D.N.D.NALP3N.D.Protozoan parasitesGPIsTLR2, TLR4N.D.N.D.N.D.malarial hemozoinTLR9N.D.N.D.N.D.proteins (T. cruzi Tc52, profilin)TLR2, TLR11N.D.N.D.N.D.DNATLR9N.D.N.D.N.D.HelminthslipidsTLR2N.D.N.D.N.D.RNATLR3N.D.N.D.N.D.FungiCell wall components (i.e., GlcNAc, mannan, β-glucan)TLR2, TLR4, TLR6N.D.N.D.mannose receptor, DC-SIGN, Dectin 1 and 2, CARD9DNATLR9N.D.N.D.N.D.There are specific and shared microbial signatures, such as bacterial cell wall components and nucleic acids, respectively, most (if not all) of which are recognized by host innate immune receptors categorized into TLRs, NLRs, RLRs, and CLRs. N.D., not determined. FcγR, Fc receptors for IgG. GlcNAc, N-acetylglucosamine. Open table in a new tab There are specific and shared microbial signatures, such as bacterial cell wall components and nucleic acids, respectively, most (if not all) of which are recognized by host innate immune receptors categorized into TLRs, NLRs, RLRs, and CLRs. N.D., not determined. FcγR, Fc receptors for IgG. GlcNAc, N-acetylglucosamine. Toll in Drosophila melanogaster was initially discovered as an essential receptor for embryonic patterning and was subsequently identified as a critical component of host defense against fungal and Gram-positive bacterial infections (reviewed in Leulier and Lemaitre, 2008Leulier F. Lemaitre B. Toll-like receptors—Taking an evolutionary approach.Nat. Rev. Genet. 2008; 9: 165-178Crossref PubMed Scopus (150) Google Scholar). Since then, its mammalian homologs, designated TLRs, have been identified and functionally characterized as critical components of the innate immune system (Takeda et al., 2003Takeda K. Kaisho T. Akira S. Toll-like receptors.Annu. Rev. Immunol. 2003; 21: 335-376Crossref PubMed Scopus (3200) Google Scholar, Beutler, 2004Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling.Nature. 2004; 430: 257-263Crossref PubMed Scopus (827) Google Scholar). TLRs are type I transmembrane proteins characterized by an ectodomain that contains varying numbers of leucine-rich-repeat (LRR) motifs and a cytoplasmic signaling domain homologous to that of the interleukin 1 receptor (IL-1R), termed the Toll/IL-1R homology (TIR) domain (Figure 2A). Mammalian TLRs consist of at least 11 members that recognize not only microbial-specific elements, including proteins, lipids, and nucleic acids derived from viruses, bacteria, parasites, and fungi, but also damaged host cell components, such as nucleic acids (Table 1). The issues of why and how TLRs recognize such a diverse range of microbial ligands, which are structurally and biochemically distinct, have been enigmatic. Recently, crystal structural analyses of the ectodomains of some TLRs have revealed their shape and how they bind to their cognate ligands. TLR3 (Choe et al., 2005Choe J. Kelker M.S. Wilson I.A. Crystal structure of human toll-like receptor 3 (TLR3) ectodomain.Science. 2005; 309: 581-585Crossref PubMed Scopus (306) Google Scholar, Bell et al., 2006Bell J.K. Botos I. Hall P.R. Askins J. Shiloach J. Davies D.R. Segal D.M. The molecular structure of the TLR3 extracellular domain.J. Endotoxin Res. 2006; 12: 375-378Crossref PubMed Scopus (17) Google Scholar), TLR4, and a heterodimer of TLR2 and TLR1 (Kim et al., 2007Kim H.M. Park B.S. Kim J.I. Kim S.E. Lee J. Oh S.C. Enkhbayar P. Matsushima N. Lee H. Yoo O.J. Lee J.O. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.Cell. 2007; 130: 906-917Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar, Ohto et al., 2007Ohto U. Fukase K. Miyake K. Satow Y. Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa.Science. 2007; 316: 1632-1634Crossref PubMed Scopus (186) Google Scholar, Jin et al., 2007Jin M.S. Kim S.E. Heo J.Y. Lee M.E. Kim H.M. Paik S.G. Lee H. Lee J.O. Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide.Cell. 2007; 130: 1071-1082Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar) were confirmed to have horseshoe-like solenoid shapes consisting of 18 to 25 tandem copies of LRR motifs with 20 to 30 characteristically spaced hydrophobic amino acid residues (Figure 2A). These LRR motifs are responsible for both receptor dimerization and ligand recognition. In fact, direct binding of TLR2-TLR1 complexes, TLR3, TLR5, and TLR9 to their cognate ligands has been demonstrated, whereas TLR4 binds lipopolysaccharide (LPS) through an associated molecule (MD-2) (Jin et al., 2007Jin M.S. Kim S.E. Heo J.Y. Lee M.E. Kim H.M. Paik S.G. Lee H. Lee J.O. Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide.Cell. 2007; 130: 1071-1082Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar, Leonard et al., 2008Leonard J.N. Ghirlando R. Askins J. Bell J.K. Margulies D.H. Davies D.R. Segal D.M. The TLR3 signaling complex forms by cooperative receptor dimerization.Proc. Natl. Acad. Sci. USA. 2008; 105: 258-263Crossref PubMed Scopus (80) Google Scholar, Andersen-Nissen et al., 2007Andersen-Nissen E. Smith K.D. Bonneau R. Strong R.K. Aderem A. A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin.J. Exp. Med. 2007; 204: 393-403Crossref PubMed Scopus (71) Google Scholar, Haas et al., 2008Haas T. Metzger J. Schmitz F. Heit A. Muller T. Latz E. Wagner H. The DNA sugar backbone 2′ deoxyribose determines Toll-like receptor 9 activation.Immunity. 2008; 28: 315-323Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, Ohto et al., 2007Ohto U. Fukase K. Miyake K. Satow Y. Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa.Science. 2007; 316: 1632-1634Crossref PubMed Scopus (186) Google Scholar). Direct binding between TLRs and their cognate ligands is essential, but not sufficient for sequential activation. Although TLRs form homodimers or heterodimers before ligand stimulation (Triantafilou et al., 2006Triantafilou M. Gamper F.G. Haston R.M. Mouratis M.A. Morath S. Hartung T. Triantafilou K. Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting.J. Biol. Chem. 2006; 281: 31002-31011Crossref PubMed Scopus (187) Google Scholar), further structural modifications of these TLR dimers seem to be necessary for their activation of downstream signaling via the TIR domains (Gay et al., 2006Gay N.J. Gangloff M. Weber A.N. Toll-like receptors as molecular switches.Nat. Rev. Immunol. 2006; 6: 693-698Crossref PubMed Scopus (100) Google Scholar) (Figure 2B). Direct binding of triacylated lipopeptides to the C termini close to the ectodomain of the TLR2-TLR1 heterodimer appears to induce rearrangement of the preformed and weakly bound dimer to a much more rigid and stabilized structure (Jin et al., 2007Jin M.S. Kim S.E. Heo J.Y. Lee M.E. Kim H.M. Paik S.G. Lee H. Lee J.O. Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide.Cell. 2007; 130: 1071-1082Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar), which seems to be critical for optimal interactions between the cytoplasmic TIR domains and adaptor proteins, such as myeloid differentiation primary response protein 88 (MyD88). In the case of TLR9, which can bind to single-stranded (ss) DNA containing either agonistic CpG motifs or antagonistic G-rich “inhibitory” sequences (forming a G-tetrad structure), only the agonistic CpG sequence confers conformational changes in the TLR9 ectodomain that brings the two cytoplasmic TIR domains together in the dimer (Latz et al., 2007Latz E. Verma A. Visintin A. Gong M. Sirois C.M. Klein D.C. Monks B.G. McKnight C.J. Lamphier M.S. Duprex W.P. et al.Ligand-induced conformational changes allosterically activate Toll-like receptor 9.Nat. Immunol. 2007; 8: 772-779Crossref PubMed Scopus (204) Google Scholar) (Figure 2B). In this regard, a recent report demonstrated that the sugar-backbone 2′-deoxyribose of DNA binds to TLR9 and is sufficient as a ligand to act as a “mild agonist,” and that this agonistic activity is further enhanced by the presence of a CpG motif (Haas et al., 2008Haas T. Metzger J. Schmitz F. Heit A. Muller T. Latz E. Wagner H. The DNA sugar backbone 2′ deoxyribose determines Toll-like receptor 9 activation.Immunity. 2008; 28: 315-323Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). Notably, a phosphorothioate-modified DNA backbone (resistant to deoxyribonuclease [DNase]), on which most studies of TLR9 have been based, actually acts as an antagonist unless the base contains CpG motifs (Haas et al., 2008Haas T. Metzger J. Schmitz F. Heit A. Muller T. Latz E. Wagner H. The DNA sugar backbone 2′ deoxyribose determines Toll-like receptor 9 activation.Immunity. 2008; 28: 315-323Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). As more pieces of evidence continue to accumulate, more questions are being raised, such as why and how agonists, but not antagonists, induce conformational changes of TLRs and how the LRR motifs of each TLR confer ligand-specificity and/or flexibility. Clarification of these issues will be of considerable interest, since the LRR motifs can interact with a variety of ligands such as proteins, lipids, carbohydrates, and nucleic acids. Direct recognition of the ligands by TLRs, as described above, were demonstrated; however, there seem to be many other steps in which the host innate immune system distinguishes microbes as nonself and host cells as safe self. In fact, microbial infections change the microenvironments of infected sites in the body, including tissue damage. In such cases, recognition of ligands by the LRR motifs of TLRs can be influenced by many cofactors, which play important roles in regulating TLR-mediated innate immune responses to microbes, or in some cases, to host self-components. In particular, TLR7/8 and TLR9 recognize not only microbial nucleic acids but also host RNA and DNA, and additional factors can skew TLR recognition of microbial versus host nucleic acids (Marshak-Rothstein and Rifkin, 2007Marshak-Rothstein A. Rifkin I.R. Immunologically active autoantigens: The role of toll-like receptors in the development of chronic inflammatory disease.Annu. Rev. Immunol. 2007; 25: 419-441Crossref PubMed Scopus (186) Google Scholar). For example, host DNA can form a complex with anti-DNA or anti-nuclear (chromatin) antibodies in the case of systemic autoimmune diseases such as systemic lupus erythematosus, with HMGB1, a nuclear DNA-binding protein released from necrotic cells during tissue damage (Tian et al., 2007Tian J. Avalos A.M. Mao S.Y. Chen B. Senthil K. Wu H. Parroche P. Drabic S. Golenbock D. Sirois C. et al.Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE.Nat. Immunol. 2007; 8: 487-496Crossref PubMed Scopus (541) Google Scholar), or with the antimicrobial peptide cathelicidin, also known as LL37 (Lande et al., 2007Lande R. Gregorio J. Facchinetti V. Chatterjee B. Wang Y.H. Homey B. Cao W. Wang Y.H. Su B. Nestle F.O. et al.Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.Nature. 2007; 449: 564-569Crossref PubMed Scopus (573) Google Scholar). All of these complex formations can stabilize DNA to protect it against degradation and facilitate its uptake by immune cells, thereby turning host self-DNA, which is generally inert, into a potent TLR9 agonist (Figure 3). As a result, host DNA can trigger, or at least modify, autoimmune responses through increased type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) and/or polyclonal activation of autoreactive B cells. Recently, cathepsins, which are lysosomal cysteine proteases, were reported to be other factors required for TLR9 responses (Asagiri et al., 2008Asagiri M. Hirai T. Kunigami T. Kamano S. Gober H.J. Okamoto K. Nishikawa K. Latz E. Golenbock D.T. Aoki K. et al.Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis.Science. 2008; 319: 624-627Crossref PubMed Scopus (136) Google Scholar, Matsumoto et al., 2008Matsumoto F. Saitoh S. Fukui R. Kobayashi T. Tanimura N. Konno K. Kusumoto Y. Akashi-Takamura S. Miyake K. Cathepsins are required for Toll-like receptor 9 responses.Biochem. Biophys. Res. Commun. 2008; 367: 693-699Crossref PubMed Scopus (68) Google Scholar). Although the precise mechanisms remain to be fully clarified, the data obtained suggest that the proteolytic activities of these enzymes play roles in TLR9-DNA recognition. Thus, the agonistic, inert, or antagonistic activities of TLR-ligand interactions do not seem to be determined by the origins of the ligands, which are rather controlled by the immunological milieu of the tissue microenvironment and may instead depend on a variety of factors including the type, magnitude, and duration of the infection as well as damage to the host tissues and cells. As described above, the cytoplasmic TIR domains of TLRs represent a platform for downstream signaling (Figure 1), which involves recruitment and interactions with TIR domain-containing adapters, including MyD88, TIR domain-containing adaptor (TIRAP, also known as MAL), TIR domain-containing adaptor inducing IFN-β (TRIF, also known as TICAM1), TRIF-related adaptor molecule (TRAM, also known as TICAM2), and sterile alpha and HEAT-Armadillo motifs (SARM) (O'Neill and Bowie, 2007O'Neill L.A. Bowie A.G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling.Nat. Rev. Immunol. 2007; 7: 353-364Crossref PubMed Scopus (951) Google Scholar). While all TLRs activate nuclear factor-kappaB (NF-κB) through MyD88- or TRIF-dependent pathways (TLR3) or both pathways (TLR4) for the production of proinflammatory cytokines, type I IFN (IFN-α, β) inductions are differentially regulated, since TLR4 and TLR3 activate interferon regulatory factor 3 (IRF3) through TRIF, while TLR7 and TLR9 activate IRF7 through MyD88 (Figure 4). Recent studies have revealed new roles for TIRAP and TRAM, in which they function as sorting adaptors for the recruitment of MyD88 to TLR4 on the cell surface and TRIF to endosomal TLR4, respectively, via unique mechanisms, and these roles can explain their distinct signaling cascades in spatial and temporal manners (Kagan and Medzhitov, 2006Kagan J.C. Medzhitov R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling.Cell. 2006; 125: 943-955Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar, Kagan et al., 2008Kagan J.C. Su T. Horng T. Chow A. Akira S. Medzhitov R. TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta.Nat. Immunol. 2008; 9: 361-368Crossref PubMed Scopus (374) Google Scholar) (Figure 4A). Moreover, TIRAP was shown to possess another function, involving its cleavage by caspase-1. Specifically, caspase-1 is required for the ability of TIRAP to activate NF-κB, whereas TIRAP is not required for caspase-1 activation, suggesting intracellular crosstalk between TLR signaling and caspase-1, while its physiological role remains to be confirmed in vivo (Miggin et al., 2007Miggin S.M. Palsson-McDermott E. Dunne A. Jefferies C. Pinteaux E. Banahan K. Murphy C. Moynagh P. Yamamoto M. Akira S. et al.NF-kappaB activation by the Toll-IL-1 receptor domain protein MyD88 adapter-like is regulated by caspase-1.Proc. Natl. Acad. Sci. USA. 2007; 104: 3372-3377Crossref PubMed Scopus (64) Google Scholar). SARM inhibited the TRIF-dependent pathway in human cell lines (Carty et al., 2006Carty M. Goodbody R. Schroder M. Stack J. Moynagh P.N. Bowie A.G. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling.Nat. Immunol. 2006; 7: 1074-1081Crossref PubMed Scopus (211) Google Scholar), and its physiological relevance also remains to be determined. All of these newly revealed functions of TLR adaptor molecules not only suggest the importance of the location in which the initial signal occurs, but also imply their potential interactions with other innate immune signaling and/or membrane sorting machineries. Distinct from TLRs on the cell surface such as TLR1, TLR2, TLR4, TLR5, TLR6, and probably TLR10 and TLR11, TLRs that recognize nucleic acids such as TLR3, TLR7, TLR8, and TLR9 are not on the cell surface, but rather found in the endoplasmic reticulum (ER). These nucleic acid-sensing TLRs are thus delivered to subcellular location (Figures 3 and 4B). In this regard, the recently identified ER protein UNC93B1 found by a forward genetic approach (Tabeta et al., 2004Tabeta K. Georgel P. Janssen E. Du X. Hoebe K. Crozat K. Mudd S. Shamel L. Sovath S. Goode J. et al.Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection.Proc. Natl. Acad. Sci. USA. 2004; 101: 3516-3521Crossref PubMed Scopus (553) Google Scholar) turns out to be associated with TLR3, TLR7, TLR9, and TLR13 (Brinkmann et al., 2007Brinkmann M.M. Spooner E. Hoebe K. Beutler B. Ploegh H.L. Kim Y.M. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling.J. Cell Biol. 2007; 177: 265-275Crossref PubMed Scopus (202) Google Scholar) and essential for trafficking of TLR7 and TLR9 from the ER to the endosome, whereby their ligands are delivered from the outside of cells (Kim et al., 2008bKim Y.M. Brinkmann M.M. Paquet M.E. Ploegh H.L. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes.Nature. 2008; 452: 234-238Crossref PubMed Scopus (244) Google Scholar). UNC93B1 was also found to be physiologically relevant to herpes encephalitis, a rare complication of infection with herpes simplex virus (HSV), in which TLR3 plays preventive roles (Casrouge et al., 2006Casrouge A. Zhang S.Y. Eidenschenk C. Jouanguy E. Puel A. Yang K. Alcais A. Picard C. Mahfoufi N. Nicolas N. et al.Herpes simplex virus encephalitis in human UNC-93B deficiency.Science. 2006; 314: 308-312Crossref PubMed Scopus (319) Google Scholar, Zhang et al., 2007Zhang S.Y. Jouanguy E. Ugolini S. Smahi A. Elain G. Romero P. Segal D. Sancho-Shimizu V. Lorenzo L. Puel A. et al.TLR3 deficiency in patients with herpes simplex encephalitis.Science. 2007; 317: 1522-1527Crossref PubMed Scopus (393) Google Scholar). It is therefore conceivable that TLR-mediated recognition of microbial nucleic acid ligands through endosomal pathways is a “safety mechanism” by which ER-retained TLRs must be delivered to endosomes to meet their ligands, although the trigger for this TLR trafficking from the ER to endosomes before TLR-mediated recognition of and activation by nucleic acids remains to be elucidated. While TLR trafficking from the ER or cell surface via endosomes to the lysosome may be constitutive in cells under steady-state conditions, recent evidence has emerged from another biological process for membrane trafficking known as autophagy. Autophagy is a cellular process for recycling cytoplasmic constituents and is often linked to cell death, but can be used for detecting and/or clearing invading microbes in the cytosol, referred to as xenophagy (Levine, 2005Levine B. Eating oneself and uninvited guests: Autophagy-related pathways in cellular defense.Cell. 2005; 120: 159-162PubMed Google Scholar). While many biological stressors, including TLR ligands, can induce autophagy directly and indirectly (Xu et al., 2007Xu Y. Jagannath C. Liu X.D. Sharafkhaneh A. Kolodziejska K.E. Eissa N.T. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity.Immunity. 2007; 27: 135-144Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar, Delgado et al., 2008Delgado M.A. Elmaoued R.A. Davis A.S. Kyei G. Deretic V. Toll-like receptors control autophagy.EMBO J. 2008; 27: 1110-1121Crossref PubMed Scopus (276) Google Scholar), it is unclear whether autophagy itself plays a role in recruiting TLR-membrane trafficking, and its physiological relevance to host defense is therefore being actively investigated. A recent report suggested that pDCs may utilize this pathway of TLR sorting of their ligands. Recognition of cytoplasmic RNA by TLR7 during viral replication requires autophagy-related proteins, such as ATG5 and ATG7 (Lee et al., 2007Lee H.K. Lund J.M. Ramanathan B. Mizushima N. Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells.Science. 2007; 315: 1398-1401Crossref PubMed Scopus (385) Google Scholar), suggesting that viral RNAs in the cytosol are trapped by autophagosomes and carried to the lysosome where TLR7 is activated (Figure 4B). The noncanonical roles of ATG5 and ATG7 in antiviral responses, however, are opposite in the case of viral infection of nonimmune cells. ATG5 and ATG7 are in fact negative regulators of type I IFN responses through direct interactions with the caspase recruitment domains (CARDs) presented by RIG-I and IFN-β promoter stimulator 1 (IPS-1) (Jounai et al., 2007Jounai N. Takeshita F. Kobiyama K. Sawano A. Miyawaki A. Xin K.Q. Ishii K.J. Kawai T. Akira S. Suzuki K. Okuda K. The Atg5 Atg12 conjugate associates with innate antiviral immune responses.Proc. Natl. Acad. Sci. USA. 2007; 104: 14050-14055Crossref PubMed Scopus (197) Google Scholar) (Figure 4B). The physiological relevance of these autophagy-related proteins is of considerable interest, not only to TLR-membrane trafficking, but also to immunological outcomes in vivo. Proteins of interest include the other ATG protein family members and LC3, a frequently used specific marker for autophagosomes. However, a more careful interpretation seems to be required for discrimin" @default.
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• W2020996714 date "2008-06-01" @default.
• W2020996714 modified "2023-10-16" @default.
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