Pattern-Recognition Receptors.PDF

See online version for legend,abbreviations,and references.1024 Cell 129,June 1,2007 2007 Elsevier Inc.DOI 10.1016/j.cell.2007.05.017 SnapShot:Pattern-Recognition ReceptorsTaro Kawai and Shizuo AkiraResearch Institute for Microbial Diseases,Osaka University,Osaka,JapanSnapShot:Pattern-Recognition ReceptorsTaro Kawai and Shizuo AkiraResearch Institute for Microbial Diseases,Osaka University,Osaka,Japan1024.e1 Cell 129,June 1,2007 2007 Elsevier Inc.DOI 10.1016/j.cell.2007.05.017(A)Toll-like receptor signaling.Toll-like receptor(TLR)3 recognizes polyinosinic-polycytidylic acid(poly IC),whereas TLR4 recognizes lipopolysaccharide(LPS).TLR2 recog-nizes various components such as lipoprotein and peptidoglycan(PGN).TLR5 detects flagellin.TLR7 and TLR9 detect single-stranded(ss)RNA and CpG DNA,respectively.Each TLR recruits a distinct set of Toll/interleukin-1 receptor(TIR)domain-containing adaptor molecules such as myeloid differentiation primary response gene 88(MyD88),TIR-containing adaptor protein(TIRAP,also known as MAL),TIR-containing adaptor-inducing IFN(TRIF,also known as TICAM1)and TRIF-related adaptor molecule(TRAM,also known as TICAM2).TLR3 uses TRIF,and TLR5,7,and 9 use MyD88.TLR2 uses MyD88 and TIRAP,and TLR4 uses MyD88,TIRAP,TRIF,and TRAM.MyD88 binds to inter-leukin-1 receptor-associated kinase 4(IRAK4)and TRAF6.TRIF binds receptor-interacting protein 1(RIP1)and TRAF6.TRAF6 forms a complex with Ubc13,Uev1A,and ECSIT(evolutionarily conserved signaling intermediate in Toll/IL-1R pathways)to activate a complex containing transforming growth factor-activated kinase 1(TAK1),TAK1-binding protein 1(TAB1),TAB2,and TAB3.TAK1 activates IB kinase(IKK)complex consisting of IKK,IKK,and Nemo(also known as IKK),which results in the phosphorylation and proteasomal degradation of IB proteins and the release of a transcription factor NFB to the nucleus to regulate expression of inflammatory cytokines such as interleukin-6(IL-6)and tumor necrosis factor (TNF).TAK1 simultaneously activates the MAPK(JNK,p38,and ERK)pathway,leading to activation of AP-1 that controls expression of inflammatory cytokines.TRIF recruits TRAF3,which interacts with IKK-related kinases,TANK-binding kinase 1(TBK1,also known as T2K and NAK),and IKKi(also known as IKK).These kinases,together with adaptors TANK and NAP1,catalyze the phosphorylation of IRF3.Phosphorylated IRF3 forms a dimer,translocates into the nuclei,binds to DNA,and regulates the expression of interferon (IFN)in collaboration with AP-1 and NFB.IRF3 is also activated by phosphatidylinositol 3 kinase(PI3K),which interacts with TLR3.In TLR2,4,5,7,and 9 signaling,IRF5 is recruited to the MyD88-IRAK4-TRAF6 complex,then translocates into the nuclei to control the induction of inflammatory cytokines.In TLR7 and 9 signaling,a signaling complex consisting of TRAF3,osteopontin(OPN),IRAK1,IKK,and IRF7 is recruited to the MyD88-IRAK4-TRAF6 complex.IRF7 is phosphorylated by IRAK1 and IKK,forms a dimer,and translocates into the nuclei to express IFN and IFN genes.IRF1 is also recruited to the MyD88-IRAK4-TRAF6 complex and participates in TLR7-and 9-mediated production of IL-12 p35,inducible nitric oxide synthase(iNOS),and IFN.Unc93B,a twelve-pass membrane protein local-ized to the endoplasmic reticulum(ER),is required for the activation of signaling pathways triggered by TLR3,7,and 9.(B)RIG-I like RNA helicase signaling.After recognition of viral RNA,retinoic acid-inducible gene-I(RIG-I)and Mda5 recruit IFN promoter stimulator-1(IPS-1,also known as MAVS,Cardif,and VISA)via CARD-CARD(caspase recruitment domain)interaction.IPS-1 is localized to mitochondria and acts as an adaptor that links RIG-I-like RNA helicase(RLH)and the TRAF3 complex,which subsequently activates IRF3 and IRF7 in a TBK1-and IKKi-dependent manner.IPS-1 also interacts with the Fas-associated death domain protein(FADD),which is required for the activation of IRF3 and NFB.FADD interacts with and activates caspase-10(Casp-10)and Casp-8,driving NFB activation.(C)NOD-like receptor signaling.Nucleotide-binding oligomerization domain 1(NOD1,also known as CARD4)and NOD2(also known as CARD15)detect PGN-derived molecules diaminopimelic acid(DAP)and muramyl dipeptide(MDP),respectively,and recruit RIP2(also known as RICK or CARDIAK)to activate NFB.NOD2 also recruits CARD9 to facilitate the MAPK pathway.MDP is also detected by NACHT-LRR-PYD-containing protein 3(NALP3,also known as cryopyrin or PYPAF1),which forms an inflammasome along with ASC(apoptosis-associated speck-like protein containing a CARD)and Casp-1,inducing the processing of pro-IL-1 and pro-IL-18 that results in the release of IL-1 and IL-18,respectively.Bacterial RNA,toxin,monosodium urate crystal(MSU),ATP,or infection with Listeria or Staphylococcus trig-gers IL-1 and IL-18 releases via the NALP3 inflammsome.Detection of flagellin released into cytosol following Legionella infection is dependent on IL-1-converting enzyme protease-activating factor(IPAF,also known as CLAN or CARD12)and neuronal apoptosis inhibitor protein 5(NAIP5,also known as Birc1e).IPAF also partici-pates in the recognition of Salmonella.IPAF and NAIP5 trigger Casp-1 activation as well as cell death.NALP1b-mediated Casp-1 activation is linked to susceptibility of mouse macrophages to lethal toxin of Bacillus anthracis.(D)Lectin signaling.C-type lectin Dectin-1 binds to-glucan found in fungal cell wall components to activate tyrosine kinase Syk,which leads to the activation of CARD9.Activated CARD9 forms a complex with Bcl-10 and MALT1 to activate NFB.(E)Unknown pathway.Double-stranded(ds)DNA released by DNA viruses,bacteria,and damaged host cells trigger induction of IFN via TBK1/IKKi-dependent mechanisms.(F)Negative regulators.An E3 ubiquitin ligase Triad3A downregulates TLR expression,and members the of IL-1 receptor family,SIGIRR and ST2L,and a leucine-rich repeat(LRR)-containing cell-surface molecule RP105 inhibit TLR signaling(1).The function of MyD88 is blocked by a short form of MyD88 termed MyD88s(2),and the function of TRIF is suppressed by a TIR-domain-containing protein SARM and tyrosine phosphatase SHP2(3).Suppressor of cytokine signaling 1(SOCS1)mediates TIRAP degradation(4).Activation of IRAK4 is inhibited by IRAK-M,splicing variants of IRAK1(IRAK1c)and IRAK2(IRAK2c,IRAK2d),and Toll-interacting protein(Tollip)(5).Oligomerization and ubiquitination of TRAF6 are suppressed by-arrestin and A20,respectively(6).IRF4 prevents a recruitment of IRF5 to the receptor complex(7)and PI3K negatively regulates the MAPK pathway(8).PIN1 mediates degradation of IRF3 to terminate type I IFN responses(9),and ATF3 and the nuclear hormone receptors such as PPAR and glucocorticoid receptor(GR)suppress expression of NFB target genes(10).Casp-1 activation is negatively regulated by Pyrin and CARD-containing proteins such as Casp-12,CARD only protein(COP,also known as Pseudo-ICE),ICEBERG,and inhibitory CARD(INCA)(11).AbbreviationsIRF,interferon regulatory factorMAL,MyD88-adaptor-likeMAVS,mitochondrial antiviral signalingPYD,pyrin domainPYPAF1,Pyrin-containing Apaf-1-like protein 1RICK,RIP-like interacting caspase-like apoptosis-regulatory protein kinaseTANK,TRAF family member-associated NFB activatorRefeRencesAkira,S.,Uematsu,S.,and Takeuchi,O.(2006).Pathogen recognition and innate immunity.Cell 124,783801.Fritz,J.H.,Ferrero,R.L.,Philpott,D.J.,and Girardin,S.E.(2006).Nod-like proteins in immunity,inflammation and disease.Nat.Immunol.7,12501257.Honda,K.,Takaoka,A.,and Taniguchi,T.(2006).Type I interferon gene induction by the interferon regulatory factor family of transcription factors.Immunity 25,349360.Ishii,K.J.,and Akira,S.(2006).Innate immune recognition of,and regulation by,DNA.Trends Immunol.27,525532.Kawai,T.,and Akira,S.(2006).Innate immune recognition of viral infection.Nat.Immunol.7,131137.Mariathasan,S.,and Monack,D.M.(2007).Inflammasome adaptors and sensors:Intracellular regulators of infection and 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