Innate immune pattern recognition: a cell biological perspective.

Receptors of the innate immune system detect conserved determinants of microbial and viral origin. Activation of these receptors initiates signaling events that culminate in an effective immune response. Recently, the view that innate immune signaling events rely on and operate within a complex cellular infrastructure has become an important framework for understanding the regulation of innate immunity. Compartmentalization within this infrastructure provides the cell with the ability to assign spatial information to microbial detection and regulate immune responses. Several cell biological processes play a role in the regulation of innate signaling responses; at the same time, innate signaling can engage cellular processes as a form of defense or to promote immunological memory. In this review, we highlight these aspects of cell biology in pattern-recognition receptor signaling by focusing on signals that originate from the cell surface, from endosomal compartments, and from within the cytosol.

[1]  P. Cossart,et al.  Diverse intracellular pathogens activate Type III Interferon expression from peroxisomes , 2014, Nature Immunology.

[2]  Vishva M. Dixit,et al.  Mechanisms and Functions of Inflammasomes , 2014, Cell.

[3]  J. Bertin,et al.  The immune receptor NOD1 and kinase RIP2 interact with bacterial peptidoglycan on early endosomes to promote autophagy and inflammatory signaling. , 2014, Cell host & microbe.

[4]  K. Miyake,et al.  UNC93B1 is essential for the plasma membrane localization and signaling of Toll-like receptor 5 , 2014, Proceedings of the National Academy of Sciences.

[5]  Zhaoshi Jiang,et al.  Endosomes are specialized platforms for bacterial sensing and NOD2 signalling , 2014, Nature.

[6]  Chen Wang,et al.  MAVS-MKK7-JNK2 Defines a Novel Apoptotic Signaling Pathway during Viral Infection , 2014, PLoS pathogens.

[7]  D. Schadendorf,et al.  Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma , 2014, Nature.

[8]  K. Debatin,et al.  Mitophagy Enhances Oncolytic Measles Virus Replication by Mitigating DDX58/RIG-I-Like Receptor Signaling , 2014, Journal of Virology.

[9]  D. Underhill,et al.  Cutting Edge: FYCO1 Recruitment to Dectin-1 Phagosomes Is Accelerated by Light Chain 3 Protein and Regulates Phagosome Maturation and Reactive Oxygen Production , 2014, The Journal of Immunology.

[10]  Nicholas T. Ingolia,et al.  A Bicistronic MAVS Transcript Highlights a Class of Truncated Variants in Antiviral Immunity , 2014, Cell.

[11]  A. Iwasaki,et al.  A Promiscuous Lipid-Binding Protein Diversifies the Subcellular Sites of Toll-like Receptor Signal Transduction , 2014, Cell.

[12]  Christoph Borner,et al.  A Novel Mitochondrial MAVS/Caspase-8 Platform Links RNA Virus–Induced Innate Antiviral Signaling to Bax/Bak-Independent Apoptosis , 2014, The Journal of Immunology.

[13]  N. Krogan,et al.  IFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV , 2014, Science.

[14]  P. Taylor,et al.  Integrin CD11b positively regulates TLR4-induced signalling pathways in dendritic cells but not in macrophages , 2014, Nature Communications.

[15]  Gordon D. Brown,et al.  Signalling C‐Type lectin receptors, microbial recognition and immunity , 2014, Cellular microbiology.

[16]  N. Gay,et al.  An Alanine-to-Proline Mutation in the BB-Loop of TLR3 Toll/IL-1R Domain Switches Signalling Adaptor Specificity from TRIF to MyD88 , 2013, The Journal of Immunology.

[17]  J. Tavernier,et al.  The Small GTPase Arf6 Is Essential for the Tram/Trif Pathway in TLR4 Signaling* , 2013, The Journal of Biological Chemistry.

[18]  E. Pearlman,et al.  CD14 Mediates Toll-like Receptor 4 (TLR4) Endocytosis and Spleen Tyrosine Kinase (Syk) and Interferon Regulatory Transcription Factor 3 (IRF3) Activation in Epithelial Cells and Impairs Neutrophil Infiltration and Pseudomonas aeruginosa Killing in Vivo* , 2013, The Journal of Biological Chemistry.

[19]  D. Standley,et al.  Structures and interface mapping of the TIR domain-containing adaptor molecules involved in interferon signaling , 2013, Proceedings of the National Academy of Sciences.

[20]  E. Sundberg,et al.  Recruitment of TLR adapter TRIF to TLR4 signaling complex is mediated by the second helical region of TRIF TIR domain , 2013, Proceedings of the National Academy of Sciences.

[21]  Leonie Unterholzner The interferon response to intracellular DNA: why so many receptors? , 2013, Immunobiology.

[22]  Bihui Huang,et al.  Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals , 2013, Science.

[23]  G. Barber,et al.  Cyclic Dinucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling , 2013, Cell.

[24]  R. Bak,et al.  IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication , 2013, Proceedings of the National Academy of Sciences.

[25]  Jie-Oh Lee,et al.  The crystal structure of lipopolysaccharide binding protein reveals the location of a frequent mutation that impairs innate immunity. , 2013, Immunity.

[26]  K. Tracey,et al.  Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis , 2013, Nature Medicine.

[27]  F. Granucci,et al.  IL-15 cis presentation is required for optimal NK cell activation in lipopolysaccharide-mediated inflammatory conditions. , 2013, Cell reports.

[28]  Shizuo Akira,et al.  Autophagy in infection, inflammation and immunity , 2013, Nature Reviews Immunology.

[29]  B. Verrier,et al.  Dectin-1 Is Essential for Reverse Transcytosis of Glycosylated SIgA-Antigen Complexes by Intestinal M Cells , 2013, PLoS biology.

[30]  Patrick G. A. Pedrioli,et al.  Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains , 2013, Proceedings of the National Academy of Sciences.

[31]  Changying Jiang,et al.  C-type lectin receptors Dectin-3 and Dectin-2 form a heterodimeric pattern-recognition receptor for host defense against fungal infection. , 2013, Immunity.

[32]  Duen-Yi Huang,et al.  The Tyrosine Kinase Syk Differentially Regulates Toll-like Receptor Signaling Downstream of the Adaptor Molecules TRAF6 and TRAF3 , 2013, Science Signaling.

[33]  C. Creighton,et al.  Cleavage of Fibrinogen by Proteinases Elicits Allergic Responses Through Toll-Like Receptor 4 , 2013, Science.

[34]  Zhijian J. Chen,et al.  MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades , 2013, eLife.

[35]  Yanhong Zhang,et al.  MAVS Regulates Apoptotic Cell Death by Decreasing K48-Linked Ubiquitination of Voltage-Dependent Anion Channel 1 , 2013, Molecular and Cellular Biology.

[36]  Christine E. Becker,et al.  CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation , 2013, Nature Immunology.

[37]  Christine E. Becker,et al.  Dectin-1 Activation Controls Maturation of β-1,3-Glucan-containing Phagosomes* , 2013, The Journal of Biological Chemistry.

[38]  R. Vance,et al.  Recognition of bacteria by inflammasomes. , 2013, Annual review of immunology.

[39]  S. Grinstein,et al.  Multimolecular signaling complexes enable Syk-mediated signaling of CD36 internalization. , 2013, Developmental cell.

[40]  R. Schekman,et al.  UNC93B1 mediates differential trafficking of endosomal TLRs , 2013, eLife.

[41]  Zhijian J. Chen,et al.  Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA , 2013, Science.

[42]  Zhijian J. Chen,et al.  Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway , 2013, Science.

[43]  E. Im,et al.  PTEN regulates TLR5‐induced intestinal inflammation by controlling Mal/TIRAP recruitment , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[44]  T. Tang,et al.  COX5B Regulates MAVS-mediated Antiviral Signaling through Interaction with ATG5 and Repressing ROS Production , 2012, PLoS pathogens.

[45]  Xin Lin,et al.  Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and TGFβ-activated Kinase 1 (TAK1) Play Essential Roles in the C-type Lectin Receptor Signaling in Response to Candida albicans Infection* , 2012, The Journal of Biological Chemistry.

[46]  N. DeLuca,et al.  Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein , 2012, Proceedings of the National Academy of Sciences.

[47]  S. Akira,et al.  PRAT4A-dependent expression of cell surface TLR5 on neutrophils, classical monocytes and dendritic cells. , 2012, International immunology.

[48]  B. Vanhaesebroeck,et al.  The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock , 2012, Nature Immunology.

[49]  G. Voeltz,et al.  Endoplasmic reticulum–mitochondria contacts: function of the junction , 2012, Nature Reviews Molecular Cell Biology.

[50]  J. Cox,et al.  Extracellular M. tuberculosis DNA Targets Bacteria for Autophagy by Activating the Host DNA-Sensing Pathway , 2012, Cell.

[51]  D. Underhill,et al.  Dectin-1-triggered Recruitment of Light Chain 3 Protein to Phagosomes Facilitates Major Histocompatibility Complex Class II Presentation of Fungal-derived Antigens* , 2012, The Journal of Biological Chemistry.

[52]  S. Mukhopadhyay,et al.  Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance , 2012, Nature Medicine.

[53]  Xian Chen,et al.  The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. , 2012, Immunity.

[54]  Yuan Tian,et al.  Cyclic di-GMP sensing via the innate immune signaling protein STING. , 2012, Molecular cell.

[55]  G. Cheng,et al.  Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding. , 2012, Immunity.

[56]  D. Lu,et al.  Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP , 2012, Nature Structural &Molecular Biology.

[57]  X. Su,et al.  The structural basis for the sensing and binding of cyclic di-GMP by STING , 2012, Nature Structural &Molecular Biology.

[58]  I. Cristea,et al.  Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16 , 2012, Proceedings of the National Academy of Sciences.

[59]  S. Vogel,et al.  Targeting Toll-like Receptor (TLR) Signaling by Toll/Interleukin-1 Receptor (TIR) Domain-containing Adapter Protein/MyD88 Adapter-like (TIRAP/Mal)-derived Decoy Peptides* , 2012, The Journal of Biological Chemistry.

[60]  C. Kao,et al.  Structure of STING bound to c-di-GMP Reveals the Mechanism of Cyclic Dinucleotide Recognition by the Immune System , 2012, Nature Structural &Molecular Biology.

[61]  M. Katze,et al.  The mitochondrial targeting chaperone 14-3-3ε regulates a RIG-I translocon that mediates membrane association and innate antiviral immunity. , 2012, Cell host & microbe.

[62]  F. Granucci,et al.  CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice. , 2012, The Journal of clinical investigation.

[63]  I. Wilson,et al.  Structural Basis of TLR5-Flagellin Recognition and Signaling , 2012, Science.

[64]  H. Urlaub,et al.  Syk Kinase-Coupled C-type Lectin Receptors Engage Protein Kinase C-δ to Elicit Card9 Adaptor-Mediated Innate Immunity , 2012, Immunity.

[65]  S. Gringhuis,et al.  Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome , 2012, Nature Immunology.

[66]  A. Luganini,et al.  The Intracellular DNA Sensor IFI16 Gene Acts as Restriction Factor for Human Cytomegalovirus Replication , 2012, PLoS pathogens.

[67]  Chih-yuan Chiang,et al.  Phospholipase Cγ-2 and Intracellular Calcium Are Required for Lipopolysaccharide-induced Toll-like Receptor 4 (TLR4) Endocytosis and Interferon Regulatory Factor 3 (IRF3) Activation* , 2011, The Journal of Biological Chemistry.

[68]  Sarah E. Ewald,et al.  Transmembrane mutations in Toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation. , 2011, Immunity.

[69]  F. Granucci,et al.  CD14 Controls the LPS-Induced Endocytosis of Toll-like Receptor 4 , 2011, Cell.

[70]  Yong‐jun Liu,et al.  The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells , 2011, Nature Immunology.

[71]  D. Golenbock,et al.  Genome-Wide Expression Profiling and Mutagenesis Studies Reveal that Lipopolysaccharide Responsiveness Appears To Be Absolutely Dependent on TLR4 and MD-2 Expression and Is Dependent upon Intermolecular Ionic Interactions , 2011, The Journal of Immunology.

[72]  M. Saleh The machinery of Nod‐like receptors: refining the paths to immunity and cell death , 2011, Immunological reviews.

[73]  Yoshihiro Hayakawa,et al.  STING is a direct innate immune sensor of cyclic-di-GMP , 2011, Nature.

[74]  M. Gale,et al.  Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus , 2011, Proceedings of the National Academy of Sciences.

[75]  Zhijian J. Chen,et al.  MAVS Forms Functional Prion-like Aggregates to Activate and Propagate Antiviral Innate Immune Response , 2011, Cell.

[76]  Gordon D. Brown,et al.  The role of Dectin-1 in the host defence against fungal infections. , 2011, Current opinion in microbiology.

[77]  M. Gale,et al.  Immune signaling by RIG-I-like receptors. , 2011, Immunity.

[78]  B. Chandran,et al.  IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. , 2011, Cell host & microbe.

[79]  Sarah E. Ewald,et al.  Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase , 2011, The Journal of experimental medicine.

[80]  Jun Ma,et al.  Activation of the innate immune receptor Dectin-1 upon formation of a “phagocytic synapse” , 2011, Nature.

[81]  Sarah E. Ewald,et al.  Nucleic acid recognition by the innate immune system. , 2011, Annual review of immunology.

[82]  G. Stark,et al.  The Dual Functions of IL-1 Receptor-Associated Kinase 2 in TLR9-Mediated IFN and Proinflammatory Cytokine Production , 2011, The Journal of Immunology.

[83]  Yusuke Yanagi,et al.  Mitochondrial Membrane Potential Is Required for MAVS-Mediated Antiviral Signaling , 2011, Science Signaling.

[84]  S. Akira,et al.  TLR5 functions as an endocytic receptor to enhance flagellin‐specific adaptive immunity , 2011, European journal of immunology.

[85]  S. Gringhuis,et al.  Selective C-Rel Activation via Malt1 Controls Anti-Fungal TH-17 Immunity by Dectin-1 and Dectin-2 , 2011, PLoS pathogens.

[86]  S. Akira,et al.  Pathogen Recognition by the Innate Immune System , 2011, International reviews of immunology.

[87]  M. Okabe,et al.  The ubiquitin ligase Riplet is essential for RIG-I-dependent innate immune responses to RNA virus infection. , 2010, Cell host & microbe.

[88]  A. Bowie,et al.  IFI16 is an innate immune sensor for intracellular DNA , 2010, Nature Immunology.

[89]  E. Latz,et al.  The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes. , 2010, Immunity.

[90]  A. Iwasaki,et al.  Bifurcation of Toll-Like Receptor 9 Signaling by Adaptor Protein 3 , 2010, Science.

[91]  M. Yoneyama,et al.  Virus-Infection or 5′ppp-RNA Activates Antiviral Signal through Redistribution of IPS-1 Mediated by MFN1 , 2010, PLoS pathogens.

[92]  C. Erridge Endogenous ligands of TLR2 and TLR4: agonists or assistants? , 2010, Journal of leukocyte biology.

[93]  S. Akira,et al.  Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. , 2010, Immunity.

[94]  N. Hacohen,et al.  Peroxisomes Are Signaling Platforms for Antiviral Innate Immunity , 2010, Cell.

[95]  Y. Lo,et al.  Helical assembly in the MyD88:IRAK4:IRAK2 complex in TLR/IL-1R signaling , 2010, Nature.

[96]  N. Dietrich,et al.  Murine Toll-Like Receptor 2 Activation Induces Type I Interferon Responses from Endolysosomal Compartments , 2010, PloS one.

[97]  A. Vazquez,et al.  Mitochondrial dynamics regulate the RIG‐I‐like receptor antiviral pathway , 2010, EMBO reports.

[98]  V. Hornung,et al.  Intracellular DNA recognition , 2010, Nature Reviews Immunology.

[99]  K. Moore,et al.  CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer , 2009, Nature Immunology.

[100]  Yi-Ling Lin,et al.  The Interferon Stimulator Mitochondrial Antiviral Signaling Protein Facilitates Cell Death by Disrupting the Mitochondrial Membrane Potential and by Activating Caspases , 2009, Journal of Virology.

[101]  S. Paik,et al.  Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer. , 2009, Immunity.

[102]  K. Ishii,et al.  Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response , 2009, Proceedings of the National Academy of Sciences.

[103]  S. Maschalidi,et al.  Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. , 2009, Immunity.

[104]  Trees Jansen,et al.  Human dectin-1 deficiency and mucocutaneous fungal infections. , 2009, The New England journal of medicine.

[105]  G. Barber,et al.  STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity , 2009, Nature.

[106]  A. Israël,et al.  NEMO specifically recognizes K63‐linked poly‐ubiquitin chains through a new bipartite ubiquitin‐binding domain , 2009, The EMBO journal.

[107]  R. Locksley,et al.  Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands , 2009, Nature Immunology.

[108]  D. Golenbock,et al.  MyD88 Adaptor-Like Is Not Essential for TLR2 Signaling and Inhibits Signaling by TLR31 , 2009, The Journal of Immunology.

[109]  S. Kawabata,et al.  Mitofusin 2 Inhibits Mitochondrial Antiviral Signaling , 2009, Science Signaling.

[110]  Zhijian J. Chen,et al.  Direct Activation of Protein Kinases by Unanchored Polyubiquitin Chains , 2009, Nature.

[111]  Zhijian J. Chen,et al.  RNA Polymerase III Detects Cytosolic DNA and Induces Type I Interferons through the RIG-I Pathway , 2009, Cell.

[112]  S. Akira,et al.  Activation of MDA5 Requires Higher-Order RNA Structures Generated during Virus Infection , 2009, Journal of Virology.

[113]  D. Golenbock,et al.  Mal connects TLR2 to PI3Kinase activation and phagocyte polarization , 2009, The EMBO journal.

[114]  C. Robinson,et al.  An Oligomeric Signaling Platform Formed by the Toll-like Receptor Signal Transducers MyD88 and IRAK-4* , 2009, The Journal of Biological Chemistry.

[115]  M. Foti,et al.  CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation , 2009, Nature.

[116]  S. Gringhuis,et al.  Signalling through C-type lectin receptors: shaping immune responses , 2009, Nature Reviews Immunology.

[117]  C. Eder Mechanisms of interleukin-1beta release. , 2009, Immunobiology.

[118]  G. Barton,et al.  A cell biological view of Toll-like receptor function: regulation through compartmentalization , 2009, Nature Reviews Immunology.

[119]  R. Medzhitov Approaching the asymptote: 20 years later. , 2009, Immunity.

[120]  K. Lam,et al.  Activated Dectin-1 Localizes to Lipid Raft Microdomains for Signaling and Activation of Phagocytosis and Cytokine Production in Dendritic Cells* , 2009, The Journal of Biological Chemistry.

[121]  Xiaoping Zhou,et al.  ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization , 2009, Proceedings of the National Academy of Sciences.

[122]  M. Colonna,et al.  Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization , 2009, European journal of immunology.

[123]  Hayyoung Lee,et al.  The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex , 2009, Nature.

[124]  Nobuhiro Suzuki,et al.  Specific Recognition of Linear Ubiquitin Chains by NEMO Is Important for NF-κB Activation , 2009, Cell.

[125]  Zhijian J. Chen,et al.  MAVS-Mediated Apoptosis and Its Inhibition by Viral Proteins , 2009, PloS one.

[126]  G. Superti-Furga,et al.  An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome , 2009, Nature Immunology.

[127]  L. Gehrke,et al.  Nucleotide Sequences and Modifications That Determine RIG-I/RNA Binding and Signaling Activities , 2009, Journal of Virology.

[128]  G. Núñez,et al.  NOD-like receptors: role in innate immunity and inflammatory disease. , 2009, Annual review of pathology.

[129]  S. Gringhuis,et al.  Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk , 2009, Nature Immunology.

[130]  E. Alnemri,et al.  AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA , 2009, Nature.

[131]  Daniel R. Caffrey,et al.  AIM2 recognizes cytosolic dsDNA and forms a caspase-1 activating inflammasome with ASC , 2009, Nature.

[132]  S. Hatakeyama,et al.  Riplet/RNF135, a RING Finger Protein, Ubiquitinates RIG-I to Promote Interferon-β Induction during the Early Phase of Viral Infection* , 2009, Journal of Biological Chemistry.

[133]  Ruslan Medzhitov,et al.  Pattern recognition receptors and control of adaptive immunity , 2009, Immunological reviews.

[134]  H. Ploegh,et al.  Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9 , 2008, Nature Immunology.

[135]  Y. Li,et al.  The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. , 2008, Immunity.

[136]  B. Pulendran,et al.  Toll-like receptor–mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway , 2008, Nature Immunology.

[137]  Sarah E. Ewald,et al.  The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor , 2008, Nature.

[138]  G. Barber,et al.  STING an Endoplasmic Reticulum Adaptor that Facilitates Innate Immune Signaling , 2008, Nature.

[139]  S. Akira,et al.  Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid–inducible gene-I and melanoma differentiation–associated gene 5 , 2008, The Journal of experimental medicine.

[140]  M. Gale,et al.  Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA , 2008, Nature.

[141]  Osamu Takeuchi,et al.  Sequential control of Toll-like receptor–dependent responses by IRAK1 and IRAK2 , 2008, Nature Immunology.

[142]  J. Tschopp,et al.  TRADD protein is an essential component of the RIG-like helicase antiviral pathway. , 2008, Immunity.

[143]  D. Davies,et al.  Structural Basis of Toll-Like Receptor 3 Signaling with Double-Stranded RNA , 2008, Science.

[144]  K. Miyake,et al.  Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. , 2008, Biochemical and biophysical research communications.

[145]  H. Ploegh,et al.  UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes , 2008, Nature.

[146]  S. Akira,et al.  TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-β , 2008, Nature Immunology.

[147]  A. Marshak‐Rothstein,et al.  Toll-like receptors and innate immune responses in systemic lupus erythematosus , 2007, Arthritis research & therapy.

[148]  S. Paik,et al.  Crystal Structure of the TLR1-TLR2 Heterodimer Induced by Binding of a Tri-Acylated Lipopeptide , 2007, Cell.

[149]  A. Dolganiuc,et al.  Toll‐like receptors 1 and 6 are involved in TLR2‐mediated macrophage activation by hepatitis C virus core and NS3 proteins , 2007, Journal of leukocyte biology.

[150]  W. Nacken,et al.  Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock , 2007, Nature Medicine.

[151]  A. Miyawaki,et al.  The Atg5–Atg12 conjugate associates with innate antiviral immune responses , 2007, Proceedings of the National Academy of Sciences.

[152]  G. Dubyak,et al.  Nonclassical IL-1β Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages1 , 2007, The Journal of Immunology.

[153]  J. Hiscott,et al.  Retinoic Acid-inducible Gene-I and Interferon-β Promoter Stimulator-1 Augment Proapoptotic Responses Following Mammalian Reovirus Infection via Interferon Regulatory Factor-3* , 2007, Journal of Biological Chemistry.

[154]  J. Weiss,et al.  Regulation of interactions of Gram-negative bacterial endotoxins with mammalian cells , 2007, Immunologic research.

[155]  J. Ruland,et al.  Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17 , 2007, Nature Immunology.

[156]  Gemma L. J. Fuller,et al.  The C-type Lectin Receptors CLEC-2 and Dectin-1, but Not DC-SIGN, Signal via a Novel YXXL-dependent Signaling Cascade* , 2007, Journal of Biological Chemistry.

[157]  H. Ploegh,et al.  The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling , 2007, The Journal of cell biology.

[158]  Osamu Takeuchi,et al.  TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity , 2007, Nature.

[159]  D. Underhill,et al.  Dectin-1 Stimulation by Candida albicans Yeast or Zymosan Triggers NFAT Activation in Macrophages and Dendritic Cells1 , 2007, The Journal of Immunology.

[160]  J. Tavernier,et al.  MAPPIT analysis of TLR adaptor complexes , 2007, FEBS letters.

[161]  G. Núñez,et al.  RICK/RIP2 Mediates Innate Immune Responses Induced through Nod1 and Nod2 but Not TLRs1 , 2007, The Journal of Immunology.

[162]  T. Compton,et al.  Human Cytomegalovirus Envelope Glycoproteins B and H Are Necessary for TLR2 Activation in Permissive Cells1 , 2006, The Journal of Immunology.

[163]  Gunther Hartmann,et al.  5'-Triphosphate RNA Is the Ligand for RIG-I , 2006, Science.

[164]  A. Pichlmair,et al.  RIG-I-Mediated Antiviral Responses to Single-Stranded RNA Bearing 5'-Phosphates , 2006, Science.

[165]  B. Cookson,et al.  Caspase‐1‐dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages , 2006, Cellular microbiology.

[166]  E. Fish,et al.  Contribution of Interferon-β to the Murine Macrophage Response to the Toll-like Receptor 4 Agonist, Lipopolysaccharide* , 2006, Journal of Biological Chemistry.

[167]  T. Hartung,et al.  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* , 2006, Journal of Biological Chemistry.

[168]  R. Medzhitov,et al.  Phosphoinositide-Mediated Adaptor Recruitment Controls Toll-like Receptor Signaling , 2006, Cell.

[169]  E. Kurt-Jones,et al.  Role for TLR2 in NK Cell-Mediated Control of Murine Cytomegalovirus In Vivo , 2006, Journal of Virology.

[170]  S. Akira,et al.  The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[171]  S. Akira,et al.  TLR1- and TLR6-independent Recognition of Bacterial Lipopeptides* , 2006, Journal of Biological Chemistry.

[172]  S. Fields,et al.  Binding specificity of Toll‐like receptor cytoplasmic domains , 2006, European journal of immunology.

[173]  M. Mann,et al.  Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6 , 2006, Nature.

[174]  J. Gready,et al.  The C‐type lectin‐like domain superfamily , 2005, The FEBS journal.

[175]  G. Prestwich,et al.  Regulation of lung injury and repair by Toll-like receptors and hyaluronan , 2005, Nature Medicine.

[176]  Ralf Bartenschlager,et al.  Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus , 2005, Nature.

[177]  Osamu Takeuchi,et al.  IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction , 2005, Nature Immunology.

[178]  D. Underhill,et al.  Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. , 2005, Blood.

[179]  Z. Zhai,et al.  VISA Is an Adapter Protein Required for Virus-Triggered IFN-β Signaling , 2005 .

[180]  Zhijian J. Chen,et al.  Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3 , 2005, Cell.

[181]  Shizuo Akira,et al.  Shared and Unique Functions of the DExD/H-Box Helicases RIG-I, MDA5, and LGP2 in Antiviral Innate Immunity1 , 2005, The Journal of Immunology.

[182]  Marian F Young,et al.  The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. , 2005, The Journal of clinical investigation.

[183]  D. Chan,et al.  Disruption of Fusion Results in Mitochondrial Heterogeneity and Dysfunction* , 2005, Journal of Biological Chemistry.

[184]  H. Reinecker,et al.  Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor–κB activation in muramyl dipeptide recognition , 2005, The Journal of cell biology.

[185]  D. S. Worrall,et al.  Toll-Like Receptor 4–Dependent and –Independent Cytokine Secretion Induced by Minimally Oxidized Low-Density Lipoprotein in Macrophages , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[186]  Zhengfan Jiang,et al.  CD14 is required for MyD88-independent LPS signaling , 2005, Nature Immunology.

[187]  K. Honda,et al.  Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction , 2005, Nature.

[188]  Hideo Negishi,et al.  IRF-7 is the master regulator of type-I interferon-dependent immune responses , 2005, Nature.

[189]  K. Tracey,et al.  The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion , 2005, The Journal of experimental medicine.

[190]  S. Gordon,et al.  Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. , 2005, Immunity.

[191]  S. Paik,et al.  Crystal Structure of CD14 and Its Implications for Lipopolysaccharide Signaling*♦ , 2005, Journal of Biological Chemistry.

[192]  C. Coban,et al.  Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction , 2005, The Journal of experimental medicine.

[193]  H. Heine,et al.  Binding of lipopeptide to CD14 induces physical proximity of CD14, TLR2 and TLR1 , 2005, European journal of immunology.

[194]  Thomas Hartung,et al.  CD36 is a sensor of diacylglycerides , 2005, Nature.

[195]  S. Gordon,et al.  Dectin-1 uses novel mechanisms for yeast phagocytosis in macrophages. , 2004, Blood.

[196]  T. Hartung,et al.  Lateral diffusion of Toll-like receptors reveals that they are transiently confined within lipid rafts on the plasma membrane , 2004, Journal of Cell Science.

[197]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[198]  Shizuo Akira,et al.  The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses , 2004, Nature Immunology.

[199]  S. Akira,et al.  The Roles of Two IκB Kinase-related Kinases in Lipopolysaccharide and Double Stranded RNA Signaling and Viral Infection , 2004, The Journal of experimental medicine.

[200]  R. Bronson,et al.  Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[201]  T. Maniatis,et al.  IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[202]  A. Aderem,et al.  Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility , 2003, Nature Immunology.

[203]  S. Akira,et al.  TRAM is specifically involved in the Toll-like receptor 4–mediated MyD88-independent signaling pathway , 2003, Nature Immunology.

[204]  Daniel R. Caffrey,et al.  LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF , 2003, The Journal of experimental medicine.

[205]  S. Akira,et al.  Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway , 2003, Science.

[206]  S. Foster,et al.  An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid , 2003, Nature Immunology.

[207]  J. Bertin,et al.  Nod1 Detects a Unique Muropeptide from Gram-Negative Bacterial Peptidoglycan , 2003, Science.

[208]  T. Giese,et al.  Activation with CpG-A and CpG-B Oligonucleotides Reveals Two Distinct Regulatory Pathways of Type I IFN Synthesis in Human Plasmacytoid Dendritic Cells 1 , 2003, The Journal of Immunology.

[209]  T. Maniatis,et al.  IKKε and TBK1 are essential components of the IRF3 signaling pathway , 2003, Nature Immunology.

[210]  M. Chamaillard,et al.  Nod2 Is a General Sensor of Peptidoglycan through Muramyl Dipeptide (MDP) Detection* , 2003, The Journal of Biological Chemistry.

[211]  S. Akira,et al.  Cutting Edge: A Novel Toll/IL-1 Receptor Domain-Containing Adapter That Preferentially Activates the IFN-β Promoter in the Toll-Like Receptor Signaling1 , 2002, The Journal of Immunology.

[212]  R. Flavell,et al.  The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors , 2002, Nature.

[213]  S. Akira,et al.  Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4 , 2002, Nature.

[214]  L. Kwak,et al.  Toll-Like Receptor 4-Dependent Activation of Dendritic Cells by β-Defensin 2 , 2002, Science.

[215]  F. Gruber,et al.  Protective role of phospholipid oxidation products in endotoxin-induced tissue damage , 2002, Nature.

[216]  D. Golenbock,et al.  Cutting Edge: The Immunostimulatory Activity of the Lung Surfactant Protein-A Involves Toll-Like Receptor 41 , 2002, The Journal of Immunology.

[217]  S. Akira,et al.  Essential role of MD-2 in LPS responsiveness and TLR4 distribution , 2002, Nature Immunology.

[218]  J. Platt,et al.  Receptor-Mediated Monitoring of Tissue Well-Being Via Detection of Soluble Heparan Sulfate by Toll-Like Receptor 41 , 2002, The Journal of Immunology.

[219]  Carsten J. Kirschning,et al.  HSP70 as Endogenous Stimulus of the Toll/Interleukin-1 Receptor Signal Pathway* , 2002, The Journal of Biological Chemistry.

[220]  T. Mak,et al.  Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4 , 2002, Nature.

[221]  S. Ross,et al.  Murine retroviruses activate B cells via interaction with toll-like receptor 4 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[222]  H. Karahashi,et al.  Chlamydial Heat Shock Protein 60 Activates Macrophages and Endothelial Cells Through Toll-Like Receptor 4 and MD2 in a MyD88-Dependent Pathway1 , 2002, The Journal of Immunology.

[223]  T. Ahrens,et al.  Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4 , 2002, The Journal of experimental medicine.

[224]  B. Kobe,et al.  The leucine-rich repeat as a protein recognition motif. , 2001, Current opinion in structural biology.

[225]  R. North,et al.  Rapid secretion of interleukin-1β by microvesicle shedding , 2001 .

[226]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[227]  Dirk E. Smith,et al.  Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction , 2001, Nature.

[228]  R. Medzhitov,et al.  TIRAP: an adapter molecule in the Toll signaling pathway , 2001, Nature Immunology.

[229]  P. Godowski,et al.  Cutting Edge: Bacterial Flagellin Activates Basolaterally Expressed TLR5 to Induce Epithelial Proinflammatory Gene Expression1 , 2001, The Journal of Immunology.

[230]  Zhijian J. Chen,et al.  TAK1 is a ubiquitin-dependent kinase of MKK and IKK , 2001, Nature.

[231]  R. Ulevitch,et al.  Lipopolysaccharide Is in Close Proximity to Each of the Proteins in Its Membrane Receptor Complex , 2001, The Journal of Biological Chemistry.

[232]  S. Akira,et al.  The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5 , 2001, Nature.

[233]  Jerome F. Strauss,et al.  The Extra Domain A of Fibronectin Activates Toll-like Receptor 4* , 2001, The Journal of Biological Chemistry.

[234]  S. Grinstein,et al.  Localized Biphasic Changes in Phosphatidylinositol-4,5-Bisphosphate at Sites of Phagocytosis , 2000, The Journal of cell biology.

[235]  S. Akira,et al.  A Toll-like receptor recognizes bacterial DNA , 2000, Nature.

[236]  A. Aderem,et al.  The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[237]  Douglas T. Golenbock,et al.  Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus , 2000, Nature Immunology.

[238]  Zhijian J. Chen,et al.  Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain , 2000, Cell.

[239]  Kai Simons,et al.  Lipid rafts and signal transduction , 2000, Nature Reviews Molecular Cell Biology.

[240]  P. Lucas,et al.  An Induced Proximity Model for NF-κB Activation in the Nod1/RICK and RIP Signaling Pathways , 2000 .

[241]  S. South,et al.  Pex19 Binds Multiple Peroxisomal Membrane Proteins, Is Predominantly Cytoplasmic, and Is Required for Peroxisome Membrane Synthesis , 2000, The Journal of cell biology.

[242]  T. Yoshida,et al.  Mouse Toll-like Receptor 4·MD-2 Complex Mediates Lipopolysaccharide-mimetic Signal Transduction by Taxol* , 2000, The Journal of Biological Chemistry.

[243]  H. Kolb,et al.  Cutting Edge: Heat Shock Protein 60 Is a Putative Endogenous Ligand of the Toll-Like Receptor-4 Complex1 , 2000, The Journal of Immunology.

[244]  M. Torrisi,et al.  The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles. , 1999, Molecular biology of the cell.

[245]  G. McFadden,et al.  Apoptosis: an innate immune response to virus infection. , 1999, Trends in microbiology.

[246]  P. Ricciardi-Castagnoli,et al.  Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. , 1998, Science.

[247]  C. Janeway,et al.  MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. , 1998, Molecular cell.

[248]  L. Kline,et al.  Cell Activation Mediated by Glycosylphosphatidylinositol-Anchored or Transmembrane Forms of CD14 , 1998, Infection and Immunity.

[249]  P. Feng,et al.  IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. , 1997, Science.

[250]  C. Janeway,et al.  A human homologue of the Drosophila Toll protein signals activation of adaptive immunity , 1997, Nature.

[251]  Zhaodan Cao,et al.  TRAF6 is a signal transducer for interleukin-1 , 1996, Nature.

[252]  E. Unanue,et al.  Release of IL-1 from mononuclear phagocytes. , 1991, Journal of immunology.

[253]  R. Ulevitch,et al.  Structure and function of lipopolysaccharide binding protein. , 1990, Science.

[254]  F. Cozzolino,et al.  A novel secretory pathway for interleukin‐1 beta, a protein lacking a signal sequence. , 1990, The EMBO journal.

[255]  D. Choubey,et al.  Interferon-inducible p200-family protein IFI16, an innate immune sensor for cytosolic and nuclear double-stranded DNA: regulation of subcellular localization. , 2012, Molecular immunology.

[256]  D. Philpott,et al.  Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry , 2010, Nature Immunology.

[257]  M. Karin,et al.  Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines , 2010, Nature Immunology.

[258]  S. Gordon,et al.  Dectin-1 is required for β-glucan recognition and control of fungal infection , 2007, Nature Immunology.

[259]  Adrian Ozinsky,et al.  Phagocytosis of microbes: complexity in action. , 2002, Annual review of immunology.

[260]  C. Janeway Approaching the asymptote? Evolution and revolution in immunology. , 1989, Cold Spring Harbor symposia on quantitative biology.