A cell biological view of Toll-like receptor function: regulation through compartmentalization

An emerging paradigm in innate immune signalling is that cell biological context can influence the outcome of a ligand–receptor interaction. In this Review we discuss how Toll-like receptor (TLR) activation and signal transduction are regulated by subcellular compartmentalization of receptors and downstream signalling components. In particular, we focus on the functional specialization of TLRs in the endosomal system. We discuss recent studies that illustrate how basic aspects of the cellular machinery contribute to TLR function and regulation. This emerging area of research will provide important information on how immune signal transduction networks depend on (and in some cases influence) the generic regulators that organize eukaryotic cells.

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

[2]  C. Janeway,et al.  Innate Immunity: The Virtues of a Nonclonal System of Recognition , 1997, Cell.

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

[4]  H. Mischak,et al.  CpG‐DNA‐specific activation of antigen‐presenting cells requires stress kinase activity and is preceded by non‐specific endocytosis and endosomal maturation , 1998, The EMBO journal.

[5]  A. Aderem,et al.  The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens , 1999, Nature.

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

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

[8]  M. Shlomchik,et al.  Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors , 2002, Nature.

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

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

[11]  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.

[12]  J. Weiss.  Faculty Opinions recommendation of Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14. , 2003 .

[13]  K. Fukase,et al.  Lipopolysaccharide Interaction with Cell Surface Toll-like Receptor 4-MD-2 , 2003, The Journal of experimental medicine.

[14]  T. Akazawa,et al.  TICAM-1, an adaptor molecule that participates in Toll-like receptor 3–mediated interferon-β induction , 2003, Nature Immunology.

[15]  A. Yamamoto,et al.  Subcellular Localization of Toll-Like Receptor 3 in Human Dendritic Cells 1 , 2003, The Journal of Immunology.

[16]  T. Fujita,et al.  TIR-containing Adapter Molecule (TICAM)-2, a Bridging Adapter Recruiting to Toll-like Receptor 4 TICAM-1 That Induces Interferon-β* , 2003, Journal of Biological Chemistry.

[17]  S. Akira,et al.  Toll-like receptors. , 2003, Annual review of immunology.

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

[19]  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.

[20]  S. Akira,et al.  SubsetsDistinct CpG DNAs on Dendritic Cell Catalytic Subunit in the Effects of Two and DNA-Dependent Protein Kinase The Roles of Toll-Like Receptor 9 , MyD 88 , 2003 .

[21]  J. Tschopp,et al.  MyD88S, a splice variant of MyD88, differentially modulates NF‐κB‐ and AP‐1‐dependent gene expression , 2003, FEBS letters.

[22]  A. Iwasaki,et al.  Toll-like receptor control of the adaptive immune responses , 2004, Nature Immunology.

[23]  C. Coban,et al.  Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6 , 2004, Nature Immunology.

[24]  S. Akira,et al.  Toll-like Receptor 9–Dependent and –Independent Dendritic Cell Activation by Chromatin–Immunoglobulin G Complexes , 2004, The Journal of experimental medicine.

[25]  M. Kruhlak,et al.  TLR9 Is Localized in the Endoplasmic Reticulum Prior to Stimulation , 2004, The Journal of Immunology.

[26]  B. Monks,et al.  TLR9 signals after translocating from the ER to CpG DNA in the lysosome , 2004, Nature Immunology.

[27]  M. Matteis,et al.  PI-loting membrane traffic , 2004, Nature Cell Biology.

[28]  S. Akira,et al.  Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus , 2005, The Journal of experimental medicine.

[29]  S. Akira,et al.  RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement , 2005, The Journal of experimental medicine.

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

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

[32]  D. Davies,et al.  The dsRNA binding site of human Toll‐like receptor 3 , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Akira,et al.  Innate immune recognition of viral infection. , 2006, Nature immunology.

[34]  E. Latz,et al.  Endocytic pathways regulate Toll‐like receptor 4 signaling and link innate and adaptive immunity , 2006, The EMBO journal.

[35]  A. Satterthwaite,et al.  Autoreactive B Cell Responses to RNA-Related Antigens Due to TLR7 Gene Duplication , 2006, Science.

[36]  A. Marshak‐Rothstein.  Toll-like receptors in systemic autoimmune disease , 2006, Nature Reviews Immunology.

[37]  S. Akira,et al.  Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. , 2006, Immunity.

[38]  R. Medzhitov,et al.  Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA , 2006, Nature Immunology.

[39]  山本 雅裕.  Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway , 2006 .

[40]  Quanzhen Li,et al.  A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Shupe,et al.  Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. , 2006, Immunity.

[42]  S. Akira,et al.  TLR signaling. , 2006, Cell death and differentiation.

[43]  S. Grinstein,et al.  The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9 , 2006, Nature Immunology.

[44]  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.

[45]  F. Obermeier,et al.  Surface Expression of Toll-Like Receptor 9 Is Upregulated on Intestinal Epithelial Cells in Response to Pathogenic Bacterial DNA , 2007, Infection and Immunity.

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

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

[48]  B. Monks,et al.  Ligand-induced conformational changes allosterically activate Toll-like receptor 9 , 2007, Nature Immunology.

[49]  Hayyoung Lee,et al.  Crystal Structure of the TLR4-MD-2 Complex with Bound Endotoxin Antagonist Eritoran , 2007, Cell.

[50]  G. Barton.  Viral recognition by Toll-like receptors. , 2007, Seminars in immunology.

[51]  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.

[52]  I. Mellman,et al.  Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide , 2007, Nature.

[53]  R. Medzhitov.  Recognition of microorganisms and activation of the immune response , 2007, Nature.

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

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

[56]  K. Miyake,et al.  Cathepsins are required for Toll-like receptor 9 responses. , 2008, Biochemical and biophysical research communications.

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

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

[59]  K. Miyazono,et al.  Cathepsin K-Dependent Toll-Like Receptor 9 Signaling Revealed in Experimental Arthritis , 2008, Science.

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

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

[62]  M. Karin,et al.  Essential Cytoplasmic Translocation of a Cytokine Receptor–Assembled Signaling Complex , 2008, Science.

[63]  D. Golenbock,et al.  TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88–independent TLR4 pathway , 2009, Nature Immunology.

[64]  J. Lippincott-Schwartz,et al.  New roles for endosomes: from vesicular carriers to multi-purpose platforms , 2009, Nature Reviews Molecular Cell Biology.