Skip to main content

Advertisement

SpringerLink
Log in

Compartmentalizing intestinal epithelial cell toll-like receptors for immune surveillance

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Toll-like receptors (TLRs) are membrane-bound microbial sensors that mediate important host-to-microbe responses. Cell biology aspects of TLR function have been intensively studied in professional immune cells, in particular the macrophages and dendritic cells, but not well explored in other specialized epithelial cell types. The adult intestinal epithelial cells are in close contact with trillions of enteric microbes and engage in lifelong immune surveillance. Mature intestinal epithelial cells, in contrast to immune cells, are highly polarized. Recent studies suggest that distinct mechanisms may govern TLR traffic and compartmentalization in these specialized epithelial cells to establish and maintain precise signaling of individual TLRs. We, using immune cells as references, discuss here the shared and/or unique molecular machineries used by intestinal epithelial cells to control TLR transport, localization, processing, activation, and signaling. A better understanding of these mechanisms will certainly generate important insights into both the mechanism and potential intervention of leading digestive disorders, in particular inflammatory bowel diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Koropatkin NM, Cameron EA, Martens EC (2012) How glycan metabolism shapes the human gut microbiota. Nat Rev Microbiol 10(5):323–335

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Kashyap PC et al (2013) Genetically dictated change in host mucus carbohydrate landscape exerts a diet-dependent effect on the gut microbiota. Proc Natl Acad Sci USA 110(42):17059–17064

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Erkosar B et al (2013) Host-intestinal microbiota mutualism: “learning on the fly”. Cell Host Microbe 13(1):8–14

    Article  CAS  PubMed  Google Scholar 

  4. Pickard JM et al (2014) Rapid fucosylation of intestinal epithelium sustains host–commensal symbiosis in sickness. Nature 514(7524):638–641

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Brestoff JR, Artis D (2013) Commensal bacteria at the interface of host metabolism and the immune system. Nat Immunol 14(7):676–684

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Belkaid Y, Hand TW (2014) Role of the microbiota in immunity and inflammation. Cell 157(1):121–141

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Buffie CG, Pamer EG (2013) Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol 13(11):790–801

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Maier L et al (2013) Microbiota-derived hydrogen fuels Salmonella typhimurium invasion of the gut ecosystem. Cell Host Microbe 14(6):641–651

    Article  CAS  PubMed  Google Scholar 

  9. Clemente JC et al (2012) The impact of the gut microbiota on human health: an integrative view. Cell 148(6):1258–1270

    Article  CAS  PubMed  Google Scholar 

  10. Sekirov I et al (2010) Gut microbiota in health and disease. Physiol Rev 90(3):859–904

    Article  CAS  PubMed  Google Scholar 

  11. Crosnier C, Stamataki D, Lewis J (2006) Organizing cell renewal in the intestine: stem cells, signals and combinatorial control. Nat Rev Genet 7(5):349–359

    Article  CAS  PubMed  Google Scholar 

  12. Barker N (2014) Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol 15(1):19–33

    Article  CAS  PubMed  Google Scholar 

  13. Mabbott NA et al (2013) Microfold (M) cells: important immunosurveillance posts in the intestinal epithelium. Mucosal Immunol 6(4):666–677

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Wells JM et al (2011) Epithelial crosstalk at the microbiota-mucosal interface. Proc Natl Acad Sci USA 108(Suppl 1):4607–4614

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Abreu MT (2010) Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 10(2):131–144

    Article  CAS  PubMed  Google Scholar 

  16. Peterson LW, Artis D (2014) Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 14(3):141–153

    Article  CAS  PubMed  Google Scholar 

  17. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34(5):637–650

    Article  CAS  PubMed  Google Scholar 

  18. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4(7):499–511

    Article  CAS  PubMed  Google Scholar 

  19. Kang JY et al (2009) Recognition of lipopeptide patterns by toll-like receptor 2-toll-like receptor 6 heterodimer. Immunity 31(6):873–884

    Article  CAS  PubMed  Google Scholar 

  20. Jin MS et al (2007) Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130(6):1071–1082

    Article  CAS  PubMed  Google Scholar 

  21. Koblansky AA et al (2013) Recognition of profilin by toll-like receptor 12 is critical for host resistance to Toxoplasma gondii. Immunity 38(1):119–130

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Oldenburg M et al (2012) TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification. Science 337(6098):1111–1115

    Article  CAS  PubMed  Google Scholar 

  23. Rifkin IR et al (2005) Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev 204:27–42

    Article  CAS  PubMed  Google Scholar 

  24. Rakoff-Nahoum S, Medzhitov R (2009) Toll-like receptors and cancer. Nat Rev Cancer 9(1):57–63

    Article  CAS  PubMed  Google Scholar 

  25. Zhang P et al (2009) Cutting edge: cardiac myosin activates innate immune responses through TLRs. J Immunol 183(1):27–31

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Barton GM, Kagan JC (2009) A cell biological view of toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol 9(8):535–542

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Gay NJ et al (2014) Assembly and localization of toll-like receptor signalling complexes. Nat Rev Immunol 14(8):546–558

    Article  CAS  PubMed  Google Scholar 

  28. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol 11(5):373–384

    Article  CAS  PubMed  Google Scholar 

  29. O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in toll-like receptor signalling. Nat Rev Immunol 7(5):353–364

    Article  PubMed  CAS  Google Scholar 

  30. Blasius AL, Beutler B (2010) Intracellular toll-like receptors. Immunity 32(3):305–315

    Article  CAS  PubMed  Google Scholar 

  31. Otte JM, Cario E, Podolsky DK (2004) Mechanisms of cross hyporesponsiveness to toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology 126(4):1054–1070

    Article  CAS  PubMed  Google Scholar 

  32. Cario E et al (2002) Commensal-associated molecular patterns induce selective toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. Am J Pathol 160(1):165–173

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Melmed G et al (2003) Human intestinal epithelial cells are broadly unresponsive to toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. J Immunol 170(3):1406–1415

    Article  CAS  PubMed  Google Scholar 

  34. Lavelle EC et al (2010) The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunol 3(1):17–28

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Fusunyan RD et al (2001) Evidence for an innate immune response in the immature human intestine: toll-like receptors on fetal enterocytes. Pediatr Res 49(4):589–593

    Article  CAS  PubMed  Google Scholar 

  36. Chabot S et al (2006) TLRs regulate the gatekeeping functions of the intestinal follicle-associated epithelium. J Immunol 176(7):4275–4283

    Article  CAS  PubMed  Google Scholar 

  37. Cario E, Podolsky DK (2000) Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68(12):7010–7017

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Ortega-Cava CF et al (2003) Strategic compartmentalization of toll-like receptor 4 in the mouse gut. J Immunol 170(8):3977–3985

    Article  CAS  PubMed  Google Scholar 

  39. Hornef MW et al (2002) Toll-like receptor 4 resides in the Golgi apparatus and colocalizes with internalized lipopolysaccharide in intestinal epithelial cells. J Exp Med 195(5):559–570

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Ortega-Cava CF et al (2006) Epithelial toll-like receptor 5 is constitutively localized in the mouse cecum and exhibits distinctive down-regulation during experimental colitis. Clin Vaccine Immunol 13(1):132–138

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Gewirtz AT et al (2001) Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 167(4):1882–1885

    Article  CAS  PubMed  Google Scholar 

  42. Rhee SH et al (2005) Pathophysiological role of toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. Proc Natl Acad Sci USA 102(38):13610–13615

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Bambou JC et al (2004) In vitro and ex vivo activation of the TLR5 signaling pathway in intestinal epithelial cells by a commensal Escherichia coli strain. J Biol Chem 279(41):42984–42992

    Article  CAS  PubMed  Google Scholar 

  44. Barton GM, Kagan JC, Medzhitov R (2006) Intracellular localization of toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 7(1):49–56

    Article  CAS  PubMed  Google Scholar 

  45. Onji M et al (2013) An essential role for the N-terminal fragment of toll-like receptor 9 in DNA sensing. Nat Commun 4:1949

    Article  PubMed  CAS  Google Scholar 

  46. Ewald SE et al (2008) The ectodomain of toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456(7222):658–662

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Park B et al (2008) Proteolytic cleavage in an endolysosomal compartment is required for activation of toll-like receptor 9. Nat Immunol 9(12):1407–1414

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Ewald SE et al (2011) Nucleic acid recognition by toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J Exp Med 208(4):643–651

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Mouchess ML et al (2011) Transmembrane mutations in toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation. Immunity 35(5):721–732

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Lee J et al (2006) Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol 8(12):1327–1336

    Article  CAS  PubMed  Google Scholar 

  51. Yu S et al (2014) TLR sorting by Rab11 endosomes maintains intestinal epithelial-microbial homeostasis. EMBO J 33(17):1882–1895

    Article  CAS  PubMed  Google Scholar 

  52. Rumio C et al (2004) Degranulation of Paneth cells via toll-like receptor 9. Am J Pathol 165(2):373–381

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Rumio C et al (2012) Induction of Paneth cell degranulation by orally administered toll-like receptor ligands. J Cell Physiol 227(3):1107–1113

    Article  CAS  PubMed  Google Scholar 

  54. Schulz O, Pabst O (2013) Antigen sampling in the small intestine. Trends Immunol 34(4):155–161

    Article  CAS  PubMed  Google Scholar 

  55. De Matteis MA, Luini A (2008) Exiting the Golgi complex. Nat Rev Mol Cell Biol 9(4):273–284

    Article  PubMed  CAS  Google Scholar 

  56. Stenmark H (2009) Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10(8):513–525

    Article  CAS  PubMed  Google Scholar 

  57. Hutagalung AH, Novick PJ (2011) Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev 91(1):119–149

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Yu IM, Hughson FM (2010) Tethering factors as organizers of intracellular vesicular traffic. Annu Rev Cell Dev Biol 26:137–156

    Article  CAS  PubMed  Google Scholar 

  59. Takahashi K et al (2007) A protein associated with toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses. J Exp Med 204(12):2963–2976

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Liu B et al (2010) Folding of toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nat Commun 1:79

    Article  PubMed  CAS  Google Scholar 

  61. Yang Y et al (2007) Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 26(2):215–226

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  62. Bonifacino JS (2014) Adaptor proteins involved in polarized sorting. J Cell Biol 204(1):7–17

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Grant BD, Donaldson JG (2009) Pathways and mechanisms of endocytic recycling. Nat Rev Mol Cell Biol 10(9):597–608

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Hsu VW, Bai M, Li J (2012) Getting active: protein sorting in endocytic recycling. Nat Rev Mol Cell Biol 13(5):323–328

    CAS  PubMed  Google Scholar 

  65. Hirokawa N et al (2009) Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol 10(10):682–696

    Article  CAS  PubMed  Google Scholar 

  66. Roberts AJ et al (2013) Functions and mechanics of dynein motor proteins. Nat Rev Mol Cell Biol 14(11):713–726

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Hammer JA 3rd, Sellers JR (2012) Walking to work: roles for class V myosins as cargo transporters. Nat Rev Mol Cell Biol 13(1):13–26

    CAS  Google Scholar 

  68. Verhey KJ, Hammond JW (2009) Traffic control: regulation of kinesin motors. Nat Rev Mol Cell Biol 10(11):765–777

    Article  CAS  PubMed  Google Scholar 

  69. Seabra MC, Coudrier E (2004) Rab GTPases and myosin motors in organelle motility. Traffic 5(6):393–399

    Article  CAS  PubMed  Google Scholar 

  70. Hancock WO (2014) Bidirectional cargo transport: moving beyond tug of war. Nat Rev Mol Cell Biol 15(9):615–628

    Article  CAS  PubMed  Google Scholar 

  71. Ivanov II et al (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4(4):337–349

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Martin-Belmonte F et al (2007) PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 128(2):383–397

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Rodriguez-Boulan E, Macara IG (2014) Organization and execution of the epithelial polarity programme. Nat Rev Mol Cell Biol 15(4):225–242

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Leifer CA et al (2006) Cytoplasmic targeting motifs control localization of toll-like receptor 9. J Biol Chem 281(46):35585–35592

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Lee BL et al (2013) UNC93B1 mediates differential trafficking of endosomal TLRs. Elife 2:e00291

    PubMed Central  PubMed  Google Scholar 

  76. Ohno H (2006) Clathrin-associated adaptor protein complexes. J Cell Sci 119(Pt 18):3719–3721

    Article  CAS  PubMed  Google Scholar 

  77. Hase K et al (2013) AP-1B-mediated protein sorting regulates polarity and proliferation of intestinal epithelial cells in mice. Gastroenterology 145(3):625–635

    Article  CAS  PubMed  Google Scholar 

  78. Takahashi D et al (2011) The epithelia-specific membrane trafficking factor AP-1B controls gut immune homeostasis in mice. Gastroenterology 141(2):621–632

    Article  CAS  PubMed  Google Scholar 

  79. Shafaq-Zadah M et al (2012) AP-1 is required for the maintenance of apico-basal polarity in the C. elegans intestine. Development 139(11):2061–2070

    Article  CAS  PubMed  Google Scholar 

  80. Setta-Kaffetzi N et al (2014) AP1S3 Mutations are associated with pustular psoriasis and impaired toll-like receptor 3 trafficking. Am J Hum Genet 94(5):790–797

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Mantegazza AR et al (2012) Adaptor protein-3 in dendritic cells facilitates phagosomal toll-like receptor signaling and antigen presentation to CD4+ T cells. Immunity 36(5):782–794

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Sasai M, Linehan MM, Iwasaki A (2010) Bifurcation of toll-like receptor 9 signaling by adaptor protein 3. Science 329(5998):1530–1534

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Blasius AL et al (2010) Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for toll-like receptor signaling in plasmacytoid dendritic cells. Proc Natl Acad Sci USA 107(46):19973–19978

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Weisz OA, Rodriguez-Boulan E (2009) Apical trafficking in epithelial cells: signals, clusters and motors. J Cell Sci 122(Pt 23):4253–4266

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Weber AN, Morse MA, Gay NJ (2004) Four N linked glycosylation sites in human toll-like receptor 2 cooperate to direct efficient biosynthesis and secretion. J Biol Chem 279(33):34589–34594

    Article  CAS  PubMed  Google Scholar 

  86. Sun J et al (2006) Structural and functional analyses of the human toll-like receptor 3. Role of glycosylation. J Biol Chem 281(16):11144–11151

    Article  CAS  PubMed  Google Scholar 

  87. Istomin AY, Godzik A (2009) Understanding diversity of human innate immunity receptors: analysis of surface features of leucine-rich repeat domains in NLRs and TLRs. BMC Immunol 10:48

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  88. Xu S et al (2011) A Rab11a-enriched subapical membrane compartment regulates a cytoskeleton-dependent transcytotic pathway in secretory epithelial cells of the lacrimal gland. J Cell Sci 124(Pt 20):3503–3514

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Roland JT et al (2011) Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization. Proc Natl Acad Sci USA 108(7):2789–2794

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Husebye H et al (2010) The Rab11a GTPase controls toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes. Immunity 33(4):583–596

    Article  CAS  PubMed  Google Scholar 

  91. Wang D et al (2010) Ras-related protein Rab10 facilitates TLR4 signaling by promoting replenishment of TLR4 onto the plasma membrane. Proc Natl Acad Sci USA 107(31):13806–13811

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Schuck S et al (2007) Rab10 is involved in basolateral transport in polarized Madin-Darby canine kidney cells. Traffic 8(1):47–60

    Article  CAS  PubMed  Google Scholar 

  93. Chen S et al (2014) SEC-10 and RAB-10 coordinate basolateral recycling of clathrin-independent cargo through endosomal tubules in Caenorhabditis elegans. Proc Natl Acad Sci USA 111(43):15432–15437

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Tuma P, Hubbard AL (2003) Transcytosis: crossing cellular barriers. Physiol Rev 83(3):871–932

    Article  CAS  PubMed  Google Scholar 

  95. Su T et al (2010) A kinase cascade leading to Rab11-FIP5 controls transcytosis of the polymeric immunoglobulin receptor. Nat Cell Biol 12(12):1143–1153

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Piper RC, Luzio JP (2007) Ubiquitin-dependent sorting of integral membrane proteins for degradation in lysosomes. Curr Opin Cell Biol 19(4):459–465

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Chiang CY et al (2012) Cofactors required for TLR7- and TLR9-dependent innate immune responses. Cell Host Microbe 11(3):306–318

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Husebye H et al (2006) Endocytic pathways regulate toll-like receptor 4 signaling and link innate and adaptive immunity. EMBO J 25(4):683–692

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Mashukova A, Wald FA, Salas PJ (2011) Tumor necrosis factor alpha and inflammation disrupt the polarity complex in intestinal epithelial cells by a posttranslational mechanism. Mol Cell Biol 31(4):756–765

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. St Johnston D, Ahringer J (2010) Cell polarity in eggs and epithelia: parallels and diversity. Cell 141(5):757–774

    Article  CAS  PubMed  Google Scholar 

  101. Pasparakis M (2009) Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nat Rev Immunol 9(11):778–788

    Article  CAS  PubMed  Google Scholar 

  102. Eyster KM (2007) The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non-lipid biochemist. Adv Physiol Educ 31(1):5–16

    Article  PubMed  Google Scholar 

  103. Kagan JC, Medzhitov R (2006) Phosphoinositide-mediated adaptor recruitment controls toll-like receptor signaling. Cell 125(5):943–955

    Article  CAS  PubMed  Google Scholar 

  104. Balla T (2013) Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol Rev 93(3):1019–1137

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Tabeta K et al (2006) The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via toll-like receptors 3, 7 and 9. Nat Immunol 7(2):156–164

    Article  CAS  PubMed  Google Scholar 

  106. Lee BL, Barton GM (2014) Trafficking of endosomal toll-like receptors. Trends Cell Biol 24(6):360–369

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Brinkmann MM et al (2007) The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J Cell Biol 177(2):265–275

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  108. Kim J et al (2013) Acidic amino acid residues in the juxtamembrane region of the nucleotide-sensing TLRs are important for UNC93B1 binding and signaling. J Immunol 190(10):5287–5295

    Article  CAS  PubMed  Google Scholar 

  109. Itoh H et al (2011) UNC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling. PLoS One 6(12):e28500

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Funami K et al (2004) The cytoplasmic ‘linker region’ in toll-like receptor 3 controls receptor localization and signaling. Int Immunol 16(8):1143–1154

    Article  CAS  PubMed  Google Scholar 

  111. Pohar J et al (2012) The role of UNC93B1 protein in surface localization of TLR3 receptor and in cell priming to nucleic acid agonists. J Biol Chem 288(1):442–454

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  112. Huh JW et al (2014) UNC93B1 is essential for the plasma membrane localization and signaling of toll-like receptor 5. Proc Natl Acad Sci USA 111(19):7072–7077

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. Qi R, Singh D, Kao CC (2012) Proteolytic processing regulates toll-like receptor 3 stability and endosomal localization. J Biol Chem 287(39):32617–32629

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  114. Pelka K et al (2014) Cutting edge: the UNC93B1 tyrosine-based motif regulates trafficking and TLR responses via separate mechanisms. J Immunol 193(7):3257–3261

    Article  CAS  PubMed  Google Scholar 

  115. Latz E et al (2002) Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. J Biol Chem 277(49):47834–47843

    Article  CAS  PubMed  Google Scholar 

  116. Ishihara S et al (2004) Essential role of MD-2 in TLR4-dependent signaling during Helicobacter pylori-associated gastritis. J Immunol 173(2):1406–1416

    Article  CAS  PubMed  Google Scholar 

  117. Lee CC, Avalos AM, Ploegh HL (2012) Accessory molecules for toll-like receptors and their function. Nat Rev Immunol 12(3):168–179

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Zanoni I et al (2011) CD14 controls the LPS-induced endocytosis of toll-like receptor 4. Cell 147(4):868–880

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  119. Jiang Z et al (2005) CD14 is required for MyD88-independent LPS signaling. Nat Immunol 6(6):565–570

    Article  CAS  PubMed  Google Scholar 

  120. Abreu MT et al (2002) TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells. J Biol Chem 277(23):20431–20437

    Article  CAS  PubMed  Google Scholar 

  121. Frolova L et al (2008) Expression of toll-like receptor 2 (TLR2), TLR4, and CD14 in biopsy samples of patients with inflammatory bowel diseases: upregulated expression of TLR2 in terminal ileum of patients with ulcerative colitis. J Histochem Cytochem 56(3):267–274

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Liaunardy-Jopeace A, Bryant CE, Gay NJ (2014) The COP II adaptor protein TMED7 is required to initiate and mediate the delivery of TLR4 to the plasma membrane. Sci Signal 7(336):ra70

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Institute of Health (NIH) Grants DK085194, DK093809, DK102934, and CA178599; Charles and Johanna Busch Memorial Award (659160); NSF/BIO/IDBR (1353890) and Rutgers University Faculty Research Grant (281708). S.Y. was supported by New Jersey Commission on Cancer Research Postdoctoral Fellowship (DFHS13PPC016).

Author information

Authors and Affiliations

  1. Department of Biological Sciences, Rutgers University, Room 206, 195 University Ave., Newark, NJ, 07102, USA

    Shiyan Yu & Nan Gao

  2. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA

    Nan Gao

Authors
  1. Shiyan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nan Gao.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, S., Gao, N. Compartmentalizing intestinal epithelial cell toll-like receptors for immune surveillance. Cell. Mol. Life Sci. 72, 3343–3353 (2015). https://doi.org/10.1007/s00018-015-1931-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-015-1931-1

Keywords

Search

Navigation