Innate Immune Signaling and Negative Regulators in Cancer

Chapter

Abstract

Innate immune pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors, and AIM2-like receptors (ALRs), function as pathogen pattern recognition molecules that sensor and initiate innate and adaptive immune responses against microbes and cancer cells. Recognition of pathogen-derived ligands by PRRs expressed on many types of cells, including dendritic cells (DCs) and T cells, triggers the NF-κB, type 1 interferon and inflammasome activation pathways, leading to the production of proinflammatory cytokines that are essential in inflammation and inflammation-linked cancer. Both positive and negative regulators are critical in the maintenance of innate immune homeostasis. In this review, I focus on the current understanding of PRRs, signaling pathways and their regulation through negative regulators. Their relevance to cancer will be discussed as well.

Keywords

Hepatitis Influenza Lysine Oligomerization Interferon 

Notes

Acknowledgements

This work is in part supported by grants from National Institutes of Health and Cancer Research Institute.

References

  1. Abdul-Sater AA, Said-Sadier N, Lam VM, Singh B, Pettengill MA, Soares F, Tattoli I, Lipinski S, Girardin SE, Rosenstiel P et al (2010) Enhancement of reactive oxygen species production and chlamydial infection by the mitochondrial Nod-like family member NLRX1. J Biol Chem 285:41637–41645PubMedCrossRefGoogle Scholar
  2. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511PubMedCrossRefGoogle Scholar
  3. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801PubMedCrossRefGoogle Scholar
  4. Alexander WS, Hilton DJ (2004) The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu Rev Immunol 22:503–529PubMedCrossRefGoogle Scholar
  5. Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, Cornish AL, Darwiche R, Owczarek CM et al (1999) SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98:597–608PubMedCrossRefGoogle Scholar
  6. Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, Herfarth HH, Jobin C, Ting JP (2010) The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med 207:1045–1056PubMedCrossRefGoogle Scholar
  7. Arimoto K, Takahashi H, Hishiki T, Konishi H, Fujita T, Shimotohno K (2007) Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc Natl Acad Sci USA 104:7500–7505PubMedCrossRefGoogle Scholar
  8. Arnoult D, Soares F, Tattoli I, Castanier C, Philpott DJ, Girardin SE (2009) An N-terminal addressing sequence targets NLRX1 to the mitochondrial matrix. J Cell Sci 122:3161–3168PubMedCrossRefGoogle Scholar
  9. Asagiri M, Hirai T, Kunigami T, Kamano S, Gober HJ, Okamoto K, Nishikawa K, Latz E, Golenbock DT, Aoki K et al (2008) Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science 319:624–627PubMedCrossRefGoogle Scholar
  10. Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, Schinzel AC, Sandy P, Meylan E, Scholl C et al (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462:108–112PubMedCrossRefGoogle Scholar
  11. 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 7:49–56PubMedCrossRefGoogle Scholar
  12. Becker CE, O’Neill LA (2007) Inflammasomes in inflammatory disorders: the role of TLRs and their interactions with NLRs. Semin Immunopathol 29:239–248PubMedCrossRefGoogle Scholar
  13. Benko S, Magalhaes JG, Philpott DJ, Girardin SE (2010) NLRC5 Limits the Activation of Inflammatory Pathways. J Immunol 185:1681–1691PubMedCrossRefGoogle Scholar
  14. Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR et al (2000) Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 25:160–165PubMedCrossRefGoogle Scholar
  15. Bosanac I, Wertz IE, Pan B, Yu C, Kusam S, Lam C, Phu L, Phung Q, Maurer B, Arnott D et al (2010) Ubiquitin binding to A20 ZnF4 is required for modulation of NF-kappaB signaling. Mol Cell 40:548–557PubMedCrossRefGoogle Scholar
  16. Brummelkamp TR, Nijman SM, Dirac AM, Bernards R (2003) Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424:797–801PubMedCrossRefGoogle Scholar
  17. Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL (2009) An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat ImmunolGoogle Scholar
  18. Chau TL, Gioia R, Gatot JS, Patrascu F, Carpentier I, Chapelle JP, O’Neill L, Beyaert R, Piette J, Chariot A (2008) Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated? Trends Biochem Sci 33:171–180PubMedCrossRefGoogle Scholar
  19. Chen G, Shaw MH, Kim YG, Nunez G (2009) NOD-like receptors: role in innate immunity and inflammatory disease. Annu Rev Pathol 4:365–398PubMedCrossRefGoogle Scholar
  20. Choe J, Kelker MS, Wilson IA (2005) Crystal structure of human toll-like receptor 3 (TLR3) ­ectodomain. Science 309:581–585PubMedCrossRefGoogle Scholar
  21. Chuang TH, Ulevitch RJ (2004) Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors. Nat Immunol 5:495–502PubMedCrossRefGoogle Scholar
  22. Clevers H (2004) At the crossroads of inflammation and cancer. Cell 118:671–674PubMedCrossRefGoogle Scholar
  23. Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266PubMedCrossRefGoogle Scholar
  24. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A (2010) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 16:90–97PubMedCrossRefGoogle Scholar
  25. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedCrossRefGoogle Scholar
  26. Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ et al (2010) NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell 141:483–496PubMedCrossRefGoogle Scholar
  27. Davis BK, Roberts RA, Huang MT, Willingham SB, Conti BJ, Brickey WJ, Barker BR, Kwan M, Taxman DJ, Accavitti-Loper MA et al (2011) Cutting Edge: NLRC5-Dependent Activation of the Inflammasome. J Immunol 186:1333–1337PubMedCrossRefGoogle Scholar
  28. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG (2007) Inflammation in prostate carcinogenesis. Nat Rev Cancer 7:256–269PubMedCrossRefGoogle Scholar
  29. Deng JC, Cheng G, Newstead MW, Zeng X, Kobayashi K, Flavell RA, Standiford TJ (2006) Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M. J Clin Invest 116:2532–2542PubMedGoogle Scholar
  30. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531PubMedCrossRefGoogle Scholar
  31. Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J (2008) Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674–677PubMedCrossRefGoogle Scholar
  32. Duncan JA, Bergstralh DT, Wang Y, Willingham SB, Ye Z, Zimmermann AG, Ting JP (2007) Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci USA 104:8041–8046PubMedCrossRefGoogle Scholar
  33. Dupaul-Chicoine J, Yeretssian G, Doiron K, Bergstrom KS, McIntire CR, LeBlanc PM, Meunier C, Turbide C, Gros P, Beauchemin N et al (2010) Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32:367–378PubMedCrossRefGoogle Scholar
  34. Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453:1122–1126PubMedCrossRefGoogle Scholar
  35. El-Omar EM, Ng MT, Hold GL (2008) Polymorphisms in Toll-like receptor genes and risk of cancer. Oncogene 27:244–252PubMedCrossRefGoogle Scholar
  36. Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP, Chapman HA, Barton GM (2008) The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456:658–662PubMedCrossRefGoogle Scholar
  37. Ewald SE, Engel A, Lee J, Wang M, Bogyo M, Barton GM (2011) Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J Exp MedGoogle Scholar
  38. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES (2009) AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. NatureGoogle Scholar
  39. Fernandes-Alnemri T, Yu JW, Juliana C, Solorzano L, Kang S, Wu J, Datta P, McCormick M, Huang L, McDermott E et al (2010) The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat Immunol 11:385–393PubMedCrossRefGoogle Scholar
  40. Friedman CS, O’Donnell MA, Legarda-Addison D, Ng A, Cardenas WB, Yount JS, Moran TM, Basler CF, Komuro A, Horvath CM et al (2008) The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep 9:930–936PubMedCrossRefGoogle Scholar
  41. Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, Takeuchi O, Akira S, Chen Z, Inoue S et al (2007) TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446:916–920PubMedCrossRefGoogle Scholar
  42. Gonzalez-Navajas JM, Law J, Nguyen KP, Bhargava M, Corr MP, Varki N, Eckmann L, Hoffman HM, Lee J, Raz E (2010) Interleukin 1 receptor signaling regulates DUBA expression and facilitates Toll-like receptor 9-driven antiinflammatory cytokine production. J Exp Med 207:2799–2807PubMedCrossRefGoogle Scholar
  43. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296PubMedCrossRefGoogle Scholar
  44. Gulen MF, Kang Z, Bulek K, Youzhong W, Kim TW, Chen Y, Altuntas CZ, Sass Bak-Jensen K, McGeachy MJ, Do JS et al (2010) The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. Immunity 32:54–66PubMedCrossRefGoogle Scholar
  45. Haverkamp J, Charbonneau B, Ratliff TL (2008) Prostate inflammation and its potential impact on prostate cancer: a current review. J Cell Biochem 103:1344–1353PubMedCrossRefGoogle Scholar
  46. Hayakawa S, Shiratori S, Yamato H, Kameyama T, Kitatsuji C, Kashigi F, Goto S, Kameoka S, Fujikura D, Yamada T et al (2010) ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses. Nat Immunol 12:37–44PubMedCrossRefGoogle Scholar
  47. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529PubMedCrossRefGoogle Scholar
  48. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196–200PubMedCrossRefGoogle Scholar
  49. Honda K, Taniguchi T (2006) IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 6:644–658PubMedCrossRefGoogle Scholar
  50. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, Takaoka A, Taya C, Taniguchi T (2005a) Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434:1035–1040PubMedCrossRefGoogle Scholar
  51. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T, Shimada N, Ohba Y, Takaoka A, Yoshida N et al (2005b) IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434:772–777PubMedCrossRefGoogle Scholar
  52. Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M et al (2006) 5’-Triphosphate RNA is the ligand for RIG-I. Science 314:994–997PubMedCrossRefGoogle Scholar
  53. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA (2009) AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. NatureGoogle Scholar
  54. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603PubMedCrossRefGoogle Scholar
  55. Inohara C, McDonald C, Nunez G (2005) NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem 74:355–383PubMedCrossRefGoogle Scholar
  56. Ishikawa H, Barber GN (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455:674–678PubMedCrossRefGoogle Scholar
  57. Ishikawa H, Ma Z, Barber GN (2009) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–792PubMedCrossRefGoogle Scholar
  58. Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995PubMedCrossRefGoogle Scholar
  59. Janssens S, Beyaert R (2003) Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol Cell 11:293–302PubMedCrossRefGoogle Scholar
  60. Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3:499PubMedCrossRefGoogle Scholar
  61. Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P et al (2006) Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–236PubMedCrossRefGoogle Scholar
  62. Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5:749–759PubMedCrossRefGoogle Scholar
  63. Karin M, Lawrence T, Nizet V (2006) Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124:823–835PubMedCrossRefGoogle Scholar
  64. Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O et al (2005) Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:19–28PubMedCrossRefGoogle Scholar
  65. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ et al (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105PubMedCrossRefGoogle Scholar
  66. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S (2008) Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 205:1601–1610PubMedCrossRefGoogle Scholar
  67. Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, Niwa A, Chen Y, Nakazaki K, Nomoto J et al (2009) Frequent inactivation of A20 in B-cell lymphomas. Nature 459:712–716PubMedCrossRefGoogle Scholar
  68. Kawagoe T, Takeuchi O, Takabatake Y, Kato H, Isaka Y, Tsujimura T, Akira S (2009) TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis. Nat Immunol 10:965–972PubMedCrossRefGoogle Scholar
  69. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S (2005) IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6:981–988PubMedCrossRefGoogle Scholar
  70. Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O’Rourke KM, Eby M, Pietras E, Cheng G, Bazan JF et al (2007) DUBA: a deubiquitinase that regulates type I interferon production. Science 318:1628–1632PubMedCrossRefGoogle Scholar
  71. Kerur N, Veettil MV, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P, Chandran B (2011) IFI16 Acts as a Nuclear Pathogen Sensor to Induce the Inflammasome in Response to Kaposi Sarcoma-Associated Herpesvirus Infection. Cell Host Microbe 9:363–375PubMedCrossRefGoogle Scholar
  72. Kim YM, Brinkmann MM, Paquet ME, Ploegh HL (2008) UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature 452:234–238PubMedCrossRefGoogle Scholar
  73. Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M, Yoshida H, Kubo M, Yoshimura A (2002) SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17:583–591PubMedCrossRefGoogle Scholar
  74. Kobayashi K, Hernandez LD, Galan JE, Janeway CA Jr, Medzhitov R, Flavell RA (2002) IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110:191–202PubMedCrossRefGoogle Scholar
  75. Komander D, Lord CJ, Scheel H, Swift S, Hofmann K, Ashworth A, Barford D (2008) The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Mol Cell 29:451–464PubMedCrossRefGoogle Scholar
  76. Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G (2003) The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424:801–805PubMedCrossRefGoogle Scholar
  77. Kuenzel S, Till A, Winkler M, Hasler R, Lipinski S, Jung S, Grotzinger J, Fickenscher H, Schreiber S, Rosenstiel P (2010) The nucleotide-binding oligomerization domain-like receptor NLRC5 is involved in IFN-dependent antiviral immune responses. J Immunol 184:1990–2000PubMedCrossRefGoogle Scholar
  78. Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A (2000) Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289:2350–2354PubMedCrossRefGoogle Scholar
  79. Lee AJ, Zhou X, Chang M, Hunzeker J, Bonneau RH, Zhou D, Sun SC (2010) Regulation of natural killer T-cell development by deubiquitinase CYLD. EMBO J 29:1600–1612PubMedCrossRefGoogle Scholar
  80. Lin WW, Karin M (2007) A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117:1175–1183PubMedCrossRefGoogle Scholar
  81. Loo YM, Fornek J, Crochet N, Bajwa G, Perwitasari O, Martinez-Sobrido L, Akira S, Gill MA, Garcia-Sastre A, Katze MG et al (2008) Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol 82:335–345PubMedCrossRefGoogle Scholar
  82. Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA 101:5598–5603PubMedCrossRefGoogle Scholar
  83. Luo JL, Maeda S, Hsu LC, Yagita H, Karin M (2004) Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6:297–305PubMedCrossRefGoogle Scholar
  84. Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, Kagnoff MF, Eckmann L, Karin M (2005a) Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing. Science 307:734–738PubMedCrossRefGoogle Scholar
  85. Maeda S, Kamata H, Luo JL, Leffert H, Karin M (2005b) IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121:977–990PubMedCrossRefGoogle Scholar
  86. Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7:31–40PubMedCrossRefGoogle Scholar
  87. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232PubMedCrossRefGoogle Scholar
  88. Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN (1999) SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98:609–616PubMedCrossRefGoogle Scholar
  89. Martinon F, Tschopp J (2005) NLRs join TLRs as innate sensors of pathogens. Trends Immunol 26:447–454PubMedCrossRefGoogle Scholar
  90. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241PubMedCrossRefGoogle Scholar
  91. Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fassler R (2006) Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 125:665–677PubMedCrossRefGoogle Scholar
  92. Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z et al (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 11:897–904PubMedCrossRefGoogle Scholar
  93. Meissner TB, Li A, Biswas A, Lee KH, Liu YJ, Bayir E, Iliopoulos D, van den Elsen PJ, Kobayashi KS (2010) NLR family member NLRC5 is a transcriptional regulator of MHC class I genes. Proc Natl Acad Sci USAGoogle Scholar
  94. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–1172PubMedCrossRefGoogle Scholar
  95. Meylan E, Dooley AL, Feldser DM, Shen L, Turk E, Ouyang C, Jacks T (2009) Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature 462:104–107PubMedCrossRefGoogle Scholar
  96. Moore CB, Bergstralh DT, Duncan JA, Lei Y, Morrison TE, Zimmermann AG, Accavitti-Loper MA, Madden VJ, Sun L, Ye Z et al (2008) NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451:573–577PubMedCrossRefGoogle Scholar
  97. Nakagawa R, Naka T, Tsutsui H, Fujimoto M, Kimura A, Abe T, Seki E, Sato S, Takeuchi O, Takeda K et al (2002) SOCS-1 participates in negative regulation of LPS responses. Immunity 17:677–687PubMedCrossRefGoogle Scholar
  98. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP et al (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222–230PubMedCrossRefGoogle Scholar
  99. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M (2007) Gender ­disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121–124PubMedCrossRefGoogle Scholar
  100. Neerincx A, Lautz K, Menning M, Kremmer E, Zigrino P, Hosel M, Buning H, Schwarzenbacher R, Kufer TA (2010) A role for the human nucleotide-binding domain, leucine-rich repeat-containing family member NLRC5 in antiviral responses. J Biol Chem 285:26223–26232PubMedCrossRefGoogle Scholar
  101. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606PubMedCrossRefGoogle Scholar
  102. Opipari AW Jr, Boguski MS, Dixit VM (1990) The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein. J Biol Chem 265:14705–14708PubMedGoogle Scholar
  103. Oshiumi H, Miyashita M, Inoue N, Okabe M, Matsumoto M, Seya T (2010) The Ubiquitin Ligase Riplet Is Essential for RIG-I-Dependent Innate Immune Responses to RNA Virus Infection. Cell Host Microbe 8:496–509PubMedCrossRefGoogle Scholar
  104. Park B, Brinkmann MM, Spooner E, Lee CC, Kim YM, Ploegh HL (2008) Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat Immunol 9:1407–1414PubMedCrossRefGoogle Scholar
  105. Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang R-F (2005) Toll-like receptor 8 mediated-reversal of CD4+ regulatory T cell function. Science 309:1380–1384PubMedCrossRefGoogle Scholar
  106. Peng G, Wang HY, Peng W, Kiniwa Y, Seo K, Wang R-F (2007) Tumor-infiltrating gamma-delta T cells suppress T and dendritic cell function via mechanisms controlled by a unique Toll-like receptor signaling pathway. Immunity 27:334–348PubMedCrossRefGoogle Scholar
  107. Peto J (2001) Cancer epidemiology in the last century and the next decade. Nature 411:390–395PubMedCrossRefGoogle Scholar
  108. Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, Reis e Sousa C (2006) RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science 314:997–1001PubMedCrossRefGoogle Scholar
  109. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466PubMedCrossRefGoogle Scholar
  110. Rakoff-Nahoum S, Medzhitov R (2007) Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317:124–127PubMedCrossRefGoogle Scholar
  111. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229–241PubMedCrossRefGoogle Scholar
  112. Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L, Vanaja SK, Monks BG, Ganesan S, Latz E et al (2010) The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 11:395–402PubMedCrossRefGoogle Scholar
  113. Rehwinkel J, Tan CP, Goubau D, Schulz O, Pichlmair A, Bier K, Robb N, Vreede F, Barclay W, Fodor E et al (2010) RIG-I detects viral genomic RNA during negative-strand RNA virus ­infection. Cell 140:397–408PubMedCrossRefGoogle Scholar
  114. Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC, Sun SC (2006) Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 7:411–417PubMedCrossRefGoogle Scholar
  115. Reiley WW, Jin W, Lee AJ, Wright A, Wu X, Tewalt EF, Leonard TO, Norbury CC, Fitzpatrick L, Zhang M et al (2007) Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med 204:1475–1485PubMedCrossRefGoogle Scholar
  116. Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, Hardy LL, Garceau V, Sweet MJ, Ross IL (2009) HIN-200 Proteins Regulate Caspase Activation in Response to Foreign Cytoplasmic DNA. ScienceGoogle Scholar
  117. Ryzhakov G, Randow F (2007) SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK. EMBO J 26:3180–3190PubMedCrossRefGoogle Scholar
  118. Sabbah A, Chang TH, Harnack R, Frohlich V, Tominaga K, Dube PH, Xiang Y, Bose S (2009) Activation of innate immune antiviral responses by Nod2. Nat Immunol 10:1073–1080PubMedCrossRefGoogle Scholar
  119. Saha SK, Pietras EM, He JQ, Kang JR, Liu SY, Oganesyan G, Shahangian A, Zarnegar B, Shiba TL, Wang Y et al (2006) Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J 25:3257–3263PubMedCrossRefGoogle Scholar
  120. Saito T, Hirai R, Loo YM, Owen D, Johnson CL, Sinha SC, Akira S, Fujita T, Gale M Jr (2007) Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc Natl Acad Sci USA 104:582–587PubMedCrossRefGoogle Scholar
  121. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M Jr (2008) Innate immunity induced by ­composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454:523–527PubMedCrossRefGoogle Scholar
  122. Salcedo R, Worschech A, Cardone M, Jones Y, Gyulai Z, Dai RM, Wang E, Ma W, Haines D, O’HUigin C et al (2010) MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J Exp Med 207:1625–1636PubMedCrossRefGoogle Scholar
  123. Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K, Tsujimura T, Fujita T, Akira S, Takeuchi O (2010) LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc Natl Acad Sci USA 107:1512–1517PubMedCrossRefGoogle Scholar
  124. Schmitz R, Hansmann ML, Bohle V, Martin-Subero JI, Hartmann S, Mechtersheimer G, Klapper W, Vater I, Giefing M, Gesk S et al (2009) TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 206:981–989PubMedCrossRefGoogle Scholar
  125. Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832PubMedCrossRefGoogle Scholar
  126. Seth RB, Sun L, Ea CK, Chen ZJ (2005) Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-kappaB and IRF3. Cell 122:669–682PubMedCrossRefGoogle Scholar
  127. Shaw MH, Reimer T, Sanchez-Valdepenas C, Warner N, Kim YG, Fresno M, Nunez G (2009) T cell-intrinsic role of Nod2 in promoting type 1 immunity to Toxoplasma gondii. Nat Immunol 10:1267–1274PubMedCrossRefGoogle Scholar
  128. Shembade N, Harhaj NS, Parvatiyar K, Copeland NG, Jenkins NA, Matesic LE, Harhaj EW (2008) The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20. Nat Immunol 9:254–262PubMedCrossRefGoogle Scholar
  129. Shembade N, Parvatiyar K, Harhaj NS, Harhaj EW (2009) The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling. EMBO J 28:513–522PubMedCrossRefGoogle Scholar
  130. Shembade N, Ma A, Harhaj EW (2010) Inhibition of NF-kappaB signaling by A20 through ­disruption of ubiquitin enzyme complexes. Science 327:1135–1139PubMedCrossRefGoogle Scholar
  131. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA et al (1997) A family of cytokine-inducible inhibitors of signalling. Nature 387:917–921PubMedCrossRefGoogle Scholar
  132. Sun SC (2008) Deubiquitylation and regulation of the immune response. Nat Rev Immunol 8:501–511PubMedCrossRefGoogle Scholar
  133. Sun J, Wiklund F, Zheng SL, Chang B, Balter K, Li L, Johansson JE, Li G, Adami HO, Liu W et al (2005) Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. J Natl Cancer Inst 97:525–532PubMedCrossRefGoogle Scholar
  134. Sutmuller RP, Morgan ME, Netea MG, Grauer O, Adema GJ (2006) Toll-like receptors on ­regulatory T cells: expanding immune regulation. Trends Immunol 27:387–393PubMedCrossRefGoogle Scholar
  135. Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galan JE, Askenase PW et al (2006) Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24:317–327PubMedCrossRefGoogle Scholar
  136. Suzuki N, Suzuki S, Duncan GS, Millar DG, Wada T, Mirtsos C, Takada H, Wakeham A, Itie A, Li S et al (2002) Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416:750–756PubMedCrossRefGoogle Scholar
  137. Swann JB, Vesely MD, Silva A, Sharkey J, Akira S, Schreiber RD, Smyth MJ (2008) Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci USA 105:652–656PubMedCrossRefGoogle Scholar
  138. Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, Crozat K, Mudd S, Mann N, Sovath S, Goode J et al (2006) The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol 7:156–164PubMedCrossRefGoogle Scholar
  139. Takahasi K, Yoneyama M, Nishihori T, Hirai R, Kumeta H, Narita R, Gale M Jr, Inagaki F, Fujita T (2008) Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses. Mol Cell 29:428–440PubMedCrossRefGoogle Scholar
  140. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW et al (2005) Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434:243–249PubMedCrossRefGoogle Scholar
  141. Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–14PubMedCrossRefGoogle Scholar
  142. Takeuchi O, Akira S (2008) MDA5/RIG-I and virus recognition. Curr Opin Immunol 20:17–22PubMedCrossRefGoogle Scholar
  143. Tattoli I, Carneiro LA, Jehanno M, Magalhaes JG, Shu Y, Philpott DJ, Arnoult D, Girardin SE (2008) NLRX1 is a mitochondrial NOD-like receptor that amplifies NF-kappaB and JNK ­pathways by inducing reactive oxygen species production. EMBO Rep 9:293–300PubMedCrossRefGoogle Scholar
  144. Thomassen E, Renshaw BR, Sims JE (1999) Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine 11:389–399PubMedCrossRefGoogle Scholar
  145. Ting JP, Davis BK (2005) CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu Rev Immunol 23:387–414PubMedCrossRefGoogle Scholar
  146. Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhaes JG, Yuan L, Soares F, Chea E, Le Bourhis L et al (2010) Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 11:55–62PubMedCrossRefGoogle Scholar
  147. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G (2003) CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424:793–796PubMedCrossRefGoogle Scholar
  148. Tsuchida T, Zou J, Saitoh T, Kumar H, Abe T, Matsuura Y, Kawai T, Akira S (2010) The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA. Immunity 33:765–776PubMedCrossRefGoogle Scholar
  149. Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB, Sharma S, Sirois CM, Jin T, Latz E, Xiao TS et al (2010) IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol 11:997–1004PubMedCrossRefGoogle Scholar
  150. Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, Towne J, Sims JE, Stark GR, Li X (2003) SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 4:920–927PubMedCrossRefGoogle Scholar
  151. Wertz IE, O’Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL et al (2004) De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430:694–699PubMedCrossRefGoogle Scholar
  152. Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (1999) IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J Biol Chem 274:19403–19410PubMedCrossRefGoogle Scholar
  153. Xia X, Cui J, Wang HY, Zhu L, Matsueda S, Wang Q, Yang X, Hong J, Songyang Z, Chen Z et al (2011) NLRX1 negatively regulates TLR-induced NF-κB signaling by targeting TRAF6 and IKK. Immunity 34(6):843–853PubMedCrossRefGoogle Scholar
  154. Xiao H, Gulen MF, Qin J, Yao J, Bulek K, Kish D, Altuntas CZ, Wald D, Ma C, Zhou H et al (2007) The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26:461–475PubMedCrossRefGoogle Scholar
  155. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB (2005) VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19:727–740PubMedCrossRefGoogle Scholar
  156. Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S et al (2005) TLR11 activation of dendritic cells by a ­protozoan profilin-like protein. Science 308:1626–1629PubMedCrossRefGoogle Scholar
  157. Yoneyama M, Fujita T (2009) RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev 227:54–65PubMedCrossRefGoogle Scholar
  158. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T (2004) The RNA helicase RIG-I has an essential function in double-stranded ­RNA-induced innate antiviral responses. Nat Immunol 5:730–737PubMedCrossRefGoogle Scholar
  159. You F, Sun H, Zhou X, Sun W, Liang S, Zhai Z, Jiang Z (2009) PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat Immunol 10:1300–1308PubMedCrossRefGoogle Scholar
  160. Yu Y, Hayward GS (2010) The ubiquitin E3 ligase RAUL negatively regulates type i interferon through ubiquitination of the transcription factors IRF7 and IRF3. Immunity 33:863–877PubMedCrossRefGoogle Scholar
  161. Yu Y, Wang SE, Hayward GS (2005) The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity 22:59–70PubMedCrossRefGoogle Scholar
  162. Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti TD (2010) The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32:379–391PubMedCrossRefGoogle Scholar
  163. Zeng W, Sun L, Jiang X, Chen X, Hou F, Adhikari A, Xu M, Chen ZJ (2010) Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 141:315–330PubMedCrossRefGoogle Scholar
  164. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S (2004) A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303:1522–1526PubMedCrossRefGoogle Scholar
  165. Zheng SL, Augustsson-Balter K, Chang B, Hedelin M, Li L, Adami HO, Bensen J, Li G, Johnasson JE, Turner AR et al (2004) Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer Res 64:2918–2922PubMedCrossRefGoogle Scholar
  166. Zhong B, Yang Y, Li S, Wang YY, Li Y, Diao F, Lei C, He X, Zhang L, Tien P et al (2008) The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29:538–550PubMedCrossRefGoogle Scholar
  167. Zhong B, Zhang L, Lei C, Li Y, Mao AP, Yang Y, Wang YY, Zhang XL, Shu HB (2009) The ­ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. Immunity 30:397–407PubMedCrossRefGoogle Scholar
  168. Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Departments of Pathology and Immunology, The Center for Cell and Gene TherapyBaylor College of MedicineHoustonUSA

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