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EcoSal Plus

Domain 8:


NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins

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  • Authors: Leticia A. M. Carneiro1, JÖrg H. Fritz2, Thomas A. Kufer3, Leonardo H. Travassos4, Szilvia Benko5, and Dana J. Philpott6
  • Editor: Michael S. Donnenberg7
    Affiliations: 1: Laboratory Medicine and Pathobiology; 2: Departments of Immunology; 3: University of Toronto, Toronto, Ontario M5S 1A8, Canada, and Molecular Innate Immunobiology Group, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50931 Cologne, Germany; 4: Departments of Immunology; 5: Laboratory Medicine and Pathobiology; 6: Departments of Immunology; 7: University of Maryland, School of Medicine, Baltimore, MD
  • Received 09 February 2009 Accepted 03 May 2009 Published 07 December 2009
  • Address correspondence to Dana J. Philpott [email protected]
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  • Abstract:

    Eukaryotes have evolved strategies to detect microbial intrusion and instruct immune responses to limit damage from infection. Recognition of microbes and cellular damage relies on the detection of microbe-associated molecular patterns (MAMPs, also called PAMPS, or pathogen-associated molecular patterns) and so-called "danger signals" by various families of host pattern recognition receptors (PRRs). Members of the recently identified protein family of nucleotide-binding domain andleucine-rich-repeat-containing proteins (NLR), including Nod1, Nod2, NLRP3, and NLRC4, have been shown to detect specific microbial motifs and danger signals for regulating host inflammatory responses. Moreover, with the discovery that polymorphisms in , , , and are associated with susceptibility to chronic inflammatory disorders, the view has emerged that NLRs act not only as sensors butalso can serve as signaling platforms for instructing and balancing host immune responses. In this chapter, we explore the functions of these intracellular innate immune receptors and examine their implication in inflammatory diseases.

  • Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3


1. Akira S, Yamamoto M, Takeda K. 2003. Role of adapters in Toll-like receptor signalling. Biochem Soc Trans 31:637–642. [PubMed][CrossRef]
2. Meylan E, Tschopp J. 2006. Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses. Mol Cell 22:561–569. [PubMed][CrossRef]
3. Fritz JH, Ferrero RL, Philpott DJ, Girardin SE. 2006. Nod-like proteins in immunity, inflammation and disease. Nat Immunol 7:1250–1257. [PubMed][CrossRef]
4. Rus H, Cudrici C, Niculescu F. 2005. The role of the complement system in innate immunity. Immunol Res 33:103–112. [PubMed][CrossRef]
5. Mukhopadhyay S, Gordon S. 2004. The role of scavenger receptors in pathogen recognition and innate immunity. Immunobiology 209:39–49. [PubMed][CrossRef]
6. Chaput C, Boneca IG. 2007. Peptidoglycan detection by mammals and flies. Microbes Infect 9:637–647. [PubMed][CrossRef]
7. Klesney-Tait J, Turnbull IR, Colonna M. 2006. The TREM receptor family and signal integration. Nat Immunol 7:1266–1273. [PubMed][CrossRef]
8. Crocker PR, Paulson JC, Varki A. 2007. Siglecs and their roles in the immune system. Nat Rev Immunol 7:255–266. [PubMed][CrossRef]
9. Manfredi AA, Rovere-Querini P, Bottazzi B, Garlanda C, Mantovani A. 2008. Pentraxins, humoral innate immunity and tissue injury. Curr Opin Immunol 20:538–544. [PubMed][CrossRef]
10. Robinson MJ, Sancho D, Slack EC, LeibundGut-Landmann S, Reis C e Sousa. 2006. Myeloid C-type lectins in innate immunity. Nat Immunol 7:1258–1265. [PubMed][CrossRef]
11. Shi Y. 2006. Mechanical aspects of apoptosome assembly. Curr Opin Cell Biol 18:677–684. [PubMed][CrossRef]
12. Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S, Carrio R, Merino J, Liu D, Ni J, Nuñez G. 1999. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. J Biol Chem 274:14560–14567. [PubMed][CrossRef]
13. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nuñez G. 2001. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J Biol Chem 276:4812–4818. [PubMed][CrossRef]
14. Jones JD, Dangl JL. 2006. The plant immune system. Nature 444:323–329.[PubMed]
15. Inohara N, Chamaillard M, McDonald C, Nuñez G. 2005. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem 74:355–383. [PubMed][CrossRef]
16. Martinon F, Tschopp J. 2005. NLRs join TLRs as innate sensors of pathogens. Trends Immunol 26:447–454. [PubMed][CrossRef]
17. Ting JP, Davis BK. 2005. CATERPILLER: a novel gene family important in immunity, cell death, and diseases. Annu Rev Immunol 23:387–414. [PubMed][CrossRef]
18. Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, Flavell RA, Girardin SE, Godzik A, Harton JA, Hoffman HM, Hugot JP, Inohara N, Mackenzie A, Maltais LJ, Nuñez G, Ogura Y, Otten LA, Philpott D, Reed JC, Reith W, Schreiber S, Steimle V, Ward PA. 2008. The NLR gene family: a standard nomenclature. Immunity 28:285–287. [PubMed][CrossRef]
19. Leipe DD, Koonin EV, Aravind L. 2004. STAND, a class of P-loop NTPases including animal and plant regulators of programmed cell death: multiple, complex domain architectures, unusual phyletic patterns, and evolution by horizontal gene transfer. J Mol Biol 343:1–28. [PubMed][CrossRef]
20. Kufer TA, Fritz JH, Philpott DJ. 2005. NACHT-LRR proteins (NLRs) in bacterial infection and immunity. Trends Microbiol 13:381–388. [PubMed][CrossRef]
21. Proell M, Riedl SJ, Fritz JH, Rojas AM, Schwarzenbacher R. 2008. The Nod-like receptor (NLR) family: a tale of similarities and differences. PLoS ONE 3:e2119. [PubMed][CrossRef]
22. Bell JK, Mullen GE, Leifer CA, Mazzoni A, Davies DR, Segal DM. 2003. Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol 24:528–533. [PubMed][CrossRef]
23. Kobe B, Kajava AV. 2001. The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol 11:725–732. [PubMed][CrossRef]
24. Bell JK, Askins J, Hall PR, Davies DR, Segal DM. 2006. The dsRNA binding site of human Toll-like receptor 3. Proc Natl Acad Sci USA 103:8792–8797. [PubMed][CrossRef]
25. Bell JK, Botos I, Hall PR, Askins J, Shiloach J, Segal DM, Davies DR. 2005. The molecular structure of the Toll-like receptor 3 ligand-binding domain. Proc Natl Acad Sci USA 102:10976–10980. [PubMed][CrossRef]
26. Choe J, Kelker MS, Wilson IA. 2005. Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309:581–585. [PubMed][CrossRef]
27. Girardin SE, Jehanno M, Mengin-Lecreulx D, Sansonetti PJ, Alzari PM, Philpott DJ. 2005. Identification of the critical residues involved in peptidoglycan detection by Nod1. J Biol Chem 280:38648–38656. [PubMed][CrossRef]
28. Magalhaes JG, Philpott DJ, Nahori MA, Jehanno M, Fritz J, Bourhis LL, Viala J, Hugot JP, Giovannini M, Bertin J, Lepoivre M, Mengin-Lecreulx D, Sansonetti PJ, Girardin SE. 2005. Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin. EMBO Rep 6:1201–1207. [PubMed][CrossRef]
29. Tanabe T, Chamaillard M, Ogura Y, Zhu L, Qiu S, Masumoto J, Ghosh P, Moran A, Predergast MM, Tromp G, Williams CJ, Inohara N, Nuñez G. 2004. Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition. EMBO J 23:1587–1597. [PubMed][CrossRef]
30. Medzhitov R, Janeway CA Jr. 2002. Decoding the patterns of self and nonself by the innate immune system. Science 296:298–300. [PubMed][CrossRef]
31. Zipfel C. 2008. Pattern-recognition receptors in plant innate immunity. Curr Opin Immunol 20:10–16. [PubMed][CrossRef]
32. Gottar M, Gobert V, Matskevich AA, Reichhart JM, Wang C, Butt TM, Belvin M, Hoffmann JA, Ferrandon D. 2006. Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors. Cell 127:1425–1437. [PubMed][CrossRef]
33. Sokol CL, Barton GM, Farr AG, Medzhitov R. 2008. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol 9:310–318. [PubMed][CrossRef]
34. 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 104:8041–8046. [PubMed][CrossRef]
35. Ye Z, Lich JD, Moore CB, Duncan JA, Williams KL, Ting JP. 2008. ATP binding by monarch-1/NLRP12 is critical for its inhibitory function. Mol Cell Biol 28:1841–1850. [PubMed][CrossRef]
36. Harton JA, Cressman DE, Chin KC, Der CJ, Ting JP. 1999. GTP binding by class II transactivator: role in nuclear import. Science 285:1402–1405. [PubMed][CrossRef]
37. Riedl SJ, Li W, Chao Y, Schwarzenbacher R, Shi Y. 2005. Structure of the apoptotic protease-activating factor 1 bound to ADP. Nature 434:926–933. [PubMed][CrossRef]
38. Jiang X, Wang X. 2000. Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. J Biol Chem 275:31199–31203. [PubMed][CrossRef]
39. Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF, Ogura Y, Nuñez G. 2000. An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem 275:27823–27831.[PubMed]
40. Damiano JS, Oliveira V, Welsh K, Reed JC. 2004. Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses. Biochem J 381:21.3–219.
41. Sisk TJ, Roys S, Chang CH. 2001. Self-association of CIITA and its transactivation potential. Mol Cell Biol 21:4919–4928. [PubMed][CrossRef]
42. Kufer TA. 2008. Signal transduction pathways used by NLR-type innate immune receptors. Mol Biosyst 4:380–386. [PubMed][CrossRef]
43. Inohara N, Nuñez G. 2001. The NOD: a signaling module that regulates apoptosis and host defense against pathogens. Oncogene 20:6473–6481. [PubMed][CrossRef]
44. Manon F, Favier A, Nuñez G, Simorre JP, Cusack S. 2007. Solution structure of NOD1 CARD and mutational analysis of its interaction with the CARD of downstream kinase RICK. J Mol Biol 365:160–174. [PubMed][CrossRef]
45. Coussens NP, Mowers JC, McDonald C, Nuñez G, Ramaswamy S. 2007. Crystal structure of the Nod1 caspase activation and recruitment domain. Biochem Biophys Res Commun 353:1–5. [PubMed][CrossRef]
46. Ting JP, Trowsdale J. 2002. Genetic control of MHC class II expression. Cell 109(Suppl) :S21–S33. [CrossRef]
47. Harton JA, Ting JP. 2000. Class II transactivator: mastering the art of major histocompatibility complex expression. Mol Cell Biol 20:6185–6194. [PubMed][CrossRef]
48. Wright KL, Ting JP. 2006. Epigenetic regulation of MHC-II and CIITA genes. Trends Immunol 27:405–412. [PubMed][CrossRef]
49. Boss JM. 1997. Regulation of transcription of MHC class II genes. Curr Opin Immunol 9:107–113. [PubMed][CrossRef]
50. Wong AW, Brickey WJ, Taxman DJ, van Deventer HW, Reed W, Gao JX, Zheng P, Liu Y, Li P, Blum JS, McKinnon KP, Ting JP. 2003. CIITA-regulated plexin-A1 affects T-cell-dendritic cell interactions. Nat Immunol 4:891–898. [PubMed][CrossRef]
51. Reith W, Mach B. 2001. The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol 19:331–373. [PubMed][CrossRef]
52. Accolla RS, De Lerma Barbaro A, Mazza S, Casoli C, De Maria A, Tosi G. 2001. The MHC class II transactivator: prey and hunter in infectious diseases. Trends Immunol 22:560–563. [PubMed][CrossRef]
53. Fortier A, Diez E, Gros P. 2005. Naip5/Birc1e and susceptibility to Legionella pneumophila. Trends Microbiol 13:328–335. [PubMed][CrossRef]
54. Miao EA, Andersen-Nissen E, Warren SE, Aderem A. 2007. TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Semin Immunopathol 29:275–288. [PubMed][CrossRef]
55. Lamkanfi M, Amer A, Kanneganti TD, Munoz-Planillo R, Chen G, Vandenabeele P, Fortier A, Gros P, Nuñez G. 2007. The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation. J Immunol 178:8022–8027.[PubMed]
56. Vinzing M, Eitel J, Lippmann J, Hocke AC, Zahlten J, Slevogt H, N’Guessan P D, Gunther S, Schmeck B, Hippenstiel S, Flieger A, Suttorp N, Opitz B. 2008. NAIP and Ipaf control Legionella pneumophila replication in human cells. J Immunol 180:6808–6815.[PubMed]
57. Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, Mariathasan S, Dixit VM, Flavell RA, Dietrich WF, Roy CR. 2006. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 7:318–325. [PubMed][CrossRef]
58. Fortier A, de Chastellier C, Balor S, Gros P. 2007. Birc1e/Naip5 rapidly antagonizes modulation of phagosome maturation by Legionella pneumophila. Cell Microbiol 9:910–923. [PubMed][CrossRef]
59. Amer AO, Swanson MS. 2005. Autophagy is an immediate macrophage response to Legionella pneumophila. Cell Microbiol 7:765–778. [PubMed][CrossRef]
60. Lightfield KL, Persson J, Brubaker SW, Witte CE, von Moltke J, Dunipace EA, Henry T, Sun YH, Cado D, Dietrich WF, Monack DM, Tsolis RM, Vance RE. 2008. Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat Immunol 9:1171–1178. [PubMed][CrossRef]
61. Maier JK, Lahoua Z, Gendron NH, Fetni R, Johnston A, Davoodi J, Rasper D, Roy S, Slack RS, Nicholson DW, MacKenzie AE. 2002. The neuronal apoptosis inhibitory protein is a direct inhibitor of caspases 3 and 7. J Neurosci 22:2035–2043.[PubMed]
62. Kufer TA, Kremmer E, Adam AC, Philpott DJ, Sansonetti PJ. 2008. The pattern-recognition molecule Nod1 is localized at the plasma membrane at sites of bacterial interaction. Cell Microbiol 10:477–486.[PubMed]
63. Fritz JH, Girardin SE, Fitting C, Werts C, Mengin-Lecreulx D, Caroff M, Cavaillon JM, Philpott DJ, Adib-Conquy M. 2005. Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists. Eur J Immunol 35:2459–2470. [PubMed][CrossRef]
64. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, Ogura Y, Kawasaki A, Fukase K, Kusumoto S, Valvano MA, Foster SJ, Mak TW, Nuñez G, Inohara N. 2003. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol 4:702–707. [PubMed][CrossRef]
65. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J, Tedin K, Taha MK, Labigne A, Zahringer U, Coyle AJ, DiStefano PS, Bertin J, Sansonetti PJ, Philpott DJ. 2003. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300:1584–1587. [PubMed][CrossRef]
66. Carneiro LA, Magalhaes JG, Tattoli I, Philpott DJ, Travassos LH. 2008. Nod-like proteins in inflammation and disease. J Pathol 214:136–148. [PubMed][CrossRef]
67. Girardin SE, Tournebize R, Mavris M, Page AL, Li X, Stark GR, Bertin J, DiStefano PS, Yaniv M, Sansonetti PJ, Philpott DJ. 2001. CARD4/Nod1 mediates NF-κB and JNK activation by invasive Shigella flexneri. EMBO Rep 2:736–742. [PubMed][CrossRef]
68. Glomski IJ, Fritz JH, Keppler SJ, Balloy V, Chignard M, Mock M, Goossens PL. 2007. Murine splenocytes produce inflammatory cytokines in a MyD88-dependent response to Bacillus anthracis spores. Cell Microbiol 9:502–513. [PubMed][CrossRef]
69. Ferwerda G, Girardin SE, Kullberg BJ, Le Bourhis L, de Jong DJ, Langenberg DM, van Crevel R, Adema GJ, Ottenhoff TH, Van der Meer JW, Netea MG. 2005. NOD2 and toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog 1:279–285. [PubMed][CrossRef]
70. Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Memet S, Huerre MR, Coyle AJ, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL. 2004. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 5:1166–1174. [PubMed][CrossRef]
71. Travassos LH, Carneiro LA, Girardin SE, Boneca IG, Lemos R, Bozza MT, Domingues RC, Coyle AJ, Bertin J, Philpott DJ, Plotkowski MC. 2005. Nod1 participates in the innate immune response to Pseudomonas aeruginosa. J Biol Chem 280:36714–36718. [PubMed][CrossRef]
72. Ratner AJ, Aguilar JL, Shchepetov M, Lysenko ES, Weiser JN. 2007. Nod1 mediates cytoplasmic sensing of combinations of extracellular bacteria. Cell Microbiol 9:1343–1351. [PubMed][CrossRef]
73. Lysenko ES, Clarke TB, Shchepetov M, Ratner AJ, Roper DI, Dowson CG, Weiser JN. 2007. Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing. PLoS Pathog 3:e118. [PubMed][CrossRef]
74. Kanneganti TD, Lamkanfi M, Kim YG, Chen G, Park JH, Franchi L, Vandenabeele P, Nuñez G. 2007. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 26:433–443.[PubMed]
75. Swaan PW, Bensman T, Bahadduri PM, Hall MW, Sarkar A, Bao S, Khantwal CM, Ekins S, Knoell DL. 2008. Bacterial peptide recognition and immune activation facilitated by human peptide transporter PEPT2. Am J Respir Cell Mol Biol 39:536–542. [PubMed][CrossRef]
76. Vavricka SR, Musch MW, Chang JE, Nakagawa Y, Phanvijhitsiri K, Waypa TS, Merlin D, Schneewind O, Chang EB. 2004. hPepT1 transports muramyl dipeptide, activating NF-κB and stimulating IL-8 secretion in human colonic Caco2/bbe cells. Gastroenterology 127:1401–1409. [PubMed][CrossRef]
77. Zhao L, Kwon MJ, Huang S, Lee JY, Fukase K, Inohara N, Hwang DH. 2007. Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells. J Biol Chem 282:11618–11628. [PubMed][CrossRef]
78. Inamura S, Fujimoto Y, Kawasaki A, Shiokawa Z, Woelk E, Heine H, Lindner B, Inohara N, Kusumoto S, Fukase K. 2006. Synthesis of peptidoglycan fragments and evaluation of their biological activity. Org Biomol Chem 4:232–242. [PubMed][CrossRef]
79. Travassos LH, Girardin SE, Philpott DJ, Blanot D, Nahori MA, Werts C, Boneca IG. 2004. Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep 5:1000–1006. [PubMed][CrossRef]
80. Dziarski R, Gupta D. 2005. Peptidoglycan recognition in innate immunity. J Endotoxin Res 11:304–310. [PubMed][CrossRef]
81. Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nuñez G, Janeway CA, Medzhitov R, Flavell RA. 2002. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416:194–199. [PubMed][CrossRef]
82. Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Nuñez G, Inohara N. 2008. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation. EMBO J 27:373–383. [PubMed][CrossRef]
83. Kim JY, Omori E, Matsumoto K, Nuñez G, Ninomiya-Tsuji J. 2008. TAK1 is a central mediator of NOD2 signaling in epidermal cells. J Biol Chem 283:137–144.[PubMed]
84. Abbott A. 2004. Microbiology: gut reaction. Nature 427:284–286. [PubMed][CrossRef]
85. Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M, Body-Malapel M, Inohara N, Nuñez G. 2007. RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol 178:2380–2386.[PubMed]
86. Dufner A, Pownall S, Mak TW. 2006. Caspase recruitment domain protein 6 is a microtubule-interacting protein that positively modulates NF-κB activation. Proc Natl Acad Sci USA 103:988–993. [PubMed][CrossRef]
87. Dufner A, Duncan GS, Wakeham A, Elford AR, Hall HT, Ohashi PS, Mak TW. 2008. CARD6 is interferon inducible but not involved in nucleotide-binding oligomerization domain protein signaling leading to NF-κB activation. Mol Cell Biol 28:1541–1552. [PubMed][CrossRef]
88. Li L, Bin LH, Li F, Liu Y, Chen D, Zhai Z, Shu HB. 2005. TRIP6 is a RIP2-associated common signaling component of multiple NF-κB activation pathways. J Cell Sci 118:555–563. [PubMed][CrossRef]
89. da Silva Correia J, Miranda Y, Leonard N, Ulevitch R. 2007. SGT1 is essential for Nod1 activation. Proc Natl Acad Sci USA 104:6764–6769. [PubMed][CrossRef]
90. Mayor A, Martinon F, De Smedt T, Petrilli V, Tschopp J. 2007. A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nat Immunol 8:497–503. [PubMed][CrossRef]
91. da Silva Correia J, Miranda Y, Leonard N, Ulevitch RJ. 2007. The subunit CSN6 of the COP9 signalosome is cleaved during apoptosis. J Biol Chem 282:12557–12565. [PubMed][CrossRef]
92. Yamamoto-Furusho JK, Barnich N, Xavier R, Hisamatsu T, Podolsky DK. 2006. Centaurin β1 down-regulates nucleotide-binding oligomerization domains 1- and 2-dependent NF-κB activation. J Biol Chem 281:36060–36070. [PubMed][CrossRef]
93. LeBlanc PM, Yeretssian G, Rutherford N, Doiron K, Nadiri A, Zhu L, Green DR, Gruenheid S, Saleh M. 2008. Caspase-12 modulates NOD signaling and regulates antimicrobial peptide production and mucosal immunity. Cell Host Microbe 3:146–157. [PubMed][CrossRef]
94. Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, Steinberg MH, Nolan V, Baldwin CT, Hotchkiss RS, Buchman TG, Zehnbauer BA, Hayden MR, Farrer LA, Roy S, Nicholson DW. 2004. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 429:75–79. [PubMed][CrossRef]
95. da Silva Correia J, Miranda Y, Austin-Brown N, Hsu J, Mathison J, Xiang R, Zhou H, Li Q, Han J, Ulevitch RJ. 2006. Nod1-dependent control of tumor growth. Proc Natl Acad Sci USA 103:1840–1845. [PubMed][CrossRef]
96. da Silva Correia J, Miranda Y, Leonard N, Hsu J, Ulevitch RJ. 2007. Regulation of Nod1-mediated signaling pathways. Cell Death Differ 14:830–839. [PubMed][CrossRef]
97. Carneiro LAM, Travassos LH, Soares F, Tattoli I, Magalhaes JG, Bozza MT, Plotkowski MC, Sansonetti PJ, Molkentin JD, Philpott DJ, Girardin SE. 2009. Essential role of Bnip3 and Cyclophilin D in Shigella-induced mitochondrial dysfunction. Cell Host Microbe 5:123–136. [PubMed][CrossRef]
98. Fritz JH, Le Bourhis L, Magalhaes JG, Philpott DJ. 2008. Innate immune recognition at the epithelial barrier drives adaptive immunity: APCs take the back seat. Trends Immunol 29:41–49. [PubMed][CrossRef]
99. Netea MG, Azam T, Ferwerda G, Girardin SE, Walsh M, Park JS, Abraham E, Kim JM, Yoon DY, Dinarello CA, Kim SH. 2005. IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1β and IL-6 production through a caspase 1-dependent mechanism. Proc Natl Acad Sci USA 102:16309–16314. [PubMed][CrossRef]
100. Kim YG, Park JH, Daignault S, Fukase K, Nuñez G. 2008. Cross-tolerization between Nod1 and Nod2 signaling results in reduced refractoriness to bacterial infection in Nod2-deficient macrophages. J Immunol 181:4340–4346.[PubMed]
101. Zilbauer M, Dorrell N, Elmi A, Lindley KJ, Schuller S, Jones HE, Klein NJ, Nuñez G, Wren BW, Bajaj-Elliott M. 2007. A major role for intestinal epithelial nucleotide oligomerization domain 1 (NOD1) in eliciting host bactericidal immune responses to Campylobacter jejuni. Cell Microbiol 9:2404–2416. [PubMed][CrossRef]
102. Netea MG, Ferwerda G, de Jong DJ, Werts C, Boneca IG, Jehanno M, Van Der Meer JW, Mengin-Lecreulx D, Sansonetti PJ, Philpott DJ, Dharancy S, Girardin SE. 2005. The frameshift mutation in Nod2 results in unresponsiveness not only to Nod2- but also Nod1-activating peptidoglycan agonists. J Biol Chem 280:35859–35867. [PubMed][CrossRef]
103. Watanabe T, Kitani A, Murray PJ, Strober W. 2004. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 5:800–808. [PubMed][CrossRef]
104. Watanabe T, Kitani A, Murray PJ, Wakatsuki Y, Fuss IJ, Strober W. 2006. Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis. Immunity 25:473–485. [PubMed][CrossRef]
105. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nuñez G, Flavell RA. 2005. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307:731–734. [PubMed][CrossRef]
106. Magalhaes JG, Fritz JH, Lebourhis L, Sellge G, Travassos LH, Selvanantham T, Girardin SE, Gommerman J, Philpott DJ. 2008. Nod2-dependent Th2 polarization of antigen-specific immunity. J Immunol 181:7925–7935.[PubMed]
107. Fritz JH, Le Bourhis L, Sellge G, Magalhaes JG, Fsihi H, Kufer TA, Collins C, Viala J, Ferrero RL, Girardin SE, Philpott DJ. 2007. Nod1-mediated innate immune recognition of peptidoglycan contributes to the onset of adaptive immunity. Immunity 26:445–459. [PubMed][CrossRef]
108. Bouskra D, Brezillon C, Berard M, Werts C, Varona R, Boneca IG, Eberl G. 2008. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456:507–510. [PubMed][CrossRef]
109. Hysi P, Kabesch M, Moffatt MF, Schedel M, Carr D, Zhang Y, Boardman B, von Mutius E, Weiland SK, Leupold W, Fritzsch C, Klopp N, Musk AW, James A, Nuñez G, Inohara N, Cookson WO. 2005. NOD1 variation, immunoglobulin E and asthma. Hum Mol Genet 14:935–941. [PubMed][CrossRef]
110. McGovern DP, Hysi P, Ahmad T, van Heel DA, Moffatt MF, Carey A, Cookson WO, Jewell DP. 2005. Association between a complex insertion/deletion polymorphism in NOD1(CARD4) and susceptibility to inflammatory bowel disease. Hum Mol Genet 14:1245–1250. [PubMed][CrossRef]
111. Weidinger S, Klopp N, Rummler L, Wagenpfeil S, Novak N, Baurecht HJ, Groer W, Darsow U, Heinrich J, Gauger A, Schafer T, Jakob T, Behrendt H, Wichmann HE, Ring J, Illig T. 2005. Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J Allergy Clin Immunol 116:177–184. [PubMed][CrossRef]
112. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ. 2003. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 278:8869–8872. [PubMed][CrossRef]
113. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M, Foster SJ, Moran AP, Fernandez-Luna JL, Nuñez G. 2003. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J Biol Chem 278:5509–5512. [PubMed][CrossRef]
114. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. 2001. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411:599–603. [PubMed][CrossRef]
115. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH. 2001. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411:603–606. [PubMed][CrossRef]
116. Begue B, Dumant C, Bambou JC, Beaulieu JF, Chamaillard M, Hugot JP, Goulet O, Schmitz J, Philpott DJ, Cerf-Bensussan N, Ruemmele FM. 2006. Microbial induction of CARD15 expression in intestinal epithelial cells via toll-like receptor 5 triggers an antibacterial response loop. J Cell Physiol 209:241–252. [PubMed][CrossRef]
117. Gutierrez O, Pipaon C, Inohara N, Fontalba A, Ogura Y, Prosper F, Nuñez G, Fernandez-Luna JL. 2002. Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation. J Biol Chem 277:41701–41705. [PubMed][CrossRef]
118. Rosenstiel P, Fantini M, Brautigam K, Kuhbacher T, Waetzig GH, Seegert D, Schreiber S. 2003. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Gastroenterology 124:1001–1009. [PubMed][CrossRef]
119. Barnich N, Aguirre JE, Reinecker HC, Xavier R, Podolsky DK. 2005. Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-κB activation in muramyl dipeptide recognition. J Cell Biol 170:21–26. [PubMed][CrossRef]
120. Lecine P, Esmiol S, Metais JY, Nicoletti C, Nourry C, McDonald C, Nuñez G, Hugot JP, Borg JP, Ollendorff V. 2007. The NOD2-RICK complex signals from the plasma membrane. J Biol Chem 282:15197–15207. [PubMed][CrossRef]
121. Legrand-Poels S, Kustermans G, Bex F, Kremmer E, Kufer TA, Piette J. 2007. Modulation of Nod2-dependent NF-κB signaling by the actin cytoskeleton. J Cell Sci 120:1299–1310. [PubMed][CrossRef]
122. Girardin SE, Travassos LH, Herve M, Blanot D, Boneca IG, Philpott DJ, Sansonetti PJ, Mengin-Lecreulx D. 2003. Peptidoglycan molecular requirements allowing detection by Nod1 and Nod2. J Biol Chem 278:41702–41708. [PubMed][CrossRef]
123. Pan Q, Kravchenko V, Katz A, Huang S, Ii M, Mathison JC, Kobayashi K, Flavell RA, Schreiber RD, Goeddel D, Ulevitch RJ. 2006. NF-κB-inducing kinase regulates selected gene expression in the Nod2 signaling pathway. Infect Immun 74:2121–2127. [PubMed][CrossRef]
124. Barnich N, Hisamatsu T, Aguirre JE, Xavier R, Reinecker HC, Podolsky DK. 2005. GRIM-19 interacts with NOD2 and serves as down-stream effector of anti-bacterial function in intestinal epithelial cells. J Biol Chem 280:19021–19026. [PubMed][CrossRef]
125. Hsu YM, Zhang Y, You Y, Wang D, Li H, Duramad O, Qin XF, Dong C, Lin X. 2007. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat Immunol 8:198–205. [PubMed][CrossRef]
126. Wegener E, Krappmann D. 2007. CARD-Bcl10-Malt1 signalosomes: missing link to NF-κB. Sci STKE 2007:pe21. [PubMed][CrossRef]
127. Chen CM, Gong Y, Zhang M, Chen JJ. 2004. Reciprocal cross-talk between Nod2 and TAK1 signaling pathways. J Biol Chem 279:25876–25882. [PubMed][CrossRef]
128. Hitotsumatsu O, Ahmad RC, Tavares R, Wang M, Philpott D, Turer EE, Lee BL, Shiffin N, Advincula R, Malynn BA, Werts C, Ma A. 2008. The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity 28:381–390. [PubMed][CrossRef]
129. Kufer TA, Kremmer E, Banks DJ, Philpott DJ. 2006. Role for erbin in bacterial activation of Nod2. Infect Immun 74:3115–3124. [PubMed][CrossRef]
130. McDonald C, Chen FF, Ollendorff V, Ogura Y, Marchetto S, Lecine P, Borg JP, Nuñez G. 2005. A role for Erbin in the regulation of Nod2-dependent NF-κB signaling. J Biol Chem 280:40301–40309. [PubMed][CrossRef]
131. Eitel J, Krull M, Hocke AC, N’Guessan PD, Zahlten J, Schmeck B, Slevogt H, Hippenstiel S, Suttorp N, Opitz B. 2008. Beta-PIX and Rac1 GTPase mediate trafficking and negative regulation of NOD2. J Immunol 181:2664–2671.[PubMed]
132. Rosenstiel P, Huse K, Till A, Hampe J, Hellmig S, Sina C, Billmann S, von Kampen O, Waetzig GH, Platzer M, Seegert D, Schreiber S. 2006. A short isoform of NOD2/CARD15, NOD2-S, is an endogenous inhibitor of NOD2/receptor-interacting protein kinase 2-induced signaling pathways. Proc Natl Acad Sci USA 103:3280–3285. [PubMed][CrossRef]
133. Till A, Rosenstiel P, Brautigam K, Sina C, Jacobs G, Oberg HH, Seegert D, Chakraborty T, Schreiber S. 2008. A role for membrane-bound CD147 in NOD2-mediated recognition of bacterial cytoinvasion. J Cell Sci 121:487–495. [PubMed][CrossRef]
134. Martinon F, Agostini L, Meylan E, Tschopp J. 2004. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr Biol 14:1929–1934. [PubMed][CrossRef]
135. Pan Q, Mathison J, Fearns C, Kravchenko VV, Da Silva Correia J, Hoffman HM, Kobayashi KS, Bertin J, Grant EP, Coyle AJ, Sutterwala FS, Ogura Y, Flavell RA, Ulevitch RJ. 2007. MDP-induced interleukin-1β processing requires Nod2 and CIAS1/NALP3. J Leukoc Biol 82:177–183. [PubMed][CrossRef]
136. Marina-Garcia N, Franchi L, Kim YG, Miller D, McDonald C, Boons GJ, Nuñez G. 2008. Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2. J Immunol 180:4050–4057.[PubMed]
137. van Beelen AJ, Zelinkova Z, Taanman-Kueter EW, Muller FJ, Hommes DW, Zaat SA, Kapsenberg ML, de Jong EC. 2007. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 27:660–669. [PubMed][CrossRef]
138. Inohara N, Ogura Y, Chen FF, Muto A, Nuñez G. 2001. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem 276:2551–2554. [PubMed][CrossRef]
139. Cho JH. 2008. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 8:458–466. [PubMed][CrossRef]
140. Xavier RJ, Podolsky DK. 2007. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427–434. [PubMed][CrossRef]
141. Henckaerts L, Vermeire S. 2007. NOD2/CARD15 disease associations other than Crohn's disease. Inflamm Bowel Dis 13:235–241. [PubMed][CrossRef]
142. Chamaillard M, Philpott D, Girardin SE, Zouali H, Lesage S, Chareyre F, Bui TH, Giovannini M, Zaehringer U, Penard-Lacronique V, Sansonetti PJ, Hugot JP, Thomas G. 2003. Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proc Natl Acad Sci USA 100:3455–3460. [PubMed][CrossRef]
143. Rosenstiel P, Hellmig S, Hampe J, Ott S, Till A, Fischbach W, Sahly H, Lucius R, Folsch UR, Philpott D, Schreiber S. 2006. Influence of polymorphisms in the NOD1/CARD4 and NOD2/CARD15 genes on the clinical outcome of Helicobacter pylori infection. Cell Microbiol 8:1188–1198. [PubMed][CrossRef]
144. Conti BJ, Davis BK, Zhang J, O’Connor W Jr, Williams KL, Ting JP. 2005. Caterpiller 16.2 (CLR16.2): a novel NBD/LRR family member that negatively regulates T cell function. J Biol Chem 280:18375–18385. [PubMed][CrossRef]
145. Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, Grant EP, Nuñez G. 2006. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in Salmonella-infected macrophages. Nat Immunol 7:576–582. [PubMed][CrossRef]
146. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A. 2006. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 7:569–575. [PubMed][CrossRef]
147. Franchi L, Stoolman J, Kanneganti TD, Verma A, Ramphal R, Nuñez G. 2007. Critical role for Ipaf in Pseudomonas aeruginosa-induced caspase-1 activation. Eur J Immunol 37:3030–3039. [PubMed][CrossRef]
148. Miao EA, Ernst RK, Dors M, Mao DP, Aderem A. 2008. Pseudomonas aeruginosa activates caspase 1 through Ipaf. Proc Natl Acad Sci USA 105:2562–2567. [PubMed][CrossRef]
149. Sutterwala FS, Mijares LA, Li L, Ogura Y, Kazmierczak BI, Flavell RA. 2007. Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome. J Exp Med 204:3235–3245. [PubMed][CrossRef]
150. Shin H, Cornelis GR. 2007. Type III secretion translocation pores of Yersinia enterocolitica trigger maturation and release of pro-inflammatory IL-1β. Cell Microbiol 9:2893–2902. [PubMed][CrossRef]
151. Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C, Nuñez G. 2007. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog 3:e111. [PubMed][CrossRef]
152. Molofsky AB, Byrne BG, Whitfield NN, Madigan CA, Fuse ET, Tateda K, Swanson MS. 2006. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J Exp Med 203:1093–1104. [PubMed][CrossRef]
153. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM. 2004. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213–218. [PubMed][CrossRef]
154. Martinon F, Burns K, Tschopp J. 2002. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417–426. [PubMed][CrossRef]
155. Keller M, Ruegg A, Werner S, Beer HD. 2008. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132:818–831.[PubMed]
156. Mariathasan S, Monack DM. 2007. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7:31–40. [PubMed][CrossRef]
157. Amer A, Franchi L, Kanneganti TD, Body-Malapel M, Ozoren N, Brady G, Meshinchi S, Jagirdar R, Gewirtz A, Akira S, Nuñez G. 2006. Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf. J Biol Chem 281:35217–35223. [PubMed][CrossRef]
158. Henry T, Monack DM. 2007. Activation of the inflammasome upon Francisella tularensis infection: interplay of innate immune pathways and virulence factors. Cell Microbiol 9:2543–2551. [PubMed][CrossRef]
159. Moore CB, Bergstralh DT, Duncan JA, Lei Y, Morrison TE, Zimmermann AG, Accavitti-Loper MA, Madden VJ, Sun L, Ye Z, Lich JD, Heise MT, Chen Z, Ting JP. 2008. NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451:573–577. [PubMed][CrossRef]
160. 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-κB and JNK pathways by inducing reactive oxygen species production. EMBO Rep 9:293–300. [PubMed][CrossRef]
161. Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, Liu PP, Kastner DL. 2003. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell 11:591–604. [PubMed][CrossRef]
162. Boyden ED, Dietrich WF. 2006. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 38:240–244. [PubMed][CrossRef]
163. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA. 2007. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 356:1216–1225.[PubMed]
164. Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, van Bruggen R, Tschopp J. 2007. Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J Histochem Cytochem 55:443–452. [PubMed][CrossRef]
165. Friedlander AM. 1986. Macrophages are sensitive to anthrax lethal toxin through an acid-dependent process. J Biol Chem 261:7123–7126.[PubMed]
166. Wickliffe KE, Leppla SH, Moayeri M. 2008. Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell Microbiol 10:332–343. [PubMed][CrossRef]
167. Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. 2007. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 14:1583–1589. [PubMed][CrossRef]
168. Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC. 2007. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell 25:713–724. [PubMed][CrossRef]
169. Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, Xu C, Kress CL, Bailly-Maitre B, Li X, Osterman A, Matsuzawa S, Terskikh AV, Faustin B, Reed JC. 2007. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell 129:45–56. [PubMed][CrossRef]
170. Benko S, Philpott DJ, Girardin SE. 2008. The microbial and danger signals that activate Nod-like receptors. Cytokine 43:368–373. [PubMed][CrossRef]
171. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT. 2008. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9:857–865. [PubMed][CrossRef]
172. Surprenant A, Rassendren F, Kawashima E, North RA, Buell G. 1996. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272:735–738. [PubMed][CrossRef]
173. Pelegrin P, Surprenant A. 2006. Pannexin-1 mediates large pore formation and interleukin-1β release by the ATP-gated P2X7 receptor. EMBO J 25:5071–5082. [PubMed][CrossRef]
174. 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 320:674–677. [PubMed][CrossRef]
175. Meissner F, Molawi K, Zychlinsky A. 2008. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol 9:866–872. [PubMed][CrossRef]
176. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E. 2008. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9:847–856. [PubMed][CrossRef]
177. Willingham SB, Bergstralh DT, O’Connor W, Morrison AC, Taxman DJ, Duncan JA, Barnoy S, Venkatesan MM, Flavell RA, Deshmukh M, Hoffman HM, Ting JP. 2007. Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe 2:147–159. [PubMed][CrossRef]
178. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. 2004. NALP3 forms an IL-1 beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20:319–325. [PubMed][CrossRef]
179. 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 440:228–232. [PubMed][CrossRef]
180. Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, Bertin J, Coyle AJ, Galan JE, Askenase PW, Flavell RA. 2006. Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 24:317–327. [PubMed][CrossRef]
181. Gurcel L, Abrami L, Girardin S, Tschopp J, van der Goot FG. 2006. Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 126:1135–1145. [PubMed][CrossRef]
182. De Gregorio E, Tritto E, Rappuoli R. 2008. Alum adjuvanticity: Unraveling a century old mystery. Eur J Immunol 38:2068–2071. [PubMed][CrossRef]
183. Franchi L, Nuñez G. 2008. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1β secretion but dispensable for adjuvant activity. Eur J Immunol 38:2085–2089. [PubMed][CrossRef]
184. Martinon F, Gaide O, Petrilli V, Mayor A, Tschopp J. 2007. NALP inflammasomes: a central role in innate immunity. Semin Immunopathol 29:213–229. [PubMed][CrossRef]
185. Fujisawa A, Kambe N, Saito M, Nishikomori R, Tanizaki H, Kanazawa N, Adachi S, Heike T, Sagara J, Suda T, Nakahata T, Miyachi Y. 2007. Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells. Blood 109:2903–2911.[PubMed]
186. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. 2006. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241. [PubMed][CrossRef]
187. Master SS, Rampini SK, Davis AS, Keller C, Ehlers S, Springer B, Timmins GS, Sander P, Deretic V. 2008. Mycobacterium tuberculosis prevents inflammasome activation. Cell Host Microbe 3:224–232. [PubMed][CrossRef]
188. Williams KL, Lich JD, Duncan JA, Reed W, Rallabhandi P, Moore C, Kurtz S, Coffield VM, Accavitti-Loper MA, Su L, Vogel SN, Braunstein M, Ting JP. 2005. The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals. J Biol Chem 280:39914–39924. [PubMed][CrossRef]
189. Jeru I, Duquesnoy P, Fernandes-Alnemri T, Cochet E, Yu JW, Lackmy-Port-Lis M, Grimprel E, Landman-Parker J, Hentgen V, Marlin S, McElreavey K, Sarkisian T, Grateau G, Alnemri ES, Amselem S. 2008. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci USA 105:1614–1619. [PubMed][CrossRef]

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Eukaryotes have evolved strategies to detect microbial intrusion and instruct immune responses to limit damage from infection. Recognition of microbes and cellular damage relies on the detection of microbe-associated molecular patterns (MAMPs, also called PAMPS, or pathogen-associated molecular patterns) and so-called "danger signals" by various families of host pattern recognition receptors (PRRs). Members of the recently identified protein family of nucleotide-binding domain andleucine-rich-repeat-containing proteins (NLR), including Nod1, Nod2, NLRP3, and NLRC4, have been shown to detect specific microbial motifs and danger signals for regulating host inflammatory responses. Moreover, with the discovery that polymorphisms in , , , and are associated with susceptibility to chronic inflammatory disorders, the view has emerged that NLRs act not only as sensors butalso can serve as signaling platforms for instructing and balancing host immune responses. In this chapter, we explore the functions of these intracellular innate immune receptors and examine their implication in inflammatory diseases.

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Image of Figure 1
Figure 1

NOD-like receptors (NLRs) are characterized by three distinct domains: an N-terminal effector domain, being either a pyrin (PYD), a CARD (caspase activation and recruitment domain), or a BIR (baculovirus IAP [inhibitor of apoptosis] repeat) domain; a central NACHT domain (domain present in IP [neuronal apoptosis inhibitor protein], IITA [major histocompatibility complex class II transactivator], ET-E [plant gene product involved in vegetative incompatibility], P-1 [telomerase-associated protein 1]) which is common to all NLR members and in many cases extended by a helical NACHT-associated domain (NAD); and a C-terminal leucine-rich repeats (LRR) domain, which is thought to constitute the microbial-sensing portion of the molecule. Both NACHT and NAD domains are key features of a recently defined STAND (signal transduction ATPase with numerous domains) family of P-loop NTPases, which are distantly related to AAA+ ATPases (ATPases associated with diverse cellular activities). The NACHT and NAD domains are homologous to domains of related proteins, the proapoptotic regulators such as APAF-1 (apoptotic protease-activating factor-1) in mammals, CED-4 ( death protein 4) in nematodes, and disease resistance genes encoding R-proteins in plants such as RPS4 (). The CARD and PYD counterparts in plants are coiled coil (CC) and Toll/interleukin-1 receptor (TIR) domains. Pyrin, which is related to the other PYD containing NLRs and similarly implicated in fever-related disorders, also comprises a zinc finger B-box (zf-B-box), a dual-specificity kinase SplA and ryanodine receptor domain (SPRY), and a SPRY-associated (PRY) domain in addition to PYD. Finally, a schematic representation of adaptors involved in NLR-signaling such as Rip2 (receptor-interacting protein 2), ASC (apoptosis-associated speck-like protein containing a CARD domain), and CARDINAL (CARD-inhibitor of NF-κB-activating ligand) is outlined. FIIND, function to find; AD, activation domain.

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Image of Figure 2
Figure 2

Peptidoglycan is a polymer of alternating -acetylglucosamine (NAG) and -acetylmuramic (NAM) linked by peptide bridges. A lysine residue is present in the peptidoglycan of most gram-positive bacteria (Lys-PGN), and a meso-diaminopimelic acid in the peptidoglycan of most gram-negative bacteria (DAP-PGN). With regard to DAP-PGN, green shows the naturally occurring substructure recognized by human Nod1, while the motif favored by murine Nod1 is blue. The minimal structure recognized by Nod1 is the amino acid -Glu-meso-DAP (also known as iE-DAP), outlined in red. Gray in both DAP-PGN and Lys-PGN refers to the common motif, muramyl dipeptide, recognized by Nod2. Within Lys-PGN, the substructure in pink is also a trigger of Nod2.

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Figure 3

The Nod1 ligand is sensed in the cytosol of the cell, either indirectly or directly by the LRR domain of Nod1. The protein then oligomerizes through the NBD, recruiting Rip2, a kinase that leads to the activation of NF-κB (mainly the p50/p65 component) through TAK1. Nod1 triggering also activates ERK/p38 and JNK signaling. Nod1 triggers caspase 8 (if the cells are coincubated with cycloheximide), which can lead to apoptosis, and caspase 12, an amplifier of the inflammatory response. Designated in red are the proteins that have been shown to interact with Nod1 or other components of the pathway to modify signaling, either positively or negatively.

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Figure 4

The Nod2 ligand MDP triggers Nod2 oligomerization and subsequent recruitment and activation of Rip2 and TAK1, leading to activation of the canonical NF-κB pathway. Through NIK, Nod2 can also activate the noncanonical NF-κB pathway leading to the activation of NF-κB composed of RelB/p52. In conjunction with TLR signaling, this pathway has been shown to be required for induction of BLC (B-lymphocyte chemokine, also known as CXCL13). Triggering of Nod2 activates ERK/p38 and JNK signaling. Nalp3 induction and subsequent processing of pro-IL-1β is in some cases triggered by MDP, but may or may not require Nod2 (see text). Shown in red are proteins that positively or negatively regulate Nod2 function. Grim19 is an associated regulator that may be required for NF-κB induction. Rac1 may help tether Nod2 to the membrane via Erbin.

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Figure 5

NLRP1, NLRP3, and NLRC4 can form functional “inflammasomes” that interact with caspase-1 and lead to the processing of proforms of IL-1β, IL-18, IL-33, and possibly other secreted effectors. Inflammasome activation requires a “double hit,” in that the target cell must be first prestimulated with TLR or perhaps Nod1/Nod2 ligands to upregulate gene expression of NF-κB-dependent, caspase-1 targets, including pro-IL-1β. The second “hit” is activation of the particular NLR by (a) a microbial signal, MDP or lethal toxin in the case of NLRP1 and bacterial toxins, or bacterial or viral nucleic acids in the case of NLRP3, or flagellin in the case of NLRC4, or (b) a danger signal, which can include xenogenous particles or host-derived danger signals (see Table 2 ). ROS production, potassium efflux from the cell, or lysosomal damage may be the common effector of these triggers that lead to inflammasome activation. ASC, an adaptor molecule, seems to be required for caspase-1 activation but not cell death. Naip5 (in mice) may potentiate the activation of NLRC4 by flagellin.

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Table 1

Human genetic diseases associated with polymorphisms in NLR genes

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3
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Table 2

Triggers of NLR inflammasomes

Citation: Carneiro L, Fritz J, Kufer T, Travassos L, Benko S, Philpott D. 2009. NLRs: Nucleotide-Binding Domain and Leucine-Rich-Repeat-Containing Proteins, EcoSal Plus 2009; doi:10.1128/ecosalplus.8.8.3

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