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NALPs: a novel protein family involved in inflammation

Key Points

  • On infection, microorganisms are efficiently recognized by Toll-like receptors (TLRs), which recognize invariant molecular structures called pathogen-associated molecular patterns (PAMPs) that are shared by many pathogens but are not expressed by their hosts.

  • Recognition of PAMPs by TLRs results in the activation of different intracellular signalling cascades, which, in turn, lead to the expression of various effector molecules. One of these, interleukin-1β (IL-1β), is defined as an 'alarm cytokine'; it is secreted by macrophages and initiates inflammation.

  • For IL-1β to be active, pro-IL-1β must first be processed to an active molecule and then secreted. The IL-1β-converting enzyme (ICE) — also known as caspase-1 — is responsible for this processing.

  • A novel family of cytoplasmic proteins containing NACHT, leucine-rich domains and either a Pyrin or CARD domain are involved in caspase-1 activation and therefore IL-1β cleavage.

  • One member of this family, designated NALP1, assembles into a complex with ASC, caspase-1 and caspase-5, forming the 'inflammasome'.

  • The NALP3 gene is mutated in three related autosomal-dominant autoinflammatory disorders, Muckle–Wells syndrome, familial cold urticaria, and in chronic infantile neurologic cutaneous and articular syndrome.


A newly discovered family of cytoplasmic proteins — the NALPs — has been implicated in the activation of caspase-1 by the Toll-like receptors (TLRs) during the cell's response to microbial infection. Like the structurally related apoptotic protease-activating factor-1 (APAF-1), which is responsible for the activation of caspase-9, the NALP1 protein forms a large, signal-induced multiprotein complex, the inflammasome, resulting in the activation of pro-inflammatory caspases.

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Figure 1: Recognition of pathogen-associated molecular patterns by Toll-like receptors.
Figure 2: Domain structures of NALPs and subfamilies of the CATERPILLER protein family.
Figure 3: The inflammasome.
Figure 4: Model of lipopolysaccharide-induced activation and secretion of pro-inflammatory caspases and interleukin-1β.
Figure 5: Hypothetical mechanism of NALP3 activation.
Figure 6: Diseases associated with mutations in NALP3.


  1. 1

    Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    CAS  Google Scholar 

  2. 2

    Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001).

    CAS  Google Scholar 

  3. 3

    Dinarello, C. A. Biologic basis for interleukin-1 in disease. Blood 87, 2095–2147 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    O'Neill, L. A. & Dinarello, C. A. The IL-1 receptor/toll-like receptor superfamily: crucial receptors for inflammation and host defense. Immunol. Today 21, 206–209 (2000).

    CAS  PubMed  Google Scholar 

  5. 5

    Burns, K. et al. MyD88, an adapter protein involved in interleukin-1 signaling. J. Biol. Chem. 273, 12203–12209 (1998).

    CAS  PubMed  Google Scholar 

  6. 6

    Muzio, M., Ni, J., Feng, P. & Dixit, V. M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278, 1612–1615 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Medzhitov, R. et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2, 253–258 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S. & Cao, Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7, 837–847 (1997).

    CAS  Article  Google Scholar 

  9. 9

    Horng, T., Barton, G. M. & Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway. Nature Immunol. 2, 835–841 (2001). This paper (together with reference 10) provides the first evidence for a role of TIRAP in the Toll-like receptor signalling pathway.

    CAS  Google Scholar 

  10. 10

    Fitzgerald, K. A. et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413, 78–83 (2001).

    CAS  PubMed  Google Scholar 

  11. 11

    Harton, J. A., Linhoff, M. W., Zhang, J. & Ting, J. P. Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J. Immunol. 169, 4088–4093 (2002).

    CAS  PubMed  Google Scholar 

  12. 12

    Inohara, N., Ogura, Y. & Nuñez, G. Nods: a family of cytosolic proteins that regulate the host response to pathogens. Curr. Opin. Microbiol. 5, 76–80 (2002).

    CAS  PubMed  Google Scholar 

  13. 13

    Ting, J. P. & Trowsdale, J. Genetic control of MHC class II expression. Cell 109, S21–S33 (2002).

    CAS  PubMed  Google Scholar 

  14. 14

    Koonin, E. V. & Aravind, L. The NACHT family — a new group of predicted NTPases implicated in apoptosis and MHC transcription activation. Trends Biochem. Sci. 25, 223–224 (2000).

    CAS  PubMed  Google Scholar 

  15. 15

    Acehan, D. et al. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol. Cell 9, 423–432 (2002). This excellent study proposes a three-dimensional model of the apoptosome.

    CAS  Google Scholar 

  16. 16

    Kobe, B. & Kajava, A. V. The leucine-rich repeat as a protein recognition motif. Curr. Opin. Struct. Biol. 11, 725–732 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Nickerson, K. et al. Dendritic cell-specific MHC class II transactivator contains a caspase recruitment domain that confers potent transactivation activity. J. Biol. Chem. 276, 19089–19093 (2001).

    CAS  PubMed  Google Scholar 

  18. 18

    Linhoff, M. W., Harton, J. A., Cressman, D. E., Martin, B. K. & Ting, J. P. Two distinct domains within CIITA mediate self-association: involvement of the GTP-binding and leucine-rich repeat domains. Mol. Cell. Biol. 21, 3001–3011 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Inohara, N. et al. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-κB. J. Biol. Chem. 274, 14560–14567 (1999).

    CAS  PubMed  Google Scholar 

  20. 20

    Bertin, J. et al. Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-κB. J. Biol. Chem. 274, 12955–12958 (1999).

    CAS  PubMed  Google Scholar 

  21. 21

    Ogura, Y. et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB. J. Biol. Chem. 276, 4812–4818 (2001).

    CAS  PubMed  Google Scholar 

  22. 22

    Inohara, N., Ogura, Y., Chen, F. F., Muto, A. & Nuñez, G. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J. Biol. Chem. 276, 2551–2554 (2001). This study provides evidence that the LRRs of NOD1 and NOD2 bind LPS.

    CAS  PubMed  Google Scholar 

  23. 23

    Girardin, S. E. et al. CARD4/Nod1 mediates NF-κB and JNK activation by invasive Shigella flexneri. EMBO Rep. 2, 736–742 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Hugot, J. P. et al. Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature 379, 821–823 (1996). First evidence for an association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease

    CAS  PubMed  Google Scholar 

  25. 25

    Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    CAS  Google Scholar 

  26. 26

    Miceli-Richard, C. et al. CARD15 mutations in Blau syndrome. Nature Genet. 29, 19–20 (2001).

    CAS  PubMed  Google Scholar 

  27. 27

    Poyet, J. L. et al. Identification of ipaf, a human caspase-1-activating protein related to Apaf-1. J. Biol. Chem. 276, 28309–28313 (2001).

    CAS  Google Scholar 

  28. 28

    Damiano, J. S., Stehlik, C., Pio, F., Godzik, A. & Reed, J. C. CLAN, a novel human CED-4-like gene. Genomics 75, 77–83 (2001).

    CAS  Google Scholar 

  29. 29

    Geddes, B. J. et al. Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis. Biochem. Biophys. Res. Commun. 284, 77–82 (2001).

    CAS  Google Scholar 

  30. 30

    Roy, N. et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80, 167–178 (1995). First evidence for an association of NAIP variants with susceptibility to spinal muscular atrophy.

    CAS  PubMed  Google Scholar 

  31. 31

    Liston, P. et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379, 349–353 (1996).

    CAS  PubMed  Google Scholar 

  32. 32

    Salvesen, G. S. & Duckett, C. S. IAP proteins: blocking the road to death's door. Nature Rev. Mol. Cell Biol. 3, 401–410 (2002).

    CAS  Google Scholar 

  33. 33

    Diez, E., Yaraghi, Z., MacKenzie, A. & Gros, P. The neuronal apoptosis inhibitory protein (Naip) is expressed in macrophages and is modulated after phagocytosis and during intracellular infection with Legionella pneumophila. J. Immunol. 164, 1470–1477 (2000).

    CAS  PubMed  Google Scholar 

  34. 34

    Diez, E. et al. Genetic and physical mapping of the mouse host resistance locus Lgn1. Mamm. Genome 8, 682–685 (1997).

    CAS  PubMed  Google Scholar 

  35. 35

    Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-1β. Mol. Cell 10, 417–426 (2002). This paper describes the existence of the inflammasome.

    CAS  Google Scholar 

  36. 36

    Pawlowski, K., Pio, F., Chu, Z., Reed, J. C. & Godzik, A. PAAD — a new protein domain associated with apoptosis, cancer and autoimmune diseases. Trends Biochem. Sci. 26, 85–87 (2001).

    CAS  PubMed  Google Scholar 

  37. 37

    Manji, G. A. et al. PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-κB. J. Biol. Chem. 277, 11570–11575 (2002).

    CAS  PubMed  Google Scholar 

  38. 38

    Reik, W. & Maher, E. R. Imprinting in clusters: lessons from Beckwith–Wiedemann syndrome. Trends Genet. 13, 330–334 (1997).

    CAS  Google Scholar 

  39. 39

    Hlaing, T. et al. Molecular cloning and characterization of DEFCAP-L and-S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins. J. Biol. Chem. 276, 9230–9238 (2001).

    CAS  PubMed  Google Scholar 

  40. 40

    Chu, Z. L. et al. A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis. J. Biol. Chem. 276, 9239–9245 (2001).

    CAS  PubMed  Google Scholar 

  41. 41

    Martinon, F., Hofmann, K. & Tschopp, J. The Pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation. Curr. Biol. 10, R118–R120 (2001).

    Google Scholar 

  42. 42

    Razmara, M. et al. CARD-8 protein, a new CARD family member that regulates caspase-1 activation and apoptosis. J. Biol. Chem. 277, 13952–13958 (2002).

    CAS  PubMed  Google Scholar 

  43. 43

    Pathan, N. et al. TUCAN, an antiapoptotic caspase-associated recruitment domain family protein overexpressed in cancer. J. Biol. Chem. 276, 32220–32229 (2001).

    CAS  PubMed  Google Scholar 

  44. 44

    Bouchier-Hayes, L. et al. CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-κB activation pathways. J. Biol. Chem. 276, 44069–44077 (2001).

    CAS  PubMed  Google Scholar 

  45. 45

    Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nature Genet. 29, 301–305 (2001).

    CAS  PubMed  Google Scholar 

  46. 46

    Aganna, E. et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum. 46, 2445–2452 (2002).

    CAS  PubMed  Google Scholar 

  47. 47

    Dean, J. Oocyte-specific genes regulate follicle formation, fertility and early mouse development. J. Reprod. Immunol. 53, 171–180 (2002).

    CAS  PubMed  Google Scholar 

  48. 48

    Tong, Z. B. et al. Mater, a maternal effect gene required for early embryonic development in mice. Nature Genet. 26, 267–268 (2000).

    CAS  PubMed  Google Scholar 

  49. 49

    Fiorentino, L. et al. A novel PAAD-containing protein that modulates NF–κB induction by cytokines TNFα and IL-1β. J. Biol. Chem. 277, 35333–35340 (2002).

    CAS  PubMed  Google Scholar 

  50. 50

    Wang, L. et al. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-κB and caspase-1-dependent cytokine processing. J. Biol. Chem. 277, 29874–29880 (2002).

    CAS  Google Scholar 

  51. 51

    Srinivasula, S. M. et al. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J. Biol. Chem. 277, 21119–21122 (2002).

    CAS  PubMed  Google Scholar 

  52. 52

    Masumoto, J. et al. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J. Biol. Chem. 274, 33835–33838 (1999).

    CAS  Google Scholar 

  53. 53

    Richards, N. et al. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J. Biol. Chem. 276, 39320–39329 (2001).

    CAS  PubMed  Google Scholar 

  54. 54

    Masumoto, J. et al. Expression of apoptosis-associated speck-like protein containing a caspase recruitment domain, a pyrin N-terminal homology domain-containing protein, in normal human tissues. J. Histochem. Cytochem. 49, 1269–1275 (2001).

    CAS  PubMed  Google Scholar 

  55. 55

    Shiohara, M. et al. ASC, which is composed of a PYD and a CARD, is up-regulated by inflammation and apoptosis in human neutrophils. Biochem. Biophys. Res. Commun. 293, 1314–1318 (2002).

    CAS  PubMed  Google Scholar 

  56. 56

    Conway, K. E. et al. TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers. Cancer Res. 60, 6236–6242 (2000).

    CAS  PubMed  Google Scholar 

  57. 57

    Thornberry, N. A. et al. A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nature 356, 768–774 (1992).

    CAS  Google Scholar 

  58. 58

    Cerretti, D. P. et al. Molecular cloning of the interleukin-1β converting enzyme. Science 256, 97–100 (1992).

    CAS  PubMed  Google Scholar 

  59. 59

    Wang, S. et al. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501–509 (1998).

    CAS  PubMed  Google Scholar 

  60. 60

    Li, P. et al. Mice deficient in IL-1β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock. Cell 80, 401–411 (1995).

    CAS  Google Scholar 

  61. 61

    Kuida, K. et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1β converting enzyme. Science 267, 2000–2003 (1995). References 60 and 61 provide the first genetic evidence for a role of caspase-1 in the processing of IL-1β.

    CAS  Google Scholar 

  62. 62

    Singer, I. I. et al. The interleukin-1β-converting enzyme (ICE) is localized on the external cell surface membranes and in the cytoplasmic ground substance of human monocytes by immuno-electron microscopy. J. Exp. Med. 182, 1447–1459 (1995).

    CAS  Google Scholar 

  63. 63

    Guichon, A., Hersh, D., Smith, M. R. & Zychlinsky, A. Structure–function analysis of the Shigella virulence factor IpaB. J. Bacteriol. 183, 1269–1276 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Hersh, D. et al. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc. Natl Acad. Sci. USA 96, 2396–2401 (1999).

    CAS  Google Scholar 

  65. 65

    Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489 (1997).

    CAS  Google Scholar 

  66. 66

    Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nature Med. 5, 1249–1255 (1999).

    CAS  Google Scholar 

  67. 67

    Vabulas, R. M. et al. The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J. Biol. Chem. 277, 20847–20853 (2002).

    CAS  PubMed  Google Scholar 

  68. 68

    Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    CAS  Google Scholar 

  69. 69

    Beutler, B. & Cerami, A. The endogenous mediator of endotoxic shock. Clin. Res. 35, 192–197 (1987).

    CAS  PubMed  Google Scholar 

  70. 70

    Druilhe, A., Srinivasula, S. M., Razmara, M., Ahmad, M. & Alnemri, E. S. Regulation of IL-1β generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. Cell Death Differ. 8, 649–657 (2001).

    CAS  PubMed  Google Scholar 

  71. 71

    Green, D. R. & Melino, G. ICE heats up. Cell Death Differ. 8, 549–550 (2001).

    CAS  PubMed  Google Scholar 

  72. 72

    Annand, R. R. et al. Caspase-1 (interleukin-1β-converting enzyme) is inhibited by the human serpin analogue proteinase inhibitor 9. Biochem. J. 342, 655–665 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Kannan-Thulasiraman, P. & Shapiro, D. J. Modulators of inflammation use NF-κB and AP-1 sites to induce the caspase-1 and granzyme B inhibitor, proteinase inhibitor 9. J. Biol. Chem. 277, 41230–41239 (2002).

    CAS  PubMed  Google Scholar 

  74. 74

    Feldmann, J. et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am. J. Hum. Genet. 71, 198–203 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Dode, C. et al. New mutations of CIAS1 that are responsible for Muckle–Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am. J. Hum. Genet. 70, 1498–1506 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    McDermott, M. F. & Frenkel, J. Hereditary periodic fever syndromes. Neth. J. Med. 59, 118–125 (2001).

    CAS  PubMed  Google Scholar 

  77. 77

    French FMF Consortium. A candidate gene for familial Mediterranean fever. The French FMF Consortium. Nature Genet. 17, 25–31 (1997).

  78. 78

    International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90, 797–807 (1997).

  79. 79

    Cuisset, L. et al. Genetic linkage of the Muckle–Wells syndrome to chromosome 1q44. Am. J. Hum. Genet. 65, 1054–1059 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    McDermott, M. F. et al. An autosomal dominant periodic fever associated with AA amyloidosis in a north Indian family maps to distal chromosome 1q. Arthritis Rheum. 43, 2034–2040 (2000).

    CAS  PubMed  Google Scholar 

  81. 81

    Hoffman, H. M., Wright, F. A., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am. J. Hum. Genet. 66, 1693–1698 (2000). First evidence for an association of NALP3/Cryopyrin variants with Muckle–Wells syndrome.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Prieur, A. M. A recently recognised chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy. Clin. Exp. Rheumatol. 19, 103–106 (2001).

    CAS  PubMed  Google Scholar 

  83. 83

    Tartaglia, L. A., Ayres, T. M., Wong, G. H. & Goeddel, D. V. A novel domain within the 55 kd TNF receptor signals cell death. Cell 74, 845–853 (1993).

    CAS  PubMed  Google Scholar 

  84. 84

    Itoh, N. & Nagata, S. A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J. Biol. Chem. 268, 10932–10937 (1993).

    CAS  PubMed  Google Scholar 

  85. 85

    Chinnaiyan, A. M. et al. FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. J. Biol. Chem. 271, 4961–4965 (1996).

    CAS  PubMed  Google Scholar 

  86. 86

    Hofmann, K., Bucher, P. & Tschopp, J. The CARD domain: a new apoptotic signalling motif. Trends Biochem. Sci. 22, 155–156 (1997).

    CAS  PubMed  Google Scholar 

  87. 87

    Bertin, J. & DiStefano, P. S. The PYRIN domain: a novel motif found in apoptosis and inflammation proteins. Cell Death Differ. 7, 1273–1274 (2000).

    CAS  PubMed  Google Scholar 

  88. 88

    Staub, E., Dahl, E. & Rosenthal, A. The DAPIN family: a novel domain links apoptotic and interferon response proteins. Trends Biochem. Sci. 26, 83–85 (2001).

    CAS  PubMed  Google Scholar 

  89. 89

    Johnstone, R. W. & Trapani, J. A. Transcription and growth regulatory functions of the HIN-200 family of proteins. Mol. Cell. Biol. 19, 5833–5838 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Tong, Z. B., Bondy, C. A., Zhou, J. & Nelson, L. M. A human homologue of mouse Mater, a maternal effect gene essential for early embryonic development. Hum. Reprod. 17, 903–911 (2002).

    CAS  PubMed  Google Scholar 

  91. 91

    Grenier, J. M. et al. Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-κB and caspase-1. FEBS Lett. 530, 73–78 (2002).

    CAS  PubMed  Google Scholar 

  92. 92

    Yaraghi, Z., Korneluk, R. G. & MacKenzie, A. Cloning and characterization of the multiple murine homologues of NAIP (neuronal apoptosis inhibitory protein). Genomics 51, 107–113 (1998).

    CAS  PubMed  Google Scholar 

  93. 93

    Reith, W. & Mach, B. The bare lymphocyte syndrome and the regulation of MHC expression. Annu. Rev. Immunol. 19, 331–373 (2001).

    CAS  PubMed  Google Scholar 

  94. 94

    Centola, M. et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95, 3223–3231 (2000).

    CAS  PubMed  Google Scholar 

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Beckwith–Wiedemann syndrome


familial cold autoinflammatory syndrome

familial Mediterranean fever

Muckle–Wells syndrome


breast cancer


Jürg Tschopp's laboratory

Pyrin domain



If a microorganism begins to replicate in a host, it is usually recognized by the mononuclear phagocytes, or macrophages, that reside in tissues. The other main family of phagocytes are the neutrophils. Both types of phagocytic cell have a key role in innate immunity.


(LPS). An important component of the outer membrane of Gram-negative bacteria (also known as endotoxin). This complex molecule consists of a lipid A anchor, a polysaccharide core and chains of carbohydrates.


A polyol phosphate polymer bearing a strong negative charge. It is covalently linked to the peptidoglycan in some Gram-positive bacteria. It is strongly antigenic, but is generally absent in Gram-negative bacteria.


Bacterial DNA containing unmethylated CpG dinucleotide motifs.


(LAM). A wall component of mycobacteria. Purified LAM from virulent and attenuated strains of mycobacteria differ structurally, and these differences could contribute to their varying abilities to stimulate cytokine production in mononuclear cell cultures.


A substance that causes the elevation of body temperature. Examples are cytokines produced by macrophages such as tumour-necrosis factor-α, interleukin (IL)-1 and IL-6.


A domain found in inhibitor of apoptosis proteins (IAP) and other proteins. Acts as a direct inhibitor of caspases.


The ability to mark a gene as coming either from the father or the mother. These differences involve methylation. Imprinting adds additional information to the inherited genome that might regulate spatial and temporal gene activity.


Two genes related by speciation events alone, which typically have the same function.

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Tschopp, J., Martinon, F. & Burns, K. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 4, 95–104 (2003).

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