Skip to main content
SpringerLink
Log in

Regulatory molecules involved in inflammasome formation with special reference to a key mediator protein, ASC

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

The recent identification of cytosolic pattern recognition receptors (PRRs) with leucine-rich repeats, which recognize pathogen-associated molecular patterns (PAMPs), has been garnering considerable attention. Activated PRRs form molecular complexes called inflammasomes, consisting of related proteins that include procaspase 1[interleukin (IL) 1β converting enzyme (ICE)]. Inflammasomes have been shown to facilitate molecular proximity, stimulate activation of procaspase 1, which consequently produces inflammatory cytokines IL-1β and IL-18 and ultimately lead to the initiation of innate immunity. An adaptor protein, apoptosis-associated speck-like protein containing a CARD (ASC), which recruits PRRs carrying the pyrin homologous domain (PYD) and procaspase 1 through PYD and CARD, respectively, is responsible for the formation of some inflammasomes and also activation of procaspase 1. In this review, our main attention will be directed to PYD region analysis of ASC to understand the interaction between PYD-carrying PRRs and ASC. Taking into consideration the other aspects of the ASC gene in the proapoptotic ability and down-regulation by methylation, the biological function of ASC will be discussed in relation to the epigenetic aspects of infection, inflammation, and cancer.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  2. Inohara N, Chamaillard M, McDonald C, Nunez G (2005) NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem 74:355–383

    Article  PubMed  CAS  Google Scholar 

  3. Ting JP, Kastner DL, Hoffman HM (2006) CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol 6:183–195

    Article  PubMed  CAS  Google Scholar 

  4. Philpott DJ, Girardin SE (2004) The role of Toll-like receptors and Nod proteins in bacterial infection. Mol Immunol 41:1099–1108

    Article  PubMed  CAS  Google Scholar 

  5. Strober W, Murray PJ, Kitani A, Watanabe T (2006) Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 6:9–20

    Article  PubMed  CAS  Google Scholar 

  6. Kufer TA, Fritz JH, Philpott DJ (2005) NACHT-LRR proteins (NLRs) in bacterial infection and immunity. Trends Microbiol 13:381–388

    Article  PubMed  CAS  Google Scholar 

  7. Viala J et al Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nature Immunol 5:1166–1174

  8. Meylan E, Tschopp J, Karin M (2006) Intracellular pattern recognition receptors in the host response. Nature 442:39–44

    Article  PubMed  CAS  Google Scholar 

  9. Martinon F, Burns K, Tschopp J (2002) The nflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-1β. Mol Cell 10:417–426

    Article  PubMed  CAS  Google Scholar 

  10. Schmitz J. et al (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–490

    Article  PubMed  CAS  Google Scholar 

  11. Thornberry NA, Molineaux SM (1995) Interleukin-1β converting enzyme: a novel cysteine protease required for IL-1β production and implicated in programmed cell death. Protein Sci 4:3–12

    Article  PubMed  CAS  Google Scholar 

  12. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD (2001) Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat Genet 29:301–305

    Article  PubMed  CAS  Google Scholar 

  13. McDermott MF, Aksentijevich I (2002) The autoinflammatory syndromes. Curr Opin Allergy Clin Immunol 2:511–516

    Article  PubMed  Google Scholar 

  14. Feldmann J et al (2002) Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 71:198–203

    Article  PubMed  CAS  Google Scholar 

  15. Martinon F, Tschopp J (2004) Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117:561–574

    Article  PubMed  CAS  Google Scholar 

  16. Solle M et al (2001) Altered cytokine production in mice lacking P2X7 receptors. J Biol Chem 276:125–132

    Article  PubMed  CAS  Google Scholar 

  17. Perregaux D, Gabel CA (1994) Interleukin-1β maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J Biol Chem 269:15195–15203

    PubMed  CAS  Google Scholar 

  18. Walev I, Reske K, Palmer M, Valeva A, Bhakdi S (1995) Potassium-inhibited processing of IL-1β in human monocytes. EMBO J 14:1607–1614

    PubMed  CAS  Google Scholar 

  19. 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

    Article  PubMed  CAS  Google Scholar 

  20. Andrei C et al (2004) Phospholipases C and A2 control lysosome-mediated IL-1β secretion: implications for inflammatory processes. Proc Natl Acad Sci USA 101:9745–9750

    Article  PubMed  CAS  Google Scholar 

  21. Masumoto J, Taniguchi S, Ayukawa K et al (1999) ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J Biol Chem 274(33):835–838

    Google Scholar 

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

    Article  Google Scholar 

  23. Masumoto J, Taniguchi S, Sagara J (2001) Pyrin N-terminal homology domain- and caspase recruitment domain-dependent oligomerization of ASC. Biochem Biophys Res Commun 280:652–655

    Article  PubMed  CAS  Google Scholar 

  24. Moriya M, Taniguchi S, Wu P, Liepinsh E, Otting G, Sagara J (2005) Role of charged and hydrophobic residues in the oligomerization of the PYRIN domain of ASC. Biochemistry 44:575–583

    Article  PubMed  CAS  Google Scholar 

  25. Masumoto J, Taniguchi S, Nakayama J et al (2001) 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

    PubMed  CAS  Google Scholar 

  26. Shiohara M, Taniguchi S, Masumoto J et al (2002) 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

    Article  PubMed  CAS  Google Scholar 

  27. Yamamoto M, Yaginuma K, Tsutsui H et al (2004) ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules. Genes Cells 9:1055–1067

    Article  PubMed  CAS  Google Scholar 

  28. Mariathasan S, Newton K, Monack DM et al (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213–218

    Article  PubMed  CAS  Google Scholar 

  29. Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095–2147

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Saleh M et al (2006) Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature 440:1064–1068

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  33. Aksentijevich I et al (1999) Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet 64:949–962

    Article  PubMed  CAS  Google Scholar 

  34. Chae JJ et al (2003) Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell 11:591–604

    Article  PubMed  CAS  Google Scholar 

  35. Inohara N, Nunez G (2003) NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3(5):371–82 (Review, May)

    Article  PubMed  CAS  Google Scholar 

  36. Chae JJ et al (2006) The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1β production. Proc Natl Acad Sci USA 103:9982–9987

    Article  PubMed  CAS  Google Scholar 

  37. Messud-Petit F et al (1998) Serp2, an inhibitor of the interleukin-1β -converting enzyme, is critical in the pathobiology of myxoma virus. J Virol 72:7830–7839

    PubMed  CAS  Google Scholar 

  38. Johnston JB et al (2005) A poxvirus-encoded pyrin domain protein interacts with ASC-1 to inhibit host inflammatory and apoptotic responses to infection. Immunity 23:587–598

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  40. Fairbrother WJ, Gordon NC, Humke EW, O’Rourke KM, Starovasnik MA, Yin JP, Dixit VM (2001) The PYRIN domain: a member of the death domain-fold superfamily. Protein Sci 10:1911–1918

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  43. Xiao T, Towb P, Wasserman SA, Sprang SR (1999) Three-dimensional structure of a complex between the death domains of Pelle and Tube. Cell 99:545–555

    Article  PubMed  CAS  Google Scholar 

  44. Qin H, Srinivasula SM, Wu G, Fernandes-Alnemri T, Alnemri ES, Shi Y (1999) Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1. Nature 399:549–557

    Article  PubMed  CAS  Google Scholar 

  45. Weber CH, Vincenz C (2001) The death domain superfamily: a tale of two interfaces? Trends Biochem Sci 26:475–481

    Article  PubMed  CAS  Google Scholar 

  46. Liepinish E, Barbals R, Dahl E, Sharipo A, Staub E, Otting G (2003) The death-domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition. J Mol Biol 332:1155–1163

    Article  CAS  Google Scholar 

  47. Hiller S, Kohl A, Fiorito F, Herrmann T, Wider G, Tschopp J, Grütter MG, Wüthrich K (2003) NMR structure of the apoptosis- and inflammation-related NALP1 pyrin domain. Structure 11:1199–1205

    Article  PubMed  CAS  Google Scholar 

  48. Siegel RM, Martin DA, Zheng L, Ng S, Bertin J, Cohen J, Lenardo MJ (1998) Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis. J Cell Biol 141:1243–1253

    Article  PubMed  CAS  Google Scholar 

  49. Perez D, White E (1998) E1B 19K inhibits Fas-mediated apoptosis through FADD-dependent sequestration of FLICE. J Cell Biol 141:1255–1266

    Article  PubMed  CAS  Google Scholar 

  50. Yan M, Lee J, Schilbach S, Godard A, Dexit V (1999) mE10, a novel caspase recruitment domain-containing proapoptotic molecule. J Biol Chem 274:10287–10292

    Article  PubMed  CAS  Google Scholar 

  51. Guiet C, Vito P (2000) Caspase recruitment domain (CARD)-dependent cytoplasmic filaments mediate Bcl 10-induced NF-κB activation. J Cell Biol 148:1131–1139

    Article  PubMed  CAS  Google Scholar 

  52. Hull KM, Shoham N, Chae JJ, Aksentijevich I, Kastner DL (2003) The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations. Curr Opin Rheumatol 15:61–69

    Article  PubMed  CAS  Google Scholar 

  53. Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors:intracellular regulatetors of infection and inflammation. Nat Immunol 70:31–40

    Google Scholar 

  54. Conway KE, McConnell BB, Bowring CE, Donald CD, Warren ST, Vertino PM (2000) TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers. Cancer Res 60:6236–42

    PubMed  CAS  Google Scholar 

  55. Guan X, Sagara J, Yokoyama T et al (2003) ASC/TMS1, a caspase-1 activating adaptor, is downregulated by aberrant methylation in human melanoma. Int J Cancer 107:202–208

    Article  PubMed  CAS  Google Scholar 

  56. Machida EO, Brock MV, Hooker CM, Nakayama J, Ishida A, Amano J, Picchi MA, Belinsky SA, Herman JG, Taniguchi S, Baylin SB (2006) Hypermethylation of ASC/TMS1 is a sputum marker for late-stage lung cancer. Cancer Res 66(12):6210–6218 (Jun 15)

    Article  PubMed  CAS  Google Scholar 

  57. Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M et al (2003) ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis. Biochem Biophys Res Commun 303:69–73

    Article  PubMed  CAS  Google Scholar 

  58. Ohtsuka T, Ryu H, Minamishima YA et al (2004) ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Nat Cell Biol 6:121–128

    Article  PubMed  CAS  Google Scholar 

  59. Hasegawa M, Kawase K, Inohara N, Imamura R, Yeh W-C, Kinoshita T, Suda T (2007) Mechanism of ASC-mediated apoptosis:Bid-dependent apoptosis in type II cells. Oncogene 26:1748–1756

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  61. Wang L et al (2002) 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

    Article  PubMed  CAS  Google Scholar 

  62. Mariathasan S, Weiss DS, Dixit VM, Monack DM (2005) Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis. Exp Med 202:1043–1049

    Article  CAS  Google Scholar 

  63. Gavrilin MA et al (2006) Internalization and phagosome escape required for Francisella to induce human monocyte IL-1β processing and release. Proc Natl Acad Sci USA 103:141–146

    Article  PubMed  CAS  Google Scholar 

  64. Zamboni DS et al (2006) The Birc1e cytosolic patternrecognition receptor contributes to the detection and control of Legionella pneumophila infection. Nature Immunol 7:318–325

    Article  CAS  Google Scholar 

  65. Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE (2006) Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog 2:e18

    Article  PubMed  CAS  Google Scholar 

  66. Molofsky AB et al (2006) Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J Exp Med 203:1093–1104

    Article  PubMed  CAS  Google Scholar 

  67. Mariathasan S. et al (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232

    Article  PubMed  CAS  Google Scholar 

  68. Kanneganti TD et al (2006) Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–236

    Article  PubMed  CAS  Google Scholar 

  69. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank our collaborators and all graduate students who have been involved in the study of ASC. This work was partially supported by a grant-in-aid from Novartis Pharma K.K.

Author information

Authors and Affiliations

  1. Department of Molecular Oncology, Institute on Aging and Adaptation, Graduate School of Medicine, Shinshu University, Matsumoto, Japan

    Shun’ichiro Taniguchi

  2. School of Health Sciences, Shinshu University, 3-1-1 Asahi, Matsumoto, 390-8621, Japan

    Junji Sagara

Authors
  1. Shun’ichiro Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junji Sagara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shun’ichiro Taniguchi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taniguchi, S., Sagara, J. Regulatory molecules involved in inflammasome formation with special reference to a key mediator protein, ASC. Semin Immunopathol 29, 231–238 (2007). https://doi.org/10.1007/s00281-007-0082-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-007-0082-3

Keywords

Search

Navigation