Skip to main content
SpringerLink
Log in

Assembly and regulation of ASC specks

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

Abstract

The inflammasome adapter ASC links activated inflammasome sensors to the effector molecule pro-caspase-1. Recruitment of pro-caspase-1 to ASC promotes the autocatalytic activation of caspase-1, which leads to the release of pro-inflammatory cytokines, such as IL-1β. Upon triggering of inflammasome sensors, ASC assembles into large helical fibrils that interact with each other serving as a supramolecular signaling platform termed the ASC speck. Alternative splicing, post-translational modifications of ASC, as well as interaction with other proteins can perturb ASC function. In several inflammatory diseases, ASC specks can be found in the extracellular space and its presence correlates with poor prognosis. Here, we review the role of ASC in inflammation, and focus on the structural mechanisms that lead to ASC speck formation, the regulation of ASC function during inflammasome assembly, and the importance of ASC specks in disease.

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
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

aa:

Amino acid

AIM2:

Absent in melanoma 2

APAF-1:

Apoptotic protease-activating factor 1

ASC:

Apoptosis-associated speck-like protein containing a CARD

CAPS:

Cryopyrin-associated periodic syndrome

CARD:

Caspase-recruitment domain

COP:

CARD-only protein

DAMP:

Damage-associated molecular pattern

DD:

Death domain

DED:

Death effector domain

E1:

Ubiquitin-activating enzyme

E2:

Ubiquitin-conjugating enzyme

E3:

Ubiquitin-ligation enzyme

EPSP:

Electrostatic potential surface patch

FCAS:

Familial cold autoinflammatory syndrome

FMF:

Familial Mediterranean fever

HIN200:

Hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats

HOIL-1:

Heme-oxidized IRP2 ubiquitin ligase-1

HOIP:

HOIL-1 interacting protein

IKK:

IκB kinase

IL:

Interleukin

Jnk:

c-Jun N-terminal kinase

LPS:

Lipopolysaccharide

LUBAC:

Linear ubiquitin chain assembly complex

MAVS:

Mitochondrial antiviral-signaling

MEFV:

Mediterranean fever

MV:

Myxoma virus

NAIP:

NLR family apoptosis inhibitory protein

NF-κB:

Nuclear factor kappa-light-chain enhancer of activated B-cells

NLR:

Nucleotide-binding oligomerization domain (NOD)-like receptor

NLRC:

NOD-, LRR-, CARD-containing

NLRP:

NOD-, leucine-rich repeat (LRR)-, PYD-containing

NOD:

Nucleotide oligomerization domain

NOMID:

Neonatal-onset multisystem inflammatory disorder

PAMP:

Pathogen-associated molecular pattern

POP:

Pyrin-only protein

PRR:

Pattern-recognition receptor

PTM:

Post-translational modification

PYCARD:

PYD and CARD domain containing

PYD:

Pyrin domain

Pydc:

Pyrin domain containing

RIPK2:

Receptor-interacting serine/threonine-protein kinase 2

SHARPIN:

SHANK-associated RH domain interactor

SPV:

Swine pox virus

STED:

Stimulated emission depletion

Syk:

Spleen tyrosine kinase

TMS1:

Target of methylation-induced gene silencing 1

TNF:

Tumor necrosis factor

TRAF3:

TNF receptor-associated factor 3

vPOP:

Virus-encoded POP

VSV:

Vesicular stomatitis virus

References

  1. Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22:240–273. doi:10.1128/CMR.00046-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5. doi:10.1189/jlb.0306164

    Article  CAS  PubMed  Google Scholar 

  3. Razani B, Cheng G (2010) NF-kappaB: much learned, much to learn. Sci Signal. doi:10.1126/scisignal.3138pe29

    PubMed Central  Google Scholar 

  4. Latz E, Xiao TS, Stutz A (2013) Activation and regulation of the inflammasomes. Nat Rev Immunol 13:397–411. doi:10.1038/nri3452

    Article  CAS  PubMed  Google Scholar 

  5. Broderick L, De Nardo D, Franklin BS et al (2015) The inflammasomes and autoinflammatory syndromes. Annu Rev Pathol Mech Dis. doi:10.1146/annurev-pathol-012414-040431

    Google Scholar 

  6. 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 274:33835–33838

    Article  CAS  PubMed  Google Scholar 

  7. 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. doi:10.1177/002215540104901009

    Article  CAS  PubMed  Google Scholar 

  8. Conway KE, Mcconnell BB, Bowring CE et al (2000) TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers. Cancer Res 60:6236–6242

    CAS  PubMed  Google Scholar 

  9. Pelegrin P, Barroso-gutierrez C, Surprenant A (2008) P2X7 receptor differentially couples to distinct release pathways for IL-1 β in mouse macrophage. J Immunol 180:7147–7157. doi:10.4049/jimmunol.180.11.7147

    Article  CAS  PubMed  Google Scholar 

  10. Fernandes-Alnemri T, Wu J, Yu J-W et al (2007) The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ 14:1590–1604. doi:10.1038/sj.cdd.4402194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Martin BN, Wang C, Willette-Brown J et al (2014) IKKα negatively regulates ASC-dependent inflammasome activation. Nat Commun 5:4977. doi:10.1038/ncomms5977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bryan NB, Dorfleutner A, Rojanasakul Y, Stehlik C (2009) Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain. J Immunol 182:3173–3182. doi:10.4049/jimmunol.0802367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang L, Manji GA, Grenier JM 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. doi:10.1074/jbc.M203915200

    Article  CAS  PubMed  Google Scholar 

  14. Srinivasula SM, Poyet JL, Razmara M et al (2002) The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J Biol Chem 277:21119–21122. doi:10.1074/jbc.C200179200

    Article  CAS  PubMed  Google Scholar 

  15. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  16. Salminen A, Kauppinen A, Hiltunen M, Kaarniranta K (2014) Epigenetic regulation of ASC/TMS1 expression: potential role in apoptosis and inflammasome function. Cell Mol Life Sci 71:1855–1864. doi:10.1007/s00018-013-1524-9

    Article  CAS  PubMed  Google Scholar 

  17. 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. doi:10.1016/S0006-291X(02)00384-4

    Article  CAS  PubMed  Google Scholar 

  18. Stehlik C, Lee SH, Dorfleutner A et al (2003) Apoptosis-associated speck-like protein containing a caspase recruitment domain is a regulator of procaspase-1 activation. J Immunol 171:6154–6163. doi:10.4049/jimmunol.171.11.6154

    Article  CAS  PubMed  Google Scholar 

  19. Drexler SK, Bonsignore L, Masin M et al (2012) Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis. Proc Natl Acad Sci USA 109:18384–18389. doi:10.1073/pnas.1209171109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Walter A, Schäfer M, Cecconi V et al (2013) Aldara activates TLR7-independent immune defence. Nat Commun 4:1560. doi:10.1038/ncomms2566

    Article  PubMed  CAS  Google Scholar 

  21. Feldmeyer L, Keller M, Niklaus G et al (2007) The inflammasome mediates UVB-induced activation and secretion of interleukin-1β by keratinocytes. Curr Biol 17:1140–1145. doi:10.1016/j.cub.2007.05.074

    Article  CAS  PubMed  Google Scholar 

  22. Dombrowski Y, Peric M, Koglin S et al (2011) Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions. Sci Transl Med. doi:10.1126/scitranslmed.3002001

    PubMed  PubMed Central  Google Scholar 

  23. Dunn JH, Liu W, Luo Y et al (2012) Dual role of apoptosis-associated speck-like protein containing a CARD (ASC) in tumorigenesis of human melanoma. J Invest Dermatol. doi:10.1038/jid.2012.317

    PubMed  PubMed Central  Google Scholar 

  24. Rathinam VAK, Fitzgerald KA (2016) Review inflammasome complexes: emerging mechanisms and effector functions. Cell 165:792–800. doi:10.1016/j.cell.2016.03.046

    Article  CAS  PubMed  Google Scholar 

  25. Dick MS, Sborgi L, Ru S et al (2016) ASC filament formation serves as a signal amplification mechanism for inflammasome. Nat Commun. doi:10.1038/ncomms11929

    Google Scholar 

  26. Broz P, Dixit VM (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. doi:10.1038/nri.2016.58

    PubMed  Google Scholar 

  27. Guo H, Callaway JB, Ting JP (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21:677–687. doi:10.1038/nm.3893

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Kayagaki N, Stowe IB, Lee BL et al (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signaling. Nature. doi:10.1038/nature15541

    Google Scholar 

  29. Shi J, Zhao Y, Wang K et al (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. doi:10.1038/nature15514

    Google Scholar 

  30. Milhavet F, Cuisset L, Hoffman HM et al (2008) The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat 29:803–808. doi:10.1002/humu.20720

    Article  PubMed  Google Scholar 

  31. Campbell L, Raheem I, Malemud CJ, Askari AD (2016) The relationship between NALP3 and autoinflammatory syndromes. Int J Mol Sci. doi:10.3390/ijms17050725

    PubMed  PubMed Central  Google Scholar 

  32. Ozen S, Bilginer Y (2014) A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol 10:135–147. doi:10.1038/nrrheum.2013.174

    Article  CAS  PubMed  Google Scholar 

  33. de Alba E (2009) Structure and interdomain dynamics of apoptosis-associated speck-like protein containing a CARD (ASC). J Biol Chem 284:32932–32941. doi:10.1074/jbc.M109.024273

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Ravotti F, Sborgi L, Cadalbert R et al (2016) Sequence-specific solid-state NMR assignments of the mouse ASC PYRIN domain in its filament form. Biomol NMR Assign 10:107–115

    Article  CAS  PubMed  Google Scholar 

  35. Park HH, Lo Y-C, Lin S-C et al (2007) The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annu Rev Immunol 25:561–586. doi:10.1146/annurev.immunol.25.022106.141656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang B, Eberstadt M, Olejniczak ET et al (1996) NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature 384:638–641

    Article  CAS  PubMed  Google Scholar 

  37. Tartaglia LA, Ayres TM, Wong GHW, Goeddel DV (1993) A novel domain within the 55 kd TNF receptor signals cell death. Cell 74:845–853

    Article  CAS  PubMed  Google Scholar 

  38. Liepinsh E, Barbals R, Dahl E et al (2003) The death-domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition. J Mol Biol 332:1155–1163. doi:10.1016/j.jmb.2003.07.007

    Article  CAS  PubMed  Google Scholar 

  39. Bae JY, Park HH (2011) Crystal structure of NALP3 protein pyrin domain (PYD) and its implications in inflammasome assembly. J Biol Chem 286:39528–39536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jin T, Perry A, Smith P et al (2013) Structure of the absent in melanoma 2 (AIM2) pyrin domain provides insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly. J Biol Chem 288:13225–13235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pinheiro AS, Proell M, Eibl C et al (2010) Three-dimensional structure of the NLRP7 pyrin domain: insight into pyrin-pyrin-mediated effector domain signaling in innate immunity. J Biol Chem 285:27402–27410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pinheiro AS, Eibl C, Ekman-Vural Z et al (2011) The NLRP12 pyrin domain: structure, dynamics, and functional insights. J Mol Biol 413:790–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hiller S, Kohl A, Fiorito F et al (2003) NMR structure of the apoptosis- and inflammation-related NALP1 pyrin domain. Structure 11:1199–1205

    Article  CAS  PubMed  Google Scholar 

  44. Eibl C, Grigoriu S, Hessenberger M et al (2012) Structural and functional analysis of the NLRP4 pyrin domain. Biochemistry 51:7330–7341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sborgi L, Ravotti F, Dandey VP et al (2015) Structure and assembly of the mouse ASC inflammasome by combined NMR spectroscopy and cryo-electron microscopy. Proc Natl Acad Sci USA. doi:10.1073/pnas.1507579112

    PubMed  PubMed Central  Google Scholar 

  46. Lu A, Magupalli VG, Ruan J et al (2014) Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156:1193–1206. doi:10.1016/j.cell.2014.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yuan S, Akey CW (2013) Apoptosome structure, assembly, and procaspase activation. Structure 21:501–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Richards N, Schaner P, Diaz A et al (2001) Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J Biol Chem 276:39320–39329. doi:10.1074/jbc.M104730200

    Article  CAS  PubMed  Google Scholar 

  49. Cai X, Chen J, Xu H et al (2014) Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156:1207–1222. doi:10.1016/j.cell.2014.01.063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lu A, Li Y, Yin Q et al (2015) Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2. Cell Discov. doi:10.1038/celldisc.2015.13

    Google Scholar 

  51. Egelman EH, Francis N, DeRosier DJ (1982) F-actin is a helix with a random variable twist. Nature 298:131–135

    Article  CAS  PubMed  Google Scholar 

  52. Chrétien D, Metoz F, Verde F et al (1992) Lattice defects in microtubules: protofilament numbers vary within individual microtubules. J Cell Biol 117:1031–1040

    Article  PubMed  Google Scholar 

  53. Broz P, von Moltke J, Jones JW et al (2010) Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing. Cell Host Microbe 8:471–483. doi:10.1016/j.chom.2010.11.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Broz P, Newton K, Lamkanfi M et al (2010) Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J Exp Med 207:1745–1755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Schmidt FI, Lu A, Chen JW et al (2016) A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly. J Exp Med. doi:10.1084/jem.20151790

    PubMed Central  Google Scholar 

  56. Sahillioglu AC, Sumbul F, Ozoren N, Haliloglu T (2014) Structural and dynamics aspects of ASC speck assembly. Structure 22:1722–1734. doi:10.1016/j.str.2014.09.011

    Article  CAS  PubMed  Google Scholar 

  57. Vajjhala PR, Mirams RE, Hill JM (2012) Multiple binding sites on the pyrin domain of ASC protein allow self-association and interaction with NLRP3 protein. J Biol Chem 287:41732–41743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stehlik C, Krajewska M, Welsh K et al (2003) The PAAD/PYRIN-only protein POP1/ASC2 is a modulator of ASC-mediated nuclear-factor-kappa B and pro-caspase-1 regulation. Biochem J 373:101–113. doi:10.1042/BJ20030304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Vajjhala PR, Kaiser S, Smith SJ et al (2014) Identification of multifaceted binding modes for pyrin and ASC pyrin domains gives insights into pyrin inflammasome assembly. J Biol Chem 289:23504–23519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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. doi:10.1006/bbrc.2000.4190

    Article  CAS  PubMed  Google Scholar 

  61. Proell M, Gerlic M, Mace PD et al (2013) The CARD plays a critical role in ASC foci formation and inflammasome signalling. Biochem J 449:613–621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Masumoto J, Taniguchi S, Nakayama K et al (2001) Murine ortholog of ASC, a CARD-containing protein, self-associates and exhibits restricted distribution in developing mouse embryos. Exp Cell Res 133:128–133. doi:10.1006/excr.2000.5078

    Article  CAS  Google Scholar 

  63. Sanders MG, Parsons MJ, Howard AG et al (2015) Single-cell imaging of inflammatory caspase dimerization reveals differential recruitment to inflammasomes. Cell Death Dis 6:e1813. doi:10.1038/cddis.2015.186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhang L, Chen S, Ruan J et al (2015) Cryo-EM structure of the activated NAIP2- NLRC4 inflammasome reveals nucleated polymerization. Sci Express 4:12–14. doi:10.1126/science.aac5789

    Google Scholar 

  65. Chen Y-R, Clark AC (2004) Kinetic traps in the folding/unfolding of procaspase-1 CARD domain. Protein Sci 13:2196–2206. doi:10.1110/ps.03521504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Thornberry NA, Bull HG, Calaycay JR et al (1992) A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 356:768–774

    Article  CAS  PubMed  Google Scholar 

  67. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell 10:417–426. doi:10.1016/S1097-2765(02)00599-3

    Article  CAS  PubMed  Google Scholar 

  68. Lu A, Wu H (2015) Structural mechanisms of inflammasome assembly. FEBS J 5:435–444. doi:10.1111/febs.13133

    Article  CAS  Google Scholar 

  69. Hu Z, Zhou Q, Zhang C et al (2015) Structural and biochemical basis for induced self-propagation of NLRC4. Sci Express 4:1–11. doi:10.1126/science.aac5489

    Article  CAS  Google Scholar 

  70. Cheng J, Waite AL, Tkaczyk ER et al (2010) Kinetic properties of ASC protein aggregation in epithelial cells. J Cell Physiol 222:738–747. doi:10.1002/jcp.22005

    CAS  PubMed  Google Scholar 

  71. Kueh HY, Mitchison TJ (2009) Structural plasticity in actin and tubulin polymer dynamics. Science 325:960–963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wu H (2013) Higher-order assemblies in a new paradigm of signal transduction. Cell 153:287–292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Daskalov A, Paoletti M, Ness F, Saupe SJ (2012) Genomic clustering and homology between HET-S and the NWD2 STAND protein in various fungal genomes. PLoS One 7:e34854. doi:10.1371/journal.pone.0034854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Qiao Q, Yang C, Zheng C et al (2013) Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly. Mol Cell 51:766–779. doi:10.1016/j.molcel.2013.08.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Li J, McQuade T, Siemer AB et al (2012) The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150:339–350. doi:10.1016/j.cell.2012.06.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gaidt MM, Ebert TS, Chauhan D et al (2016) Human monocytes engage an alternative inflammasome pathway. Immunity. doi:10.1016/j.immuni.2016.01.012

    PubMed  Google Scholar 

  77. Garlanda C, Dinarello CA, Mantovani A (2013) The interleukin-1 family: back to the future. Immunity 39:1003–1018. doi:10.1016/j.immuni.2013.11.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. de Vasconcelos NM, van Opdenbosch N, Lamkanfi M (2016) Inflammasomes as polyvalent cell death platforms. Cell Mol Life Sci 73:2335–2347. doi:10.1007/s00018-016-2204-3

    Article  PubMed  CAS  Google Scholar 

  79. Man SM, Kanneganti T-D (2015) Regulation of inflammasome activation. Immunol Rev 265:6–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Taniguchi S, Matsushita K, Takeoka M et al (2009) A splice variant of ASC regulates IL-1beta release and aggregates differently from intact ASC. Mediators Inflamm. doi:10.1155/2009/287387

    PubMed  PubMed Central  Google Scholar 

  81. Bryan NB, Dorfleutner A, Kramer SJ et al (2010) Differential splicing of the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) regulates inflammasomes. J Inflamm (Lond) 7:23. doi:10.1186/1476-9255-7-23

    Article  CAS  Google Scholar 

  82. Dorfleutner A, Chu L, Stehlik C (2015) Inhibiting the inflammasome: one domain at a time. Immunol Rev 265:205–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Le HT, Harton JA (2013) Pyrin- and CARD-only proteins as regulators of NLR functions. Front Immunol 4:1–10. doi:10.3389/fimmu.2013.00275

    Google Scholar 

  84. Pawlowski K, Pio F, Chu ZL et al (2001) PAAD—a new protein domain associated with apoptosis, cancer and autoimmune diseases. Trends Biochem Sci 26:85–87. doi:10.1016/S0968-0004(00)01729-1

    Article  CAS  PubMed  Google Scholar 

  85. Natarajan A, Ghose R, Hill JM (2006) Structure and dynamics of ASC2, a pyrin domain-only protein that regulates inflammatory signaling. J Biol Chem 281:31863–31875. doi:10.1074/jbc.M605458200

    Article  CAS  PubMed  Google Scholar 

  86. Espejo F, Patarroyo ME (2006) Determining the 3D structure of human ASC2 protein involved in apoptosis and inflammation. Biochem Biophys Res Commun 340:860–864. doi:10.1016/j.bbrc.2005.12.087

    Article  CAS  PubMed  Google Scholar 

  87. Srimathi T, Robbins SL, Dubas RL et al (2008) Mapping of POP1-binding site on pyrin domain of ASC. J Biol Chem 283:15390–15398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Atianand MK, Harton JA (2011) Uncoupling of Pyrin-only protein 2 (POP2)-mediated dual regulation of NF-κB and the inflammasome. J Biol Chem 286:40536–40547. doi:10.1074/jbc.M111.274290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. de Almeida L, Khare S, Misharin AV et al (2015) The PYRIN domain-only protein POP1 inhibits inflammasome assembly and ameliorates inflammatory disease. Immunity 43:264–276

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Verhelst K, Verstrepen L, Carpentier I, Beyaert R (2013) IkB kinase e (IKKe): a therapeutic target in inflammation and cancer. Biochem Pharmacol 85:873–880. doi:10.1016/j.bcp.2013.01.007

    Article  CAS  PubMed  Google Scholar 

  91. Dorfleutner A, Bryan NB, Talbott SJ et al (2007) Cellular pyrin domain-only protein 2 is a candidate regulator of inflammasome activation. Infect Immun 75:1484–1492

    Article  CAS  PubMed  Google Scholar 

  92. Bedoya F, Sandler LL, Harton JA (2007) Pyrin-only protein 2 modulates NF-κB and disrupts ASC:CLR interactions. J Immunol 178:3837–3845. doi:10.4049/jimmunol.178.6.3837

    Article  CAS  PubMed  Google Scholar 

  93. Atianand MK, Fuchs T, Harton JA (2011) Recent evolution of the NF-κB and inflammasome regulating protein POP2 in primates. BMC Evol Biol 11:56. doi:10.1186/1471-2148-11-56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Khare S, Ratsimandresy RA, de Almeida L et al (2014) The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses. Nat Immunol 15:343–353. doi:10.1038/ni.2829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Porter KA, Duffy EB, Nyland P et al (2014) The CLRX.1/NOD24 (NLRP2P) pseudogene codes a functional negative regulator of NF-κB, pyrin-only protein 4. Genes Immun 15:392–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dorfleutner A, Talbott SJ, Bryan NB et al (2007) A Shope Fibroma virus PYRIN-only protein modulates the host immune response. Virus Genes 35:685–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Johnston JB, Barrett JW, Nazarian SH 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. doi:10.1016/j.immuni.2005.10.003

    Article  CAS  PubMed  Google Scholar 

  98. Rahman MM, McFadden G (2011) Myxoma virus lacking the pyrin-like protein M013 is sensed in human myeloid cells by both NLRP3 and multiple Toll-like receptors, which independently activate the inflammasome and NF-κB innate response pathways. J Virol 85:12505–12517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lu A, Li Y, Schmidt FI et al (2016) Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism. Nat Struct Mol Biol 23:1–12. doi:10.1038/nsmb.3199

    Article  CAS  Google Scholar 

  100. Lamkanfi M, Denecker G, Kalai M et al (2004) INCA, a novel human caspase recruitment domain protein that inhibits interleukin-1β generation. J Biol Chem 279:51729–51738. doi:10.1074/jbc.M407891200

    Article  CAS  PubMed  Google Scholar 

  101. Karasawa T, Kawashima A, Usui F et al (2015) Oligomerized CARD16 promotes caspase-1 assembly and IL-1β processing. FEBS Open Bio 5:348–356. doi:10.1016/j.fob.2015.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Humke EW, Shriver SK, Starovasnik MA et al (2000) ICEBERG: a novel inhibitor of interleukin-1β Generation. Cell 103:99–111. doi:10.1016/S0092-8674(00)00108-2

    Article  CAS  PubMed  Google Scholar 

  103. Lee SH, Stehlik C, Reed JC (2001) COP, a caspase recruitment domain-containing protein and inhibitor of caspase-1 activation processing. J Biol Chem 276:34495–34500. doi:10.1074/jbc.M101415200

    Article  CAS  PubMed  Google Scholar 

  104. Druilhe A, Srinivasula SM, Razmara M et al (2001) Regulation of IL-1beta generation by pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. Cell Death Differ 8:649–657. doi:10.1038/sj.cdd.4400881

    Article  CAS  PubMed  Google Scholar 

  105. Kersse K, Lamkanfi M, Bertrand MJM et al (2011) Interaction patches of procaspase-1 caspase recruitment domains (CARDs) are differently involved in procaspase-1 activation and receptor-interacting protein 2 (RIP2)-dependent nuclear factor κB signaling. J Biol Chem 286:35874–35882. doi:10.1074/jbc.M111.242321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hu H, Sun S-C (2016) Ubiquitin signaling in immune responses. Cell Res 26:457–483. doi:10.1038/cr.2016.40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Cohen P (2014) Immune diseases caused by mutations in kinases and components of the ubiquitin system. Nat Immunol 15:521–529. doi:10.1038/ni.2892

    Article  CAS  PubMed  Google Scholar 

  108. Heaton SM, Borg NA, Dixit VM (2015) Ubiquitin in the activation and attenuation of innate antiviral immunity. J Exp Med 213:1–13. doi:10.1084/jem.20151531

    Article  PubMed  CAS  Google Scholar 

  109. Komander D, Rape M (2012) The ubiquitin code. Annu Rev Biochem 81:203–229. doi:10.1146/annurev-biochem-060310-170328

    Article  CAS  PubMed  Google Scholar 

  110. Hochstrasser M (2009) Origin and function of ubiquitin-like proteins. Nature. doi:10.1038/nature07958

    PubMed  PubMed Central  Google Scholar 

  111. Shimizu Y, Taraborrelli L, Walczak H (2015) Linear ubiquitination in immunity. Immunol Rev 266:190–207. doi:10.1111/imr.12309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rieser E, Cordier SM, Walczak H (2013) Linear ubiquitination: a newly discovered regulator of cell signalling. Trends Biochem Sci 38:94–102. doi:10.1016/j.tibs.2012.11.007

    Article  CAS  PubMed  Google Scholar 

  113. Rodgers MA, Bowman JW, Fujita H et al (2014) The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med 211:1333–1347. doi:10.1084/jem.20132486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Shi C-S, Shenderov K, Huang N-N et al (2012) Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13:255–263. doi:10.1038/ni.2215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Matsumoto ML, Dong KC, Yu C et al (2012) Engineering and structural characterization of a linear polyubiquitin-specific antibody. J Mol Biol 418:134–144. doi:10.1016/j.jmb.2011.12.053

    Article  CAS  PubMed  Google Scholar 

  116. Guan K, Wei C, Zheng Z et al (2015) MAVS promotes inflammasome activation by targeting ASC for K63-linked ubiquitination via the E3 ligase TRAF3. J Immunol 194:4880–4890. doi:10.4049/jimmunol.1402851

    Article  CAS  PubMed  Google Scholar 

  117. Saha SK, Pietras EM, He JQ et al (2006) Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J 25:3257–3263. doi:10.1038/sj.emboj.7601220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Park H, Ishihara D, Cox D (2011) Regulation of tyrosine phosphorylation in macrophage phagocytosis and chemotaxis. Arch Biochem Biophys 510:101–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Clark K (2014) Protein kinase networks that limit TLR signalling. Biochem Soc Trans 42:11–24

    Article  CAS  PubMed  Google Scholar 

  120. Christian F, Smith EL, Carmody RJ (2016) The regulation of NF-κB subunits by phosphorylation. Cells. doi:10.3390/cells5010012

    PubMed  PubMed Central  Google Scholar 

  121. Lin Y-C, Huang D-Y, Wang J-S et al (2015) Syk is involved in NLRP3 inflammasome-mediated caspase-1 activation through adaptor ASC phosphorylation and enhanced oligomerization. J Leukoc Biol 97:1–11. doi:10.1189/jlb.3HI0814-371RR

    Article  CAS  Google Scholar 

  122. Hara H, Tsuchiya K, Kawamura I et al (2013) Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol 14:1247–1255. doi:10.1038/ni.2749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Gross O, Poeck H, Bscheider M et al (2009) Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. doi:10.1038/nature07965

    PubMed Central  Google Scholar 

  124. Zhu F, Xia X, Liu B et al (2007) IKKa shields 14-3-3s, aG2/M cell cycle checkpoint gene, from hypermethylation, preventing its silencing. Mol Cell 27:214–227. doi:10.1016/j.molcel.2007.05.042

    Article  CAS  PubMed  Google Scholar 

  125. Lawrence T, Bebien M, Liu GY et al (2005) IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature 434:1138–1143. doi:10.1038/nature03491

    Article  CAS  PubMed  Google Scholar 

  126. Balci-Peynircioglu B, Waite AL, Schaner P et al (2008) Expression of ASC in renal tissues of familial mediterranean fever patients with amyloidosis: postulating a role for ASC in AA type amyloid deposition. Exp Biol Med (Maywood) 233:1324–1333. doi:10.3181/0803-RM-106

    Article  CAS  Google Scholar 

  127. Franklin BS, Bossaller L, De Nardo D et al (2014) The adaptor ASC has extracellular and “prionoid” activities that propagate inflammation. Nat Immunol. doi:10.1038/ni.2913

    PubMed  PubMed Central  Google Scholar 

  128. Baroja-Mazo A, Martín-Sánchez F, Gomez AI et al (2014) The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 15:1–5. doi:10.1038/ni.2919

    Article  CAS  Google Scholar 

  129. Dostert C, Pétrilli V, Van Bruggen R et al (2008) Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674–677. doi:10.1126/science.1156995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Halle A, Hornung V, Petzold GC et al (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9:857–865. doi:10.1038/ni.1636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hornung V, Bauernfeind F, Halle A et al (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9:847–856. doi:10.1038/ni.1631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Aguzzi A, Nuvolone M, Zhu C (2013) The immunobiology of prion diseases. Nat Rev Immunol 13:888–902. doi:10.1038/nri3553

    Article  CAS  PubMed  Google Scholar 

  133. Holmes BB, Diamond MI (2012) Cellular mechanisms of protein aggregate propagation. Curr Opin Neurol 25:721–726. doi:10.1097/WCO.0b013e32835a3ee0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Serpell LC (2000) Alzheimer’s amyloid fibrils: structure and assembly. Biochim Biophys Acta 1502:16–30. doi:10.1016/S0925-4439(00)00029-6

    Article  CAS  PubMed  Google Scholar 

  135. Greenwald J, Riek R (2010) Biology of amyloid: structure, function, and regulation. Structure 18:1244–1260. doi:10.1016/j.str.2010.08.009

    Article  CAS  PubMed  Google Scholar 

  136. Adamczak S, Dale G, de Rivero Vaccari JP et al (2012) Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J Neurosurg 117:1119–1125. doi:10.3171/2012.9.JNS12815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. de Rivero Vaccari JP, Lotocki G, Alonso OF et al (2009) Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab 29:1251–1261. doi:10.1038/jcbfm.2009.46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Sahillioğlu AC, Özören N (2015) Artificial loading of ASC specks with cytosolic antigens. PLoS One 10(8):e0134912. doi:10.1371/journal.pone.0134912

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Lelouard H, Gatti E, Cappello F et al (2002) Transient aggregation of ubiquitinated proteins during dendritic cell maturation. Nature 417:177–182. doi:10.1038/417177a

    Article  CAS  PubMed  Google Scholar 

  140. Knowles TPJ, Vendruscolo M, Dobson CM (2014) The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 15:384–396. doi:10.1038/nrm3810

    Article  CAS  PubMed  Google Scholar 

  141. Morales R, Moreno-Gonzalez I, Soto C (2013) Cross-seeding of misfolded proteins: implications for etiology and pathogenesis of protein misfolding diseases. PLoS Pathog 9:1–4. doi:10.1371/journal.ppat.1003537

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The ASC speck STED image showed in Fig. 2 was recorded with the help of Bjørnar Sporsheim at the Cellular and Molecular Imaging Core Facility (CMIC), Norwegian University of Science and Technology (NTNU). We thank Andrea Stutz for critical reading of the manuscript.

Author information

Author notes

    Authors and Affiliations

    1. Institute of Innate Immunity, University Hospitals, University of Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany

      Florian Hoss, Juan F. Rodriguez-Alcazar & Eicke Latz

    2. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA

      Eicke Latz

    3. German Center for Neurodegenerative Diseases, Bonn, Germany

      Eicke Latz

    4. Department of Cancer Research and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway

      Eicke Latz

    Authors
    1. Florian Hoss
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Juan F. Rodriguez-Alcazar
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Eicke Latz
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Eicke Latz.

    Additional information

    F. Hoss and J. F. Rodriguez-Alcazar contributed equally.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Hoss, F., Rodriguez-Alcazar, J.F. & Latz, E. Assembly and regulation of ASC specks. Cell. Mol. Life Sci. 74, 1211–1229 (2017). https://doi.org/10.1007/s00018-016-2396-6

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00018-016-2396-6

    Keywords

    Search

    Navigation