Skip to main content
SpringerLink
Log in

The versatile roles of CARDs in regulating apoptosis, inflammation, and NF-κB signaling

  • The Domains of Apoptosis and Inflammation
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

CARD subfamily is the second largest subfamily in the DD superfamily that plays important roles in regulating various signaling pathways, including but not limited to NF-kB activation signaling, apoptosis signaling and inflammatory signaling. The CARD subfamily contains 33 human CARD-containing proteins, regulating the assembly of many signaling complexes, including apoptosome, inflammsome, nodosome, the CBM complex, PIDDosome, the TRAF2 complex, and the MAVS signalosome, by homotypic CARD–CARD interactions. The mechanism of how CARDs find the right binding partner to form a specific complex remains unclear. This review uses different classification schemes to update the classification of CARD-containing proteins. Combining the classification based on domain structures, functions, associated signaling complexes, and roles would help better understand the structural and function diversity of CARD-containing proteins. This review also summarizes recent structural studies on CARDs. Especially, the CARD-containing complexes can be divided into the homodimeric, heterodimeric, oligomeric, filamentous CARD complexes and the CARD–ubiquitin complex. This review will give an overview of the versatile roles of CARDs in regulating signaling transduction, as well as the therapeutic drugs targeting CARD-containing proteins.

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
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Haanen C, Vermes I (1995) Apoptosis and inflammation. Mediators Inflamm 4:5–15. doi:10.1155/S0962935195000020

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Park HH, Lo YC, Lin SC, Wang L, Yang JK, Wu H (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

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Joshi VD, Kalvakolanu DV, Cross AS (2003) Simultaneous activation of apoptosis and inflammation in pathogenesis of septic shock: a hypothesis. FEBS Lett 555:180–184

    CAS  PubMed  Google Scholar 

  4. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Duvall E, Wyllie AH (1986) Death and the Cell. Immunol Today 7:115–119. doi:10.1016/0167-5699(86)90152-0

    CAS  PubMed  Google Scholar 

  6. Salvesen GS (2002) Caspases and apoptosis. Essays Biochem 38:9–19

    CAS  PubMed  Google Scholar 

  7. Riedl SJ, Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5:897–907. doi:10.1038/nrm1496

    CAS  PubMed  Google Scholar 

  8. Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462

    CAS  PubMed  Google Scholar 

  9. Fernald K, Kurokawa M (2013) Evading apoptosis in cancer. Trends Cell Biol 23:620–633. doi:10.1016/j.tcb.2013.07.006

    PubMed Central  PubMed  Google Scholar 

  10. Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11:621–632. doi:10.1038/nrm2952

    CAS  PubMed  Google Scholar 

  11. Lomonosova E, Chinnadurai G (2008) BH3-only proteins in apoptosis and beyond: an overview. Oncogene 27(1):S2–S19. doi:10.1038/onc.2009.39

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Tait SW, Green DR (2013) Mitochondrial regulation of cell death. Cold Spring Harb perspect biol. doi:10.1101/cshperspect.a008706

    PubMed  Google Scholar 

  13. Moldoveanu T, Follis AV, Kriwacki RW, Green DR (2014) Many players in BCL-2 family affairs. Trends Biochem Sci 39:101–111. doi:10.1016/j.tibs.2013.12.006

    CAS  PubMed  Google Scholar 

  14. Bao Q, Shi Y (2007) Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ 14:56–65. doi:10.1038/sj.cdd.4402028

    CAS  PubMed  Google Scholar 

  15. Shi Y (2006) Mechanical aspects of apoptosome assembly. Curr Opin Cell Biol 18:677–684. doi:10.1016/j.ceb.2006.09.006

    CAS  PubMed  Google Scholar 

  16. Riedl SJ, Salvesen GS (2007) The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol 8:405–413. doi:10.1038/nrm2153

    CAS  PubMed  Google Scholar 

  17. Silke J, Meier P (2013) Inhibitor of apoptosis (IAP) proteins-modulators of cell death and inflammation. Cold Spring Harbor perspectives in biology. doi:10.1101/cshperspect.a008730

    PubMed  Google Scholar 

  18. Sessler T, Healy S, Samali A, Szegezdi E (2013) Structural determinants of DISC function: new insights into death receptor-mediated apoptosis signalling. Pharmacol Ther 140:186–199. doi:10.1016/j.pharmthera.2013.06.009

    CAS  PubMed  Google Scholar 

  19. Lavrik I, Golks A, Krammer PH (2005) Death receptor signaling. J Cell Sci 118:265–267. doi:10.1242/jcs.01610

    CAS  PubMed  Google Scholar 

  20. Park SM, Schickel R, Peter ME (2005) Nonapoptotic functions of FADD-binding death receptors and their signaling molecules. Curr Opin Cell Biol 17:610–616. doi:10.1016/j.ceb.2005.09.010

    CAS  PubMed  Google Scholar 

  21. Reed JC, Doctor KS, Godzik A (2004) The domains of apoptosis: a genomics perspective. Sci STKE. doi:10.1126/stke.2392004re9

    PubMed  Google Scholar 

  22. Kersse K, Verspurten J, Vanden Berghe T, Vandenabeele P (2011) The death-fold superfamily of homotypic interaction motifs. Trends Biochem Sci 36:541–552. doi:10.1016/j.tibs.2011.06.006

    CAS  PubMed  Google Scholar 

  23. 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. doi:10.1038/21124

    CAS  PubMed  Google Scholar 

  24. 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

    CAS  PubMed  Google Scholar 

  25. Park HH, Logette E, Raunser S et al (2007) Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 128:533–546. doi:10.1016/j.cell.2007.01.019

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Lin SC, Lo YC, Wu H (2010) Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465:885–890. doi:10.1038/nature09121

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Scott FL, Stec B, Pop C et al (2009) The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature 457:1019–1022. doi:10.1038/nature07606

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Wang L, Yang JK, Kabaleeswaran V et al (2010) The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol 17:1324–1329. doi:10.1038/nsmb.1920

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Wu B, Peisley A, Tetrault D et al (2014) Molecular Imprinting as a Signal-Activation Mechanism of the Viral RNA Sensor RIG-I. Mol Cell 55:511–523. doi:10.1016/j.molcel.2014.06.010

    CAS  PubMed  Google Scholar 

  30. Adrain C, Martin SJ (2001) The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. Trends Biochem Sci 26:390–397

    CAS  PubMed  Google Scholar 

  31. Hong GS, Jung YK (2002) Caspase recruitment domain (CARD) as a bi-functional switch of caspase regulation and NF-kappaB signals. J Biochem Mol Biol 35:19–23

    CAS  PubMed  Google Scholar 

  32. Jiang C, Lin X (2012) Regulation of NF-kappaB by the CARD proteins. Immunol Rev 246:141–153. doi:10.1111/j.1600-065X.2012.01110.x

    PubMed Central  PubMed  Google Scholar 

  33. Kwon D, Yoon JH, Shin SY et al (2012) A comprehensive manually curated protein-protein interaction database for the Death Domain superfamily. Nucleic Acids Res 40:D331–D336. doi:10.1093/nar/gkr1149

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Bouchier-Hayes L, Martin SJ (2002) CARD games in apoptosis and immunity. EMBO Rep 3:616–621. doi:10.1093/embo-reports/kvf139

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Kufer TA, Sansonetti PJ (2011) NLR functions beyond pathogen recognition. Nat Immunol 12:121–128. doi:10.1038/ni.1985

    CAS  PubMed  Google Scholar 

  36. Rawlings DJ, Sommer K, Moreno-Garcia ME (2006) The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat Rev Immunol 6:799–812. doi:10.1038/nri1944

    CAS  PubMed  Google Scholar 

  37. Blonska M, Lin X (2011) NF-kappaB signaling pathways regulated by CARMA family of scaffold proteins. Cell Res 21:55–70. doi:10.1038/cr.2010.182

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Lopez J, John SW, Tenev T et al (2011) CARD-mediated autoinhibition of cIAP1′s E3 ligase activity suppresses cell proliferation and migration. Mol Cell 42:569–583. doi:10.1016/j.molcel.2011.04.008

    CAS  PubMed  Google Scholar 

  39. Gyrd-Hansen M, Meier P (2010) IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer 10:561–574. doi:10.1038/nrc2889

    CAS  PubMed  Google Scholar 

  40. Maelfait J, Beyaert R (2012) Emerging role of ubiquitination in antiviral RIG-I signaling. Microbiol Mol Biol Rev 76:33–45. doi:10.1128/MMBR.05012-11

    PubMed Central  PubMed  Google Scholar 

  41. O’Neill LA, Bowie AG (2011) The powerstroke and camshaft of the RIG-I antiviral RNA detection machine. Cell 147:259–261. doi:10.1016/j.cell.2011.09.027

    PubMed  Google Scholar 

  42. Tschopp J, Schroder K (2010) NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol 10:210–215. doi:10.1038/nri2725

    CAS  PubMed  Google Scholar 

  43. Yuan S, Yu X, Asara JM, Heuser JE, Ludtke SJ, Akey CW (2011) The holo-apoptosome: activation of procaspase-9 and interactions with caspase-3. Structure 19:1084–1096. doi:10.1016/j.str.2011.07.001

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Bouchier-Hayes L, Green DR (2012) Caspase-2: the orphan caspase. Cell Death Differ 19:51–57. doi:10.1038/cdd.2011.157

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Moreira LO, Zamboni DS (2012) NOD1 and NOD2 signaling in infection and inflammation. Front Immunol 3:328. doi:10.3389/fimmu.2012.00328

    PubMed Central  PubMed  Google Scholar 

  46. Thome M, Charton JE, Pelzer C, Hailfinger S (2010) Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1. Cold Spring Harb Perspect Biol 2:a003004. doi:10.1101/cshperspect.a003004

    PubMed Central  PubMed  Google Scholar 

  47. Woo HN, Hong GS, Jun JI et al (2004) Inhibition of Bcl10-mediated activation of NF-kappa B by BinCARD, a Bcl10-interacting CARD protein. FEBS Lett 578:239–244

    CAS  PubMed  Google Scholar 

  48. 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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  50. Druilhe A, Srinivasula SM, Razmara M, Ahmad M, Alnemri ES (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

    CAS  PubMed  Google Scholar 

  51. Le HT, Harton JA (2013) Pyrin- and CARD-only proteins as regulators of NLR functions. Front Immunol 4:275. doi:10.3389/fimmu.2013.00275

    PubMed Central  PubMed  Google Scholar 

  52. Koseki T, Inohara N, Chen S, Nunez G (1998) ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases. Proc Natl Acad Sci USA 95:5156–5160

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Nam YJ, Mani K, Ashton AW et al (2004) Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions. Mol Cell 15:901–912. doi:10.1016/j.molcel.2004.08.020

    CAS  PubMed  Google Scholar 

  54. Dufner A, Pownall S, Mak TW (2006) Caspase recruitment domain protein 6 is a microtubule-interacting protein that positively modulates NF-kappaB activation. Proc Natl Acad Sci USA 103:988–993. doi:10.1073/pnas.0510380103

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Zhu S, Jackson R, Flavell RA (2014) The lock-washer: a reconciliation of the RIG-I activation models. Cell Res 24:645–646. doi:10.1038/cr.2014.58

    CAS  PubMed  Google Scholar 

  56. Park HH (2012) Structural features of caspase-activating complexes. Int J Mol Sci 13:4807–4818. doi:10.3390/ijms13044807

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Vande Walle L, Lamkanfi M (2011) Inflammasomes: caspase-1-activating platforms with critical roles in host defense. Front Microbiol 2:3. doi:10.3389/fmicb.2011.00003

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Zitvogel L, Kepp O, Galluzzi L, Kroemer G (2012) Inflammasomes in carcinogenesis and anticancer immune responses. Nat Immunol 13:343–351. doi:10.1038/ni.2224

    CAS  PubMed  Google Scholar 

  59. Correa RG, Milutinovic S, Reed JC (2012) Roles of NOD1 (NLRC1) and NOD2 (NLRC2) in innate immunity and inflammatory diseases. Biosci Rep 32:597–608. doi:10.1042/BSR20120055

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Hara H, Iizasa E, Nakaya M, Yoshida H (2010) L-CBM signaling in lymphocyte development and function. J Blood Med 1:93–104. doi:10.2147/JBM.S9772

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Thome M (2008) Multifunctional roles for MALT1 in T-cell activation. Nat Rev Immunol 8:495–500. doi:10.1038/nri2338

    CAS  PubMed  Google Scholar 

  62. Beug ST, Cheung HH, LaCasse EC, Korneluk RG (2012) Modulation of immune signalling by inhibitors of apoptosis. Trends Immunol 33:535–545. doi:10.1016/j.it.2012.06.004

    CAS  PubMed  Google Scholar 

  63. Dueber EC, Schoeffler AJ, Lingel A et al (2011) Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination. Science 334:376–380. doi:10.1126/science.1207862

    CAS  PubMed  Google Scholar 

  64. Reikine S, Nguyen JB, Modis Y (2014) Pattern recognition and signaling mechanisms of RIG-I and MDA5. Front Immunol 5:342. doi:10.3389/fimmu.2014.00342

    PubMed Central  PubMed  Google Scholar 

  65. Janssens S, Tinel A (2012) The PIDDosome, DNA-damage-induced apoptosis and beyond. Cell Death Differ 19:13–20. doi:10.1038/cdd.2011.162

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Vakifahmetoglu-Norberg H, Zhivotovsky B (2010) The unpredictable caspase-2: what can it do? Trends Cell Biol 20:150–159. doi:10.1016/j.tcb.2009.12.006

    CAS  PubMed  Google Scholar 

  67. 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

    PubMed Central  PubMed  Google Scholar 

  68. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Chou JJ, Matsuo H, Duan H, Wagner G (1998) Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment. Cell 94:171–180

    CAS  PubMed  Google Scholar 

  70. Humke EW, Shriver SK, Starovasnik MA, Fairbrother WJ, Dixit VM (2000) ICEBERG: a novel inhibitor of interleukin-1beta generation. Cell 103:99–111

    CAS  PubMed  Google Scholar 

  71. Vaughn DE, Rodriguez J, Lazebnik Y, Joshua-Tor L (1999) Crystal structure of Apaf-1 caspase recruitment domain: an alpha-helical Greek key fold for apoptotic signaling. J Mol Biol 293:439–447. doi:10.1006/jmbi.1999.3177

    CAS  PubMed  Google Scholar 

  72. Chen KE, Richards AA, Caradoc-Davies TT et al (2013) The structure of the caspase recruitment domain of BinCARD reveals that all three cysteines can be oxidized. Acta Crystallogr D Biol Crystallogr 69:774–784. doi:10.1107/S0907444913001558

    CAS  PubMed  Google Scholar 

  73. Jin T, Huang M, Smith P, Jiang J, Xiao TS (2013) The structure of the CARD8 caspase-recruitment domain suggests its association with the FIIND domain and procaspases through adjacent surfaces. Acta Crystallogr Sect F 69:482–487. doi:10.1107/S1744309113010075

    CAS  Google Scholar 

  74. Jang TH, Park JH, Park HH (2013) Novel disulfide bond-mediated dimerization of the CARD domain was revealed by the crystal structure of CARMA1 CARD. PLoS One 8:e79778. doi:10.1371/journal.pone.0079778

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Yan N, Chai J, Lee ES et al (2005) Structure of the CED-4-CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans. Nature 437:831–837. doi:10.1038/nature04002

    CAS  PubMed  Google Scholar 

  76. Potter JA, Randall RE, Taylor GL (2008) Crystal structure of human IPS-1/MAVS/VISA/Cardif caspase activation recruitment domain. BMC Struct Biol 8:11. doi:10.1186/1472-6807-8-11

    PubMed Central  PubMed  Google Scholar 

  77. Jin T, Curry J, Smith P, Jiang J, Xiao TS (2013) Structure of the NLRP1 caspase recruitment domain suggests potential mechanisms for its association with procaspase-1. Proteins 81:1266–1270. doi:10.1002/prot.24287

    CAS  PubMed  Google Scholar 

  78. Coussens NP, Mowers JC, McDonald C, Nunez G, Ramaswamy S (2007) Crystal structure of the Nod1 caspase activation and recruitment domain. Biochem Biophys Res Commun 353:1–5. doi:10.1016/j.bbrc.2006.11.122

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Peisley A, Wu B, Xu H, Chen ZJ, Hur S (2014) Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I. Nature 509:110–114. doi:10.1038/nature13140

    CAS  PubMed  Google Scholar 

  80. Kowalinski E, Lunardi T, McCarthy AA et al (2011) Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA. Cell 147:423–435. doi:10.1016/j.cell.2011.09.039

    CAS  PubMed  Google Scholar 

  81. Ferrao R, Wu H (2012) Helical assembly in the death domain (DD) superfamily. Curr Opin Struct Biol 22:241–247. doi:10.1016/j.sbi.2012.02.006

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Srimathi T, Robbins SL, Dubas RL, Hasegawa M, Inohara N, Park YC (2008) Monomer/dimer transition of the caspase-recruitment domain of human Nod1. Biochemistry 47:1319–1325. doi:10.1021/bi7016602

    CAS  PubMed  Google Scholar 

  83. Liu S, Chen ZJ (2011) Expanding role of ubiquitination in NF-kappaB signaling. Cell Res 21:6–21. doi:10.1038/cr.2010.170

    PubMed Central  PubMed  Google Scholar 

  84. Ver Heul AM, Gakhar L, Piper RC, Subramanian R (2014) Crystal Structure of a Complex of NOD1 CARD and Ubiquitin. PLoS One 9:e104017. doi:10.1371/journal.pone.0104017

    PubMed Central  PubMed  Google Scholar 

  85. Ver Heul AM, Fowler CA, Ramaswamy S, Piper RC (2013) Ubiquitin regulates caspase recruitment domain-mediated signaling by nucleotide-binding oligomerization domain-containing proteins NOD1 and NOD2. J Biol Chem 288:6890–6902. doi:10.1074/jbc.M112.413781

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Gack MU, Shin YC, Joo CH et al (2007) TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446:916–920. doi:10.1038/nature05732

    CAS  PubMed  Google Scholar 

  87. Huang S, Zhao L, Kim K, Lee DS, Hwang DH (2008) Inhibition of Nod2 signaling and target gene expression by curcumin. Mol Pharmacol 74:274–281. doi:10.1124/mol.108.046169

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Lyss G, Knorre A, Schmidt TJ, Pahl HL, Merfort I (1998) The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65. J Biol Chem 273:33508–33516

    CAS  PubMed  Google Scholar 

  89. Bielig H, Velder J, Saiai A et al (2010) Anti-inflammatory arene–chromium complexes acting as specific inhibitors of NOD2 signalling. ChemMedChem 5:2065–2071. doi:10.1002/cmdc.201000320

    CAS  PubMed  Google Scholar 

  90. Zhao L, Kwon MJ, Huang S et al (2007) Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells. J Biol Chem 282:11618–11628. doi:10.1074/jbc.M608644200

    CAS  PubMed  Google Scholar 

  91. Correa RG, Khan PM, Askari N et al (2011) Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors. Chem Biol 18:825–832. doi:10.1016/j.chembiol.2011.06.009

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Magnuson G, Khan P, Yuan H et al (2010) High Throughput Screening Assays for NOD1 Inhibitors - Probe 2. Probe Reports from the NIH Molecular Libraries Program, Bethesda

    Google Scholar 

  93. Palacios-Rodriguez Y, Garcia-Lainez G, Sancho M, Gortat A, Orzaez M, Perez-Paya E (2011) Polypeptide modulators of caspase recruitment domain (CARD)-CARD-mediated protein-protein interactions. J Biol Chem 286:44457–44466. doi:10.1074/jbc.M111.255364

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Moreno L, Gatheral T (2013) Therapeutic targeting of NOD1 receptors. Br J Pharmacol 170:475–485. doi:10.1111/bph.12300

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Gatheral T, Reed DM, Moreno L et al (2012) A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses. PLoS One 7:e42386. doi:10.1371/journal.pone.0042386

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Rickard DJ, Sehon CA, Kasparcova V et al (2013) Identification of benzimidazole diamides as selective inhibitors of the nucleotide-binding oligomerization domain 2 (NOD2) signaling pathway. PLoS One 8:e69619. doi:10.1371/journal.pone.0069619

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Saiai A, Bielig H, Velder J et al (2012) Hydrophenalene-Cr(CO)(3) complexes as anti-inflammatory agents based on specific inhibition of NOD2 signalling: a SAR study. Medchemcomm 3:1377–1385. doi:10.1039/C2md20221b

    CAS  Google Scholar 

  98. Jun JC, Cominelli F, Abbott DW (2013) RIP2 activity in inflammatory disease and implications for novel therapeutics. J Leukoc Biol 94:927–932. doi:10.1189/jlb.0213109

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Tigno-Aranjuez JT, Asara JM, Abbott DW (2010) Inhibition of RIP2′s tyrosine kinase activity limits NOD2-driven cytokine responses. Genes Dev 24:2666–2677. doi:10.1101/gad.1964410

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Fulda S (2012) Novel promising IAP antagonist on the horizon for clinical translation. J Med Chem 55:4099–4100. doi:10.1021/jm300475b

    CAS  PubMed  Google Scholar 

  101. Ndubaku C, Varfolomeev E, Wang L et al (2009) Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists. ACS Chem Biol 4:557–566. doi:10.1021/cb900083m

    CAS  PubMed  Google Scholar 

  102. LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S, Korneluk RG (2008) IAP-targeted therapies for cancer. Oncogene 27:6252–6275. doi:10.1038/onc.2008.302

    CAS  PubMed  Google Scholar 

  103. Gaither A, Porter D, Yao Y et al (2007) A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling. Cancer Res 67:11493–11498. doi:10.1158/0008-5472.CAN-07-5173

    CAS  PubMed  Google Scholar 

  104. Varfolomeev E, Blankenship JW, Wayson SM et al (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 131:669–681. doi:10.1016/j.cell.2007.10.030

    CAS  PubMed  Google Scholar 

  105. Vince JE, Wong WW, Khan N et al (2007) IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131:682–693. doi:10.1016/j.cell.2007.10.037

    CAS  PubMed  Google Scholar 

  106. Bai L, Chen W, Wang X, Ju W, Xu S, Lin Y (2009) Attenuating Smac mimetic compound 3-induced NF-kappaB activation by luteolin leads to synergistic cytotoxicity in cancer cells. J Cell Biochem 108:1125–1131. doi:10.1002/jcb.22346

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Park CM, Sun C, Olejniczak ET et al (2005) Non-peptidic small molecule inhibitors of XIAP. Bioorg Med Chem Lett 15:771–775. doi:10.1016/j.bmcl.2004.11.010

    CAS  PubMed  Google Scholar 

  108. Infante JR, Dees EC, Olszanski AJ et al (2014) Phase I Dose-Escalation Study of LCL161, an Oral Inhibitor of Apoptosis Proteins Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol 32:3103–3110. doi:10.1200/JCO.2013.52.3993

    CAS  PubMed  Google Scholar 

  109. Brunckhorst MK, Lerner D, Wang S, Yu Q (2012) AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer. Cancer Biol Ther 13:804–811. doi:10.4161/cbt.20563

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Okuhira K, Ohoka N, Sai K et al (2011) Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein. FEBS Lett 585:1147–1152. doi:10.1016/j.febslet.2011.03.019

    CAS  PubMed  Google Scholar 

  111. Swinney DC, Xu YZ, Scarafia LE et al (2002) A small molecule ubiquitination inhibitor blocks NF-kappa B-dependent cytokine expression in cells and rats. J Biol Chem 277:23573–23581. doi:10.1074/jbc.M200842200

    CAS  PubMed  Google Scholar 

  112. Vicent MJ, Perez-Paya E (2006) Poly-l-glutamic acid (PGA) aided inhibitors of apoptotic protease activating factor 1 (Apaf-1): an antiapoptotic polymeric nanomedicine. J Med Chem 49:3763–3765. doi:10.1021/jm060458x

    CAS  PubMed  Google Scholar 

  113. Mondragon L, Galluzzi L, Mouhamad S et al (2009) A chemical inhibitor of Apaf-1 exerts mitochondrioprotective functions and interferes with the intra-S-phase DNA damage checkpoint. Apoptosis Int J Program Cell Death 14:182–190. doi:10.1007/s10495-008-0310-x

    CAS  Google Scholar 

  114. Wannamaker W, Davies R, Namchuk M et al (2007) (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoy l)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J Pharmacol Exp Ther 321:509–516. doi:10.1124/jpet.106.111344

    CAS  PubMed  Google Scholar 

  115. Boost KA, Hoegl S, Hofstetter C et al (2007) Targeting caspase-1 by inhalation-therapy: effects of Ac-YVAD-CHO on IL-1 beta, IL-18 and downstream proinflammatory parameters as detected in rat endotoxaemia. Intensive Care Med 33:863–871. doi:10.1007/s00134-007-0588-0

    CAS  PubMed  Google Scholar 

  116. Kast RE (2008) Ritonavir and disulfiram may be synergistic in lowering active interleukin-18 levels in acute pancreatitis, and thereby hasten recovery. JOP 9:350–353

    PubMed  Google Scholar 

  117. Pelegrin P, Surprenant A (2009) Dynamics of macrophage polarization reveal new mechanism to inhibit IL-1beta release through pyrophosphates. EMBO J 28:2114–2127. doi:10.1038/emboj.2009.163

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Lamkanfi M, Mueller JL, Vitari AC et al (2009) Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol 187:61–70. doi:10.1083/jcb.200903124

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Coll RC, Robertson A, Butler M, Cooper M, O’Neill LA (2011) The cytokine release inhibitory drug CRID3 targets ASC oligomerisation in the NLRP3 and AIM2 inflammasomes. PLoS One 6:e29539. doi:10.1371/journal.pone.0029539

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Thacker JD, Balin BJ, Appelt DM et al (2012) NLRP3 inflammasome is a target for development of broad-spectrum anti-infective drugs. Antimicrob Agents Chemother 56:1921–1930. doi:10.1128/AAC.06372-11

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by Ministry of Science and Technology Grant MOST 101-2311-B-006-008-MY3 and Academia Sinica Thematic Research Program AS-102-TP-B14-1 (to Y.C.L.), and Ministry of Science and Technology Grant MOST 101-2320-B-001-034-MY3 and Academia Sinica Thematic Research Program AS-102-TP-B14-2 (to S.C.L.), and Academia Sinica Postdoc Fellowship (to C.Y.Y.).

Author information

Authors and Affiliations

  1. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Wen-Pin Kao, Chao-Yu Yang, Tsung-Wei Su, Yin-Ting Wang & Su-Chang Lin

  2. Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan

    Yu-Chih Lo

  3. Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

    Yu-Chih Lo

Authors
  1. Wen-Pin Kao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chao-Yu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tsung-Wei Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yin-Ting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu-Chih Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Su-Chang Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yu-Chih Lo or Su-Chang Lin.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kao, WP., Yang, CY., Su, TW. et al. The versatile roles of CARDs in regulating apoptosis, inflammation, and NF-κB signaling. Apoptosis 20, 174–195 (2015). https://doi.org/10.1007/s10495-014-1062-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-014-1062-4

Keywords

Search

Navigation