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Biochem J. 2003 Jul 1; 373(Pt 1): 101–113.
PMCID: PMC1223462

The PAAD/PYRIN-only protein POP1/ASC2 is a modulator of ASC-mediated nuclear-factor-kappa B and pro-caspase-1 regulation.


Proteins containing PAAD [pyrin, AIM (absent-in-melanoma), ASC [apoptosis-associated speck-like protein containing a CARD (caspase-recruitment domain)] and DD (death domain)-like] (PYRIN, DAPIN) domains are involved in innate immunity, regulating pathways leading to nuclear-factor-kappa B (NF-kappa B) and pro-caspase-1 activation. Many PAAD-family proteins have structures reminiscent of Nod-1, a putative intracellular sensor of lipopolysaccharide. Hereditary mutations in some of the PAAD-family genes are associated with auto-inflammatory diseases. Several of these proteins utilize the bipartite PAAD- and CARD-containing adapter protein ASC/TMS-1 (target of methylation-induced silencing) for linking to downstream signalling pathways. In the present paper, we describe characterization of human PAAD-only protein-1 (POP1)/ASC2, which is highly homologous with the PAAD domain of ASC, and which probably originated by gene duplication on chromosome 16. We demonstrate that POP1/ASC2 associates with ASC via PAAD-PAAD interactions and modulates NF-kappa B and pro-caspase-1 regulation by this adapter protein. In gene transfer experiments, POP1/ASC2 suppressed cytokine-mediated NF-kappa B activation similar to other PAAD-family proteins previously tested. Immunohistochemical studies showed expression of POP1/ASC2 predominantly in macrophages and granulocytes. We propose that POP1/ASC2 functions as a modulator of multidomain PAAD-containing proteins involved in NF-kappa B and pro-caspase-1 activation and innate immunity.

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Selected References

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  • Aravind L, Dixit VM, Koonin EV. The domains of death: evolution of the apoptosis machinery. Trends Biochem Sci. 1999 Feb;24(2):47–53. [PubMed]
  • Bertin J, DiStefano PS. The PYRIN domain: a novel motif found in apoptosis and inflammation proteins. Cell Death Differ. 2000 Dec;7(12):1273–1274. [PubMed]
  • Fairbrother WJ, Gordon NC, Humke EW, O'Rourke KM, Starovasnik MA, Yin JP, Dixit VM. The PYRIN domain: a member of the death domain-fold superfamily. Protein Sci. 2001 Sep;10(9):1911–1918. [PMC free article] [PubMed]
  • 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. 2001 Feb 20;11(4):R118–R120. [PubMed]
  • Pawłowski K, Pio F, Chu Z, Reed JC, Godzik A. PAAD - a new protein domain associated with apoptosis, cancer and autoimmune diseases. Trends Biochem Sci. 2001 Feb;26(2):85–87. [PubMed]
  • Staub E, Dahl E, Rosenthal A. The DAPIN family: a novel domain links apoptotic and interferon response proteins. Trends Biochem Sci. 2001 Feb;26(2):83–85. [PubMed]
  • Weber CH, Vincenz C. The death domain superfamily: a tale of two interfaces? Trends Biochem Sci. 2001 Aug;26(8):475–481. [PubMed]
  • Feldmann Jérôme, Prieur Anne-Marie, Quartier Pierre, Berquin Patrick, Certain Stephanie, Cortis Elisabetta, Teillac-Hamel Dominique, Fischer Alain, de Saint Basile Genevieve. 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. 2002 Jul;71(1):198–203. [PMC free article] [PubMed]
  • Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 Nov;29(3):301–305. [PMC free article] [PubMed]
  • Stehlik Christian, Fiorentino Loredana, Dorfleutner Andrea, Bruey Jean-Marie, Ariza Eugenia M, Sagara Junji, Reed John C. The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways. J Exp Med. 2002 Dec 16;196(12):1605–1615. [PMC free article] [PubMed]
  • Manji Gulam A, Wang Lin, Geddes Brad J, Brown Melissa, Merriam Sarah, Al-Garawi Amal, Mak Simona, Lora Jose M, Briskin Michael, Jurman Mark, et al. PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kappa B. J Biol Chem. 2002 Mar 29;277(13):11570–11575. [PubMed]
  • Fiorentino Loredana, Stehlik Christian, Oliveira Vasco, Ariza Maria Eugenia, Godzik Adam, Reed John C. A novel PAAD-containing protein that modulates NF-kappa B induction by cytokines tumor necrosis factor-alpha and interleukin-1beta. J Biol Chem. 2002 Sep 20;277(38):35333–35340. [PubMed]
  • Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed JC. A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis. J Biol Chem. 2001 Mar 23;276(12):9239–9245. [PubMed]
  • Hlaing T, Guo RF, Dilley KA, Loussia JM, Morrish TA, Shi MM, Vincenz C, Ward PA. 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. 2001 Mar 23;276(12):9230–9238. [PubMed]
  • Masumoto J, Taniguchi S, Ayukawa K, Sarvotham H, Kishino T, Niikawa N, Hidaka E, Katsuyama T, Higuchi T, Sagara J. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J Biol Chem. 1999 Nov 26;274(48):33835–33838. [PubMed]
  • Conway KE, McConnell BB, Bowring CE, Donald CD, Warren ST, Vertino PM. TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers. Cancer Res. 2000 Nov 15;60(22):6236–6242. [PubMed]
  • Karin M, Delhase M. The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling. Semin Immunol. 2000 Feb;12(1):85–98. [PubMed]
  • Silverman N, Maniatis T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev. 2001 Sep 15;15(18):2321–2342. [PubMed]
  • Srinivasula Srinivasa M, Poyet Jean-Luc, Razmara Marjaneh, Datta Pinaki, Zhang ZhiJia, Alnemri Emad S. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J Biol Chem. 2002 Jun 14;277(24):21119–21122. [PubMed]
  • Wang Lin, Manji Gulam A, Grenier Jill M, Al-Garawi Amal, Merriam Sarah, Lora Jose M, Geddes Brad J, Briskin Michael, DiStefano Peter S, Bertin John. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. J Biol Chem. 2002 Aug 16;277(33):29874–29880. [PubMed]
  • Dinarello CA. Interleukin-1. Cytokine Growth Factor Rev. 1997 Dec;8(4):253–265. [PubMed]
  • Li W, Pio F, Pawłowski K, Godzik A. Saturated BLAST: an automated multiple intermediate sequence search used to detect distant homology. Bioinformatics. 2000 Dec;16(12):1105–1110. [PubMed]
  • Burge C, Karlin S. Prediction of complete gene structures in human genomic DNA. J Mol Biol. 1997 Apr 25;268(1):78–94. [PubMed]
  • Lee SH, Stehlik C, Reed JC. Cop, a caspase recruitment domain-containing protein and inhibitor of caspase-1 activation processing. J Biol Chem. 2001 Sep 14;276(37):34495–34500. [PubMed]
  • Perkins ND, Schmid RM, Duckett CS, Leung K, Rice NR, Nabel GJ. Distinct combinations of NF-kappa B subunits determine the specificity of transcriptional activation. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1529–1533. [PMC free article] [PubMed]
  • Schmid RM, Perkins ND, Duckett CS, Andrews PC, Nabel GJ. Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65. Nature. 1991 Aug 22;352(6337):733–736. [PubMed]
  • Krajewski S, Krajewska M, Shabaik A, Miyashita T, Wang HG, Reed JC. Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am J Pathol. 1994 Dec;145(6):1323–1336. [PMC free article] [PubMed]
  • Tschopp Jürg, Martinon Fabio, Burns Kimberly. NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol. 2003 Feb;4(2):95–104. [PubMed]
  • Richards N, Schaner P, Diaz A, Stuckey J, Shelden E, Wadhwa A, Gumucio DL. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J Biol Chem. 2001 Oct 19;276(42):39320–39329. [PubMed]
  • Carpentier I, Beyaert R. TRAF1 is a TNF inducible regulator of NF-kappaB activation. FEBS Lett. 1999 Oct 29;460(2):246–250. [PubMed]
  • Humke EW, Shriver SK, Starovasnik MA, Fairbrother WJ, Dixit VM. ICEBERG: a novel inhibitor of interleukin-1beta generation. Cell. 2000 Sep 29;103(1):99–111. [PubMed]
  • Druilhe A, Srinivasula SM, Razmara M, Ahmad M, Alnemri ES. Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. Cell Death Differ. 2001 Jun;8(6):649–657. [PubMed]
  • Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalò P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F. PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. Oncogene. 1999 Aug 5;18(31):4409–4415. [PubMed]
  • Krueger A, Schmitz I, Baumann S, Krammer PH, Kirchhoff S. Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J Biol Chem. 2001 Jun 8;276(23):20633–20640. [PubMed]
  • Masumoto J, Taniguchi S, Nakayama J, Shiohara M, Hidaka E, Katsuyama T, Murase S, Sagara J. 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. 2001 Oct;49(10):1269–1275. [PubMed]
  • Shiohara Masaaki, Taniguchi Shun'ichiro, Masumoto Junya, Yasui Kozo, Koike Kenichi, Komiyama Atsushi, Sagara Junji. ASC, which is composed of a PYD and a CARD, is up-regulated by inflammation and apoptosis in human neutrophils. Biochem Biophys Res Commun. 2002 May 24;293(5):1314–1318. [PubMed]
  • Blom N, Gammeltoft S, Brunak S. Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol. 1999 Dec 17;294(5):1351–1362. [PubMed]
  • Koonin EV, Aravind L. The NACHT family - a new group of predicted NTPases implicated in apoptosis and MHC transcription activation. Trends Biochem Sci. 2000 May;25(5):223–224. [PubMed]
  • Schulze-Osthoff K, Stroh C. Induced proximity model attracts NF-kappaB researchers. Cell Death Differ. 2000 Nov;7(11):1025–1026. [PubMed]
  • Martinon Fabio, Burns Kimberly, Tschopp Jürg. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002 Aug;10(2):417–426. [PubMed]
  • Salvesen GS, Dixit VM. Caspase activation: the induced-proximity model. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):10964–10967. [PMC free article] [PubMed]

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