Abstract
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.
Full Text
The Full Text of this article is available as a PDF (529.7 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Aravind L., Dixit V. M., Koonin E. V. The domains of death: evolution of the apoptosis machinery. Trends Biochem Sci. 1999 Feb;24(2):47–53. doi: 10.1016/s0968-0004(98)01341-3. [DOI] [PubMed] [Google Scholar]
- Bertin J., DiStefano P. S. The PYRIN domain: a novel motif found in apoptosis and inflammation proteins. Cell Death Differ. 2000 Dec;7(12):1273–1274. doi: 10.1038/sj.cdd.4400774. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1006/jmbi.1999.3310. [DOI] [PubMed] [Google Scholar]
- Burge C., Karlin S. Prediction of complete gene structures in human genomic DNA. J Mol Biol. 1997 Apr 25;268(1):78–94. doi: 10.1006/jmbi.1997.0951. [DOI] [PubMed] [Google Scholar]
- Carpentier I., Beyaert R. TRAF1 is a TNF inducible regulator of NF-kappaB activation. FEBS Lett. 1999 Oct 29;460(2):246–250. doi: 10.1016/s0014-5793(99)01356-3. [DOI] [PubMed] [Google Scholar]
- Chu Z. L., Pio F., Xie Z., Welsh K., Krajewska M., Krajewski S., Godzik A., Reed J. C. A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis. J Biol Chem. 2000 Dec 11;276(12):9239–9245. doi: 10.1074/jbc.M006309200. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1038/sj.onc.1202831. [DOI] [PubMed] [Google Scholar]
- Conway K. E., McConnell B. B., Bowring C. E., Donald C. D., Warren S. T., Vertino P. M. 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] [Google Scholar]
- Dinarello C. A. Interleukin-1. Cytokine Growth Factor Rev. 1997 Dec;8(4):253–265. doi: 10.1016/s1359-6101(97)00023-3. [DOI] [PubMed] [Google Scholar]
- Druilhe A., Srinivasula S. M., Razmara M., Ahmad M., Alnemri E. S. 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. doi: 10.1038/sj.cdd.4400881. [DOI] [PubMed] [Google Scholar]
- Fairbrother W. J., Gordon N. C., Humke E. W., O'Rourke K. M., Starovasnik M. A., Yin J. P., Dixit V. M. The PYRIN domain: a member of the death domain-fold superfamily. Protein Sci. 2001 Sep;10(9):1911–1918. doi: 10.1110/ps.13801. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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 May 24;71(1):198–203. doi: 10.1086/341357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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 Jul 1;277(38):35333–35340. doi: 10.1074/jbc.M200446200. [DOI] [PubMed] [Google Scholar]
- Hlaing T., Guo R. F., Dilley K. A., Loussia J. M., Morrish T. A., Shi M. M., Vincenz C., Ward P. A. 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. 2000 Nov 13;276(12):9230–9238. doi: 10.1074/jbc.M009853200. [DOI] [PubMed] [Google Scholar]
- Hoffman H. M., Mueller J. L., Broide D. H., Wanderer A. A., Kolodner R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 Nov;29(3):301–305. doi: 10.1038/ng756. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Humke E. W., Shriver S. K., Starovasnik M. A., Fairbrother W. J., Dixit V. M. ICEBERG: a novel inhibitor of interleukin-1beta generation. Cell. 2000 Sep 29;103(1):99–111. doi: 10.1016/s0092-8674(00)00108-2. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1006/smim.2000.0210. [DOI] [PubMed] [Google Scholar]
- Koonin E. V., 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. doi: 10.1016/s0968-0004(00)01577-2. [DOI] [PubMed] [Google Scholar]
- Krajewski S., Krajewska M., Shabaik A., Miyashita T., Wang H. G., Reed J. C. 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] [Google Scholar]
- Krueger A., Schmitz I., Baumann S., Krammer P. H., 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 Mar 5;276(23):20633–20640. doi: 10.1074/jbc.M101780200. [DOI] [PubMed] [Google Scholar]
- Lee S. H., Stehlik C., Reed J. C. Cop, a caspase recruitment domain-containing protein and inhibitor of caspase-1 activation processing. J Biol Chem. 2001 Jun 29;276(37):34495–34500. doi: 10.1074/jbc.M101415200. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1093/bioinformatics/16.12.1105. [DOI] [PubMed] [Google Scholar]
- Manji Gulam A., Wang Lin, Geddes Brad J., Brown Melissa, Merriam Sarah, Al-Garawi Amal, Mak Simona, Lora Jose M., Briskin Michael, Jurman Mark. PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kappa B. J Biol Chem. 2002 Jan 10;277(13):11570–11575. doi: 10.1074/jbc.M112208200. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1016/s0960-9822(01)00056-2. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1016/s1097-2765(02)00599-3. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1074/jbc.274.48.33835. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1177/002215540104901009. [DOI] [PubMed] [Google Scholar]
- Pawłowski K., Pio F., Chu Z., Reed J. C., Godzik A. PAAD - a new protein domain associated with apoptosis, cancer and autoimmune diseases. Trends Biochem Sci. 2001 Feb;26(2):85–87. doi: 10.1016/s0968-0004(00)01729-1. [DOI] [PubMed] [Google Scholar]
- Perkins N. D., Schmid R. M., Duckett C. S., Leung K., Rice N. R., Nabel G. J. 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. doi: 10.1073/pnas.89.5.1529. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Richards N., Schaner P., Diaz A., Stuckey J., Shelden E., Wadhwa A., Gumucio D. L. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J Biol Chem. 2001 Aug 9;276(42):39320–39329. doi: 10.1074/jbc.M104730200. [DOI] [PubMed] [Google Scholar]
- Salvesen G. S., Dixit V. M. Caspase activation: the induced-proximity model. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):10964–10967. doi: 10.1073/pnas.96.20.10964. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schmid R. M., Perkins N. D., Duckett C. S., Andrews P. C., Nabel G. J. Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65. Nature. 1991 Aug 22;352(6337):733–736. doi: 10.1038/352733a0. [DOI] [PubMed] [Google Scholar]
- Schulze-Osthoff K., Stroh C. Induced proximity model attracts NF-kappaB researchers. Cell Death Differ. 2000 Nov;7(11):1025–1026. doi: 10.1038/sj.cdd.4400752. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1016/S0006-291X(02)00384-4. [DOI] [PubMed] [Google Scholar]
- Silverman N., Maniatis T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev. 2001 Sep 15;15(18):2321–2342. doi: 10.1101/gad.909001. [DOI] [PubMed] [Google Scholar]
- 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 Apr 19;277(24):21119–21122. doi: 10.1074/jbc.C200179200. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1016/s0968-0004(00)01717-5. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1084/jem.20021552. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. doi: 10.1038/nrm1019. [DOI] [PubMed] [Google Scholar]
- 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 May 17;277(33):29874–29880. doi: 10.1074/jbc.M203915200. [DOI] [PubMed] [Google Scholar]
- Weber C. H., Vincenz C. The death domain superfamily: a tale of two interfaces? Trends Biochem Sci. 2001 Aug;26(8):475–481. doi: 10.1016/s0968-0004(01)01905-3. [DOI] [PubMed] [Google Scholar]