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PMID: 12656673 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

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

The Biochemical journal ·Vol. 373 ·No. Pt 1 ·2003-07-01 ·Pages 101-13

Stehlik C, Krajewska M, Welsh K, Krajewski S, Godzik A, Reed JC

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.

MeSH Terms
Amino Acid Sequence Animals Apoptosis Regulatory Proteins COS Cells Carrier Proteins/genetics,metabolism Caspase 1 Caspases/metabolism Cell Line Chlorocebus aethiops Cloning, Molecular Cytoskeletal Proteins Enzyme Activation Enzyme Precursors/metabolism Genes, Reporter Humans Luciferases/genetics Molecular Sequence Data NF-kappa B/metabolism Open Reading Frames Polymerase Chain Reaction Proteins/metabolism Pyrin Recombinant Proteins/metabolism Ribonucleoproteins/genetics,metabolism Sequence Alignment Sequence Homology, Amino Acid Transfection
Chemicals
Apoptosis Regulatory Proteins Carrier Proteins Cytoskeletal Proteins Enzyme Precursors MEFV protein, human NF-kappa B POP1 protein, human Proteins Pyrin Recombinant Proteins Ribonucleoproteins Luciferases Caspases Caspase 1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Stehlik Christian
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Krajewska Maryla
Welsh Kate
Krajewski Stanislaw
Godzik Adam
Reed John C
References (41)
41 references, click to expand
  1. TRAF1 is a TNF inducible regulator of NF-kappaB activation.
    FEBS Lett. 1999 Oct 29;460(2):246-50 PMID: 10544244
  2. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis.
    J Biol Chem. 2001 Oct 19;276(42):39320-9 PMID: 11498534
  3. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells.
    J Biol Chem. 1999 Nov 26;274(48):33835-8 PMID: 10567338
  4. Sequence and structure-based prediction of eukaryotic protein phosphorylation sites.
    J Mol Biol. 1999 Dec 17;294(5):1351-62 PMID: 10600390
  5. The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling.
    Semin Immunol. 2000 Feb;12(1):85-98 PMID: 10723801
  6. The NACHT family - a new group of predicted NTPases implicated in apoptosis and MHC transcription activation.
    Trends Biochem Sci. 2000 May;25(5):223-4 PMID: 10782090
  7. ICEBERG: a novel inhibitor of interleukin-1beta generation.
    Cell. 2000 Sep 29;103(1):99-111 PMID: 11051551
  8. 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):6236-42 PMID: 11103776
  9. Induced proximity model attracts NF-kappaB researchers.
    Cell Death Differ. 2000 Nov;7(11):1025-6 PMID: 11139273
  10. The DAPIN family: a novel domain links apoptotic and interferon response proteins.
    Trends Biochem Sci. 2001 Feb;26(2):83-5 PMID: 11166557
  11. PAAD - a new protein domain associated with apoptosis, cancer and autoimmune diseases.
    Trends Biochem Sci. 2001 Feb;26(2):85-7 PMID: 11166558
  12. Saturated BLAST: an automated multiple intermediate sequence search used to detect distant homology.
    Bioinformatics. 2000 Dec;16(12):1105-10 PMID: 11159329
  13. The pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation.
    Curr Biol. 2001 Feb 20;11(4):R118-20 PMID: 11250163
  14. 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):9230-8 PMID: 11076957
  15. A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis.
    J Biol Chem. 2001 Mar 23;276(12):9239-45 PMID: 11113115
  16. The PYRIN domain: a novel motif found in apoptosis and inflammation proteins.
    Cell Death Differ. 2000 Dec;7(12):1273-4 PMID: 11270363
  17. 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):20633-40 PMID: 11279218
  18. 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):301-5 PMID: 11687797
  19. 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):11570-5 PMID: 11786556
  20. 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):1314-8 PMID: 12054656
  21. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1.
    J Biol Chem. 2002 Jun 14;277(24):21119-22 PMID: 11967258
  22. 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 PMID: 12032915
  23. 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):29874-80 PMID: 12019269
  24. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.
    Mol Cell. 2002 Aug;10(2):417-26 PMID: 12191486
  25. 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):35333-40 PMID: 12093792
  26. 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):1605-15 PMID: 12486103
  27. NALPs: a novel protein family involved in inflammation.
    Nat Rev Mol Cell Biol. 2003 Feb;4(2):95-104 PMID: 12563287
  28. Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65.
    Nature. 1991 Aug 22;352(6337):733-6 PMID: 1876189
  29. 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):1529-33 PMID: 1542644
  30. Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2.
    Am J Pathol. 1994 Dec;145(6):1323-36 PMID: 7992838
  31. Prediction of complete gene structures in human genomic DNA.
    J Mol Biol. 1997 Apr 25;268(1):78-94 PMID: 9149143
  32. Interleukin-1.
    Cytokine Growth Factor Rev. 1997 Dec;8(4):253-65 PMID: 9620641
  33. The domains of death: evolution of the apoptosis machinery.
    Trends Biochem Sci. 1999 Feb;24(2):47-53 PMID: 10098397
  34. PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis.
    Oncogene. 1999 Aug 5;18(31):4409-15 PMID: 10442631
  35. Caspase activation: the induced-proximity model.
    Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):10964-7 PMID: 10500109
  36. The death domain superfamily: a tale of two interfaces?
    Trends Biochem Sci. 2001 Aug;26(8):475-81 PMID: 11504623
  37. The PYRIN domain: a member of the death domain-fold superfamily.
    Protein Sci. 2001 Sep;10(9):1911-8 PMID: 11514682
  38. Regulation of IL-1beta generation by Pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins.
    Cell Death Differ. 2001 Jun;8(6):649-57 PMID: 11536016
  39. Cop, a caspase recruitment domain-containing protein and inhibitor of caspase-1 activation processing.
    J Biol Chem. 2001 Sep 14;276(37):34495-500 PMID: 11432859
  40. 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):1269-75 PMID: 11561011
  41. NF-kappaB signaling pathways in mammalian and insect innate immunity.
    Genes Dev. 2001 Sep 15;15(18):2321-42 PMID: 11562344
Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
0264-6021
DOI
10.1042/BJ20030304
Published
2003-07-01
Pages
101-13
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1223462
Subset
IM
Grants
NIAID NIH HHS · AI-056324-01 · United States
NINDS NIH HHS · NS36821 · United States
Corrections
CommentIn
PMID: 12939166
External Links
PubMed source DOI: 10.1042/BJ20030304 PMC Full Text View journal details
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