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

Christian Stehlik, Maryla Krajewska, Kate Welsh, Stanislaw Krajewski, Adam Godzik, John C. Reed*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

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-κB (NF-κB) 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-κB and pro-caspase-1 regulation by this adapter protein. In gene transfer experiments, POP1/ASC2 suppressed cytokine-mediated NF-κB 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-κB and pro-caspase-1 activation and innate immunity.

Original languageEnglish (US)
Pages (from-to)101-113
Number of pages13
JournalBiochemical Journal
Volume373
Issue number1
DOIs
StatePublished - Jul 1 2003

Keywords

  • Cryopyrin
  • Innate immunity
  • Interleukin-1β
  • Nuclear factor (NF-)κB inhibitor kinase complex (IKK complex)
  • Pyrin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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