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.
Stehlik
Christian
C
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Krajewska
Maryla
M
Welsh
Kate
K
Krajewski
Stanislaw
S
Godzik
Adam
A
Reed
John C
JC
D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D016366:Open Reading Frames; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism*; D000071198:Pyrin; D011994:Recombinant Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004792:Enzyme Precursors; C000604192:MEFV protein, human; D016328:NF-kappa B; C490350:POP1 protein, human; D011506:Proteins; D000071198:Pyrin; D011994:Recombinant Proteins; D012261:Ribonucleoproteins; D008156:Luciferases; D020169:Caspases; D020170:Caspase 1