PYPAF3, a PYRIN-containing APAF-1-like protein, is a feedback regulator of caspase-1-dependent interleukin-1beta secretion.
PYPAF3 is a member of the PYRIN-containing apoptotic protease-activating factor-1-like proteins (PYPAFs, also called NALPs). Among the members of this family, PYPAF1, PYPAF5, PYPAF7, and NALP1 have been shown to induce caspase-1-dependent interleukin-1beta secretion and NF-kappaB activation in the presence of the adaptor molecule ASC. On the other hand, we ... recently discovered that PYNOD, another member of this family, is a suppressor of these responses. Here, we show that PYPAF3 is the second member that inhibits caspase-1-dependent interleukin-1beta secretion. In contrast, PYPAF2/NALP2 does not inhibit this response but rather inhibits the NF-kappaB activation that is induced by the combined expression of PYPAF1 and ASC. Both PYPAF2 and PYPAF3 mRNAs are broadly expressed in a variety of tissues; however, neither is expressed in skeletal muscle, and only PYPAF2 mRNA is expressed in heart and brain. They are also expressed in many cell lines of both hematopoietic and non-hematopoietic lineages. Stimulation of monocytic THP-1 cells with lipopolysaccharide or interleukin-1beta induced PYPAF3 mRNA expression. Furthermore, the stable expression of PYPAF3 in THP-1 cells abrogated the ability of the cells to produce interleukin-1beta in response to lipopolysaccharide. These results suggest that PYPAF3 is a feedback regulator of interleukin-1beta secretion. Thus, PYPAF2 and PYPAF3, together with PYNOD, constitute an anti-inflammatory subgroup of PYPAFs.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Apoptosis Regulatory Proteins, Apoptotic Protease-Activating Factor 1, Blotting, Western, Carrier Proteins, Caspase 1, Cell Line, DNA, Complementary, Epitopes, Escherichia coli, Feedback, Physiological, Gene Expression Regulation, Enzymologic, Genes, Reporter, HL-60 Cells, HeLa Cells, Hemagglutinins, Humans, Immunoprecipitation, Interleukin-1, Jurkat Cells, Leukocytes, Mononuclear, Lipopolysaccharides, Luciferases, Mice, Monocytes, Muscle, Skeletal, NF-kappa B, Plasmids, Polymerase Chain Reaction, Protein Structure, Tertiary, Proteins, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Tissue Distribution, Transfection, Tumor Necrosis Factor-alpha, U937 Cells
Adaptor Proteins, Signal Transducing, Animals, Apoptosis Regulatory Proteins, Apoptotic Protease-Activating Factor 1, Blotting, Western, Carrier Proteins, Caspase 1, Cell Line, DNA, Complementary, Epitopes, Escherichia coli, Feedback, Physiological, Gene Expression Regulation, Enzymologic, Genes, Reporter, HL-60 Cells, HeLa Cells, Hemagglutinins, Humans, Immunoprecipitation, Interleukin-1, Jurkat Cells, Leukocytes, Mononuclear, Lipopolysaccharides, Luciferases, Mice, Monocytes, Muscle, Skeletal, NF-kappa B, Plasmids, Polymerase Chain Reaction, Protein Structure, Tertiary, Proteins, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Tissue Distribution, Transfection, Tumor Necrosis Factor-alpha, U937 Cells
J Biol Chem
Date: Jun. 10, 2005
PubMed ID: 15817483
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