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.
Kinoshita
Takeshi
T
Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-0934, Japan.
Wang
Yetao
Y
Hasegawa
Mizuho
M
Imamura
Ryu
R
Suda
Takashi
T
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D015153:Blotting, Western; D002352:Carrier Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000096:biosynthesis / Q000378:metabolism*; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D004926:Escherichia coli / Q000378:metabolism; D025461:Feedback, Physiological; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D018922:HL-60 Cells; D006367:HeLa Cells; D006388:Hemagglutinins / Q000737:chemistry; D006801:Humans; D047468:Immunoprecipitation; D007375:Interleukin-1 / Q000378:metabolism*; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008070:Lipopolysaccharides / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
C506592:APAF1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C506593:Apaf1 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D002352:Carrier Proteins; D018076:DNA, Complementary; D000939:Epitopes; D006388:Hemagglutinins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; C494352:NLRP10 protein, human; C495732:NLRP2 protein, human; C502448:NLRP7 protein, human; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D020170:Caspase 1