title: Uncoupling of Pyrin-only protein 2 (POP2)-mediated dual regulation of NF-κB and the inflammasome.
abstract: Activation of transcription factor NF-κB and inflammasome-directed caspase-1 cleavage of IL-1β are key processes in the inflammatory response to pathogen or host-derived signals. Pyrin-only proteins (POPs) are restricted to Old World monkeys, apes, and humans and have previously been shown to impair inflammasome assembly and/or NF-κB p65 transcriptional activity in transfected epithelial cells. However, the biological role of POP2 and the molecular basis for its observed functions are not well understood. In this report we demonstrate that POP2 regulates TNFα and IL-1β responses in human monocytic THP-1 cells and in stable transfectants of mouse J774A.1 macrophages. Deletion analysis of POP2 revealed that the first α-helix (residues 1-19) is necessary and sufficient for both inflammasome and NF-κB inhibitory functions. Further, key acidic residues Glu(6), Asp(8), and Glu(16), believed critical for Pyrin/Pyrin domain interaction, are important for inflammasome inhibition. Moreover, these mutations did not reduce the effect of POP2 upon NF-κB, indicating that the inflammasome and NF-κB inhibitory properties of POP2 can be uncoupled mechanistically. Collectively, these data demonstrate that POP2 acts as a regulator of inflammatory signals and exerts its two known functions through distinct modalities employed by its first α-helix.
authors: Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208, USA.
authors: Maninjay K
authors: MK
authors: Atianand
authors: Jonathan A
authors: JA
authors: Harton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005603:Francisella / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016296:Mutagenesis; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017433:Protein Structure, Secondary; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C495732:NLRP2 protein, human; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha