Uncoupling of Pyrin-only Protein 2 (POP2)-mediated Dual Regulation of NF- B and the Inflammasome

Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2011; 286(47):40536-47. DOI: 10.1074/jbc.M111.274290
Source: PubMed


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 Glu6, Asp8, and Glu16, 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.

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Available from: Maninjay Atianand, Apr 01, 2014
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    • "It is anticipated, although not yet demonstrated, that POP1 should inhibit IKK activity downstream of the NODosome activation of RIP-2. Although POP1 enhanced ASC-mediated IL-1β activation (44), in a later study, POP1 did not inhibit either ASC-dependent or NLRP3 inflammasome processing of IL-1β (49). Thus, no evidence to date supports a role for POP1 in inhibiting an inflammasome, consistent with a structure-predicted inability to regulate NLRP3 inflammasome activation (39). "
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    ABSTRACT: Upon activation Nod-like receptors (NLRs) assemble into multi-protein complexes such as the NODosome and inflammasome. This process relies upon homo domain interactions between the structurally related Pyrin and caspase-recruitment (CARD) domains and adaptor proteins, such as ASC, or effector proteins, such as caspase-1. Although a variety of NLRP and NLRC complexes have been described along with their activating stimuli and associated proteins, less familiar are processes limiting assembly and/or promoting dissociation of NLR complexes. Given the importance of limiting harmful, chronic inflammation, such regulatory mechanisms are significant and likely numerous. Proteins comprised of a solitary Pyrin domain (Pyrin-only) or CARD domain (CARD-only) posses an obvious potential ability to act as competitive inhibitors of NLR complexes. Indeed, both Pyrin-only proteins (POPs) and CARD-only proteins (COPs) have been described as regulators of caspase-1 and/or NLR-inflammasome activation and not surprisingly as factors mediating pathogenesis. Although clear examples of pathogen encoded POPs are currently limited to members of the poxviridae, the human genome likely encodes three POPs (POP1, POP2, and a potential POP3), of which only POP2 is known to prevent NLR:ASC interaction, and three COPs (COP/Pseudo-ICE, INCA, and ICEBERG), initially described for their ability to inhibit caspase-1 activity. Surprisingly, among eukaryotic species POPs and COPs appear to be evolutionarily recent and restricted to higher primates, suggesting strong selective pressures driving their emergence. Despite the importance of understanding the regulation of NLR functions, relatively little attention has been devoted to revealing the biological impact of these intriguing proteins. This review highlights the current state of our understanding of POPs and COPs with attention to protein interaction, functions, evolution, implications for health and disease, and outstanding questions.
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