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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