Uncoupling of Pyrin-only Protein 2 (POP2)-mediated Dual Regulation of NF-κB and the Inflammasome
Uncoupling of Pyrin-only Protein 2 (POP2)-mediated Dual Regulation of NF-κB and the Inflammasome
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DOI：
10.1074/jbc.m111.274290
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发表时间：
2011-11-25
影响因子：
4.8
通讯作者：
Harton, Jonathan A.
中科院分区：
文献类型：
--
作者：
Atianand, Maninjay K.;Harton, Jonathan A.
转录因子NF-κ B的活化和IL-1 β的炎性体介导的半胱天冬酶-1裂解是对病原体或宿主来源的信号的炎症反应中的关键过程。仅含芘蛋白（POP）仅限于旧大陆猴、猿和人类，并且先前已显示在转染的上皮细胞中损害炎性小体组装和/或NF-κ B p65转录活性。然而，POP 2的生物学作用及其观察到的功能的分子基础还没有很好地理解。在这份报告中，我们表明，POP 2调节TNF α和IL-1 β在人单核细胞THP-1细胞和小鼠J774A.1巨噬细胞的稳定转染反应。POP 2的缺失分析显示，第一个α-螺旋（残基1-19）对于炎性小体和NF-κ B抑制功能是必需的和足够的。此外，认为对于Pyrin/Pyrin结构域相互作用至关重要的关键酸性残基Glue、Asps和Glum对于炎性小体抑制是重要的。此外，这些突变没有降低POP 2对NF-κ B的作用，表明POP 2的炎性小体和NF-κ B抑制特性可以在机械上解偶联。总的来说，这些数据表明，POP 2作为炎症信号的调节剂，并通过其第一个α-螺旋所采用的不同模式发挥其两种已知功能。
Activation of transcription factor NF-kappa B and inflammasome-directed caspase-1 cleavage of IL-1 beta 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-kappa B 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 TNF alpha and IL-1 beta responses in human monocytic THP-1 cells and in stable transfectants of mouse J774A.1 macrophages. Deletion analysis of POP2 revealed that the first a-helix (residues 1-19) is necessary and sufficient for both inflammasome and NF-kappa B inhibitory functions. Further, key acidic residues Glue, Asps, and Glum, believed critical for Pyrin/Pyrin domain interaction, are important for inflammasome inhibition. Moreover, these mutations did not reduce the effect of POP2 upon NF-kappa B, indicating that the inflammasome and NF-kappa B 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 a-helix.