Pyrin-only protein 2 modulates NFκB and disrupts ASC:CLR interactions
Pyrin-only protein 2 modulates NFκB and disrupts ASC:CLR interactions
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DOI：
10.4049/jimmunol.178.6.3837
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发表时间：
2007-03-15
影响因子：
4.4
通讯作者：
Harton, Jonathan A.
中科院分区：
文献类型：
--
作者：
Bedoya, Felipe;Sandler, Laurel L.;Harton, Jonathan A.
核因子-kappaB是细胞周期调节、细胞因子和黏附分子基因反式激活的关键，在许多癌症、神经退行性疾病和炎症性疾病中调节失调。具有吡喃和/或caspase募集结构域的蛋白质在细胞凋亡、先天免疫和炎症中发挥作用。许多吡咯结构域(PYD)蛋白调节NF..kappaB的活性，并参与组装核周的“凋亡斑点”和前-IL1β/IL-18转换的炎症体复合体。“纯吡喃”蛋白(POP)是PYD介导的功能的负调控蛋白，已有报道称POP1是此类蛋白之一。我们报告了第二个POP的识别和初步表征。POP2是一个294个核苷酸的单外显子基因，位于人类3号染色体上，编码一个97-aa的蛋白质，其序列和预测的结构与其他PYD相似。POP2与卡特彼勒(CLR，NLR，NALP)家族蛋白中的PYD高度相似，而不是典型的PYD和ASC PYD。POP2主要在外周血白细胞中表达，在肿瘤坏死因子-α刺激和p65(RetA)诱导的转基因细胞中呈现胞浆和核两种表达模式。POP2体外可通过改变核转录因子-kappa B的核输入或分布来抑制依赖于核转录的基因转录。在与ASC共定位于核周斑点的同时，POP2也抑制了CLR蛋白CIAS1/NALP3的斑点形成。综上所述，这些观察表明POP2是NF-kappa B活性的负调节因子，可能影响依赖于PYD的复合体的组装。
NF-kappa B is pivotal for transactivation of cell-cycle regulatory, cytokine, and adhesion molecule genes and is dysregulated in many cancers, neurodegenerative disorders, and inflammatory diseases. Proteins with pyrin and/or caspase recruitment domains have roles in apoptosis, innate immunity, and inflammation. Many pyrin domain (PYD) proteins modulate NF..kappa B activity as well as participate in assembling both the perinuclear "apoptotic speck" and the pro-IL1 beta/IL-18-converting inflammasome complex. "Pyrin-only" proteins (POP) are attractive as negative regulators of PYD-mediated functions and one such protein, POP1, has been reported. We report the identification and initial characterization of a second POP. POP2 is a 294 nt single exon gene located on human chromosome 3 encoding a 97-aa protein with sequence and predicted structural similarity to other PYDs. Highly similar to PYDs in CATERPILLER (CLR, NLR, NALP) family proteins, POP2 is less like the prototypic pyrin and ASC PYDs. POP2 is expressed principally in peripheral blood leukocytes and displays both cytoplasmic and nuclear expression patterns in transfected cells TNF-alpha-stimulated and p65 (RetA)induced NF-kappa B-dependent gene transcription is inhibited by POP2 in vitro by a mechanism involving changes in NF-kappa B nuclear import or distribution. While colocalizing with ASC in perinuclear specks, POP2 also inhibits the formation of specks by the CLR protein CIAS1/NALP3. Together, these observations demonstrate that POP2 is a negative regulator of NF-kappa B activity that may influence the assembly of PYD-dependent complexes.