Porter K A, Duffy E B, Nyland P, Atianand M K, Sharifi H, Harton J A
Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA.
Genes Immun. 2014 Sep;15(6):392-403. doi: 10.1038/gene.2014.30. Epub 2014 May 29.
Pseudogenes are duplicated yet defunct copies of functional parent genes. However, some pseudogenes have gained or retained function. In this study, we consider a functional role for the NLRP2-related, higher primate-specific, processed pseudogene NLRP2P, which is closely related to Pyrin-only protein 2 (POP2/PYDC2), a regulator of nuclear factor-κB (NF-κB) and the inflammasome. The NLRP2P open-reading frame on chromosome X has features consistent with a processed pseudogene (retrotransposon), yet encodes a 45-amino-acid, Pyrin-domain-related protein. The open-reading frame of NLRP2P shares 80% identity with POP2 and is under purifying selection across Old World primates. Although widely expressed, NLRP2P messenger RNA is upregulated by lipopolysaccharide in human monocytic cells. Functionally, NLRP2P impairs NF-κB p65 transactivation by reducing activating phosphorylation of RelA/p65. Reminiscent of POP2, NLRP2P reduces production of the NF-κB-dependent cytokines tumor necrosis factor alpha and interleukin (IL)-6 following toll-like receptor stimulation. In contrast to POP2, NLRP2P fails to inhibit the ASC-dependent NLRP3 inflammasome. In addition, beyond regulating cytokine production, NLRP2P has a potential role in cell cycle regulation and cell death. Collectively, our findings suggest that NLRP2P is a resurrected processed pseudogene that regulates NF-κB RelA/p65 activity and thus represents the newest member of the POP family, POP4.
假基因是功能正常的亲本基因的重复但已失去功能的拷贝。然而，一些假基因获得或保留了功能。在本研究中，我们探讨了与NLRP2相关的、高等灵长类特有的、已加工假基因NLRP2P的功能作用，该假基因与核因子κB（NF-κB）和炎性小体的调节因子仅含吡喃结构域蛋白2（POP2/PYDC2）密切相关。X染色体上的NLRP2P开放阅读框具有与已加工假基因（逆转座子）一致的特征，但编码一种45个氨基酸的、与吡喃结构域相关的蛋白。NLRP2P的开放阅读框与POP2有80%的同一性，并且在旧世界灵长类动物中受到纯化选择。尽管NLRP2P广泛表达，但其信使核糖核酸在人单核细胞中被脂多糖上调。在功能上，NLRP2P通过减少RelA/p65的激活磷酸化来损害NF-κB p65的反式激活。与POP2类似，NLRP2P在Toll样受体刺激后减少NF-κB依赖性细胞因子肿瘤坏死因子α和白细胞介素（IL）-6的产生。与POP2不同的是，NLRP2P不能抑制ASC依赖性的NLRP3炎性小体。此外，除了调节细胞因子产生外，NLRP2P在细胞周期调节和细胞死亡中具有潜在作用。总的来说，我们的研究结果表明，NLRP2P是一个复活的已加工假基因，它调节NF-κB RelA/p65的活性，因此代表了POP家族的最新成员POP4。
