POM121 inhibits the macrophage inflammatory response by impacting NF-κB P65 nuclear accumulation
POM121 inhibits the macrophage inflammatory response by impacting NF-κB P65 nuclear accumulation
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POM121 通过影响 NF-kappa B P65 核积聚来抑制巨噬细胞炎症反应
DOI：
10.1016/j.yexcr.2019.02.021
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发表时间：
2019-04-15
影响因子：
3.7
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
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作者：
Ge, Wenlong;Yue, Yan;Xiong, Sidong
核孔膜蛋白121（POM121）最初被认为是核孔复合体（NPC）的一种组成型蛋白。除了参与NPC组装外，研究发现POM121的异常表达与多种疾病相关。在本研究中，我们详细探究了POM121对巨噬细胞炎症反应的影响，发现脂多糖（LPS）刺激的巨噬细胞中POM121的表达显著降低，同时促炎细胞因子（肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6））的产生大幅增加，这表明POM121对巨噬细胞炎症具有强大的抑制作用。与此观点一致的是，与对照小鼠相比，POM121（fl/fl）Lyz2-Cre +小鼠对LPS诱导的急性肺损伤（ALI）更敏感，组织炎症也更严重，表现为肺损伤和炎症更严重、TNF-α和IL-6产生增加以及支气管肺泡灌洗液（BALF）中的蛋白质更丰富。POM121的这种炎症调节作用依赖于其通过抑制磷酸化P65（phos-P65）的核积累来抑制核因子-κB（NF-κB）信号通路的能力。在本研究中，我们报告称，除了作为NPC的组成成分外，POM121还通过抑制P65的核转位来调节LPS诱导的巨噬细胞炎症。我们的研究可能为调控LPS诱导的巨噬细胞大量炎症反应铺平道路，并为核孔蛋白（Nups）的功能多样性提供证据。
The nuclear pore membrane protein 121 (POM121) was originally thought to be a constitutive protein of the nuclear pore complex (NPC). In addition to being involved in NPC assembly, abnormal POM121 expression has been Found to be associated with many diseases. In this study, we explored, in detail, the effect of POM121 on the macrophage inflammatory response and found that its expression was significantly lower in LPS-stimulated macrophages, substantially amplifying pro-inflammatory cytokine (TNF-alpha and IL-6) production, suggesting that POM121 exerts a potent inhibitory effect on macrophage inflammation. Consistent with this notion, greater susceptibility to LPS-induced acute lung injury (ALI) as well as more severe tissue inflammation were found in POM121(fl/fl) Lyzni-Cre + mice compared to those in control mice, as evidenced by the more severe lung injury and inflammation, increased TNF-alpha and IL-6 production and more abundant proteins in bronchoalveolar lavage fluid (BALF). This inflammation-modulating effect of POM121 relied on its ability to repress the NF-kappa B signal pathway via inhibition of phosphorylated P65 (phos-P65) nuclear accumulation, In the present study, we reported that in addition to acting as a constitutive NPC component, POM121 also modulated LPS-induced macrophage inflammation via repressing nuclear P65 translocation. Our study may pave the way for regulating LPS-induced massive macrophage inflammation and providing evidence for the functional diversity of nucleoporins (Nups).