Pdcd4 Is Involved in the Formation of Stress Granule in Response to Oxidized Low-Density Lipoprotein or High-Fat Diet.
Pdcd4 Is Involved in the Formation of Stress Granule in Response to Oxidized Low-Density Lipoprotein or High-Fat Diet.
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Pdcd4 参与氧化低密度脂蛋白或高脂肪饮食引起的应激颗粒的形成
DOI：
10.1371/journal.pone.0159568
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
Bai Y;Dong Z;Shang Q;Zhao H;Wang L;Guo C;Gao F;Zhang L;Wang Q
应激颗粒（Stress granules，SGs）在各种应激反应中的作用已在许多疾病中得到报道。我们先前报道了程序性细胞死亡4（Pdcd 4）在肥胖诱导的应激反应中的意义，但Pdcd 4和SGs之间可能的联系仍然缺乏。在这项研究中，我们表明，氧化低密度脂蛋白（ox-LDL）或高脂饮食（HFD）诱导SG形成的小鼠巨噬细胞和肝组织，和Pdcd 4缺乏小鼠显着减少其形成。响应ox-LDL，无论是内源性或异位Pdcd 4显示颗粒样表达和共定位与SG标志物，包括T细胞限制性细胞内抗原-1，脆性X智力低下相关蛋白1，真核起始因子4A。缺失特定RNA结合基序的截短型Pdcd 4的异位表达显著破坏了SG的形成，表明Pdcd 4通过其RNA结合活性直接参与ox-LDL诱导的SG。此外，Pdcd 4缺陷驱动AKT激活和eIF 2 α磷酸化的抑制，从而有助于抵抗ox-LDL或HFD诱导的SG形成。总的来说，我们的数据表明，Pdcd 4作为一个重要的调节SGs诱导的ox-LDL或HFD可能是一个潜在的目标，以减轻肥胖和相关疾病的SG相关的应激反应。
Stress granules (SGs) in response to various stresses have been reported in many diseases. We previously reported the implication of programmed cell death 4 (Pdcd4) in obesity-induced stress responses, but the possible link between Pdcd4 and SGs remains lacking. In this study we showed that oxidized low-density lipoprotein (ox-LDL) or high-fat diet (HFD) induced SG formation in mouse macrophages and liver tissues, and Pdcd4 deficiency in mice remarkably reduced its formation. In response to ox-LDL, either endogenous or ectopic Pdcd4 displayed granule-like expression and co-localized with SG markers including T-cell-restricted intracellular antigen-1, fragile X mental retardation-related protein 1, and eukaryotic initiation factor 4A. Ectopic expression of truncated Pdcd4 that depleted specific RNA-binding motif significantly disrupted the SG formation, suggesting the direct involvement of Pdcd4 in ox-LDL-induced SGs through its RNA-binding activity. Additionally, Pdcd4 deficiency drove AKT activation and suppression of eIF2α phosphorylation, thereby contributing to the resistance to ox-LDL or HFD-induced SG formation. Collectively, our data suggest that Pdcd4 as a crucial regulator in SGs induced by ox-LDL or HFD maybe a potential target for mitigating SG-associated stress responses in obesity and related diseases.