Differential regulation of the PGC family of genes in a mouse model of Staphylococcus aureus sepsis.
Differential regulation of the PGC family of genes in a mouse model of Staphylococcus aureus sepsis.
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DOI：
10.1371/journal.pone.0011606
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发表时间：
2010-07-15
期刊：
影响因子：
3.7
通讯作者：
Piantadosi CA
中科院分区：
文献类型：
--
作者：
Sweeney TE;Suliman HB;Hollingsworth JW;Piantadosi CA
转录共激活因子的 PGC 家族（PGC-1α [Ppargc1a]、PGC-1β [Ppargc1b] 和 PRC [Pprc]）协调线粒体生物合成的上调，已知 Ppargc1a 在脓毒症中响应线粒体损伤而被激活。因此，我们推测PGC家族受到先天免疫系统的调节。我们研究了先天免疫功能受损的小鼠（TLR2−/− 和 TLR4−/−）和野生型对照中已建立的金黄色葡萄球菌脓毒症模型中线粒体生物发生和 PGC 基因表达是否受到破坏。我们发现 WT 小鼠感染后（6 小时）Ppargc1a 和 Ppargc1b 早期上调，但这两个基因的表达在 TLR2−/− 小鼠（6 小时无增加）和 TLR4−/− 小鼠（6 小时扩增）中一致失调。然而，第三个家族成员 PRC 受到不同的调节，在所有三种小鼠品系（WT、TLR2−/− 和 TLR4−/−）中，其表达在 24 小时时显着增加。计算机分析显示 Ppargc1a 和 Ppargc1b 共享 microRNA mmu-mir-202-3p 的结合位点。因此，miRNA 介导的转录后 mRNA 降解可能是 TLR2−/− 小鼠中这两个基因的表达未能增加的原因。通过实时 PCR 测量 mmu-mir-202-3p 的表达，发现 TLR2−/− 小鼠中 mmu-mir-202-3p 的表达显着增加，但 WT 或 TLR4−/− 小鼠中则没有。此外，还发现 mir-202-3p 在体外可功能性降低 Ppargc1a mRNA。因此，通过 TLR 的先天免疫信号传导和 mir-202-3p 介导的 mRNA 降解都与炎症期间 Ppargc1a 和 Ppargc1b 的共同调节有关。此外，将 mir-202-3p 确定为急性炎症中 Ppargc1a 和 Ppargc1b 抑制的潜在因素可能为线粒体研究和潜在的治疗开辟新途径。
The PGC family of transcriptional co-activators (PGC-1α [Ppargc1a], PGC-1β [Ppargc1b], and PRC [Pprc]) coordinates the upregulation of mitochondrial biogenesis, and Ppargc1a is known to be activated in response to mitochondrial damage in sepsis. Therefore, we postulated that the PGC family is regulated by the innate immune system. We investigated whether mitochondrial biogenesis and PGC gene expression are disrupted in an established model of Staphylococcus aureus sepsis both in mice with impaired innate immune function (TLR2−/− and TLR4−/−) and in wild-type controls. We found an early up-regulation of Ppargc1a and Ppargc1b post-infection (at 6 h) in WT mice, but the expression of both genes was concordantly dysregulated in TLR2−/− mice (no increase at 6 h) and in TLR4−/− mice (amplified at 6 h). However, the third family member, PRC, was regulated differently, and its expression increased significantly at 24 h in all three mouse strains (WT, TLR2−/−, and TLR4−/−). In silico analyses showed that Ppargc1a and Ppargc1b share binding sites for microRNA mmu-mir-202-3p. Thus, miRNA-mediated post-transcriptional mRNA degradation could account for the failure to increase the expression of both genes in TLR2−/− mice. The expression of mmu-mir-202-3p was measured by real-time PCR and found to be significantly increased in TLR2−/− but not in WT or TLR4−/− mice. In addition, it was found that mir-202-3p functionally decreases Ppargc1a mRNA in vitro. Thus, both innate immune signaling through the TLRs and mir-202-3p-mediated mRNA degradation are implicated in the co-regulation of Ppargc1a and Ppargc1b during inflammation. Moreover, the identification of mir-202-3p as a potential factor for Ppargc1a and Ppargc1b repression in acute inflammation may open new avenues for mitochondrial research and, potentially, therapy.