PUM1 is a biphasic negative regulator of innate immunity genes by suppressing LGP2
PUM1 is a biphasic negative regulator of innate immunity genes by suppressing LGP2
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PUM1 是通过抑制 LGP2 来调节先天免疫基因的双相负调节因子
DOI：
10.1073/pnas.1708713114
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发表时间：
2017-08-15
影响因子：
11.1
通讯作者：
Zhou, Grace Guoying
中科院分区：
文献类型：
--
作者：
Liu, Yonghong;Qu, Linlin;Zhou, Grace Guoying
意义我们报道了LGP 2的负调控因子，LGP 1是一种与携带同源序列的mRNA翻译控制相关的蛋白质。反过来，LGP 2作为许多先天免疫基因的双相主激活剂出现，导致干扰素的产生。这些研究实时追踪了siRNA 1 RNA转染后先天免疫应答的变化。这种方法使我们能够发现，在本报告中分析的先天免疫基因是以级联方式顺序激活的。这些研究是在不存在可能影响细胞基因表达的病毒基因产物的情况下在未感染的细胞中进行的。这份报告种子的可能性，先天性免疫反应的系统参与后，危及生命的病毒感染，通过抑制BMP 1功能。BMP 1是一种RNA结合蛋白，可调节携带特定序列的mRNA的稳定性和功能。我们报告如下：（i）一个关键的功能是，通过抑制LGP 2的表达的一个关键的先天免疫基因的阻遏物。因此，在用siRNA 1 RNA转染人细胞后12至48小时之间，存在编码LGP 2、CXCL 10、IL 6和PKR的转录物的初始（阶段1）激增。24小时后（第2阶段），编码RIG-I、SP100、MDA 5、IFIT 1、PML、STING和IFNβ的mRNA显著蓄积。未被激活的基因编码HDAC 4和NF-κB1。(ii)同时耗竭LGP 2、CXCL 10或IL 6，表明1期和2期基因的上调是LGP 2上调的结果。(iii)在转染siRNA 1后48-72小时产生的IFNβ可有效上调LGP 2和2期基因，并减少未处理细胞中HSV-1的复制。(iv)因为只有一半的基因在第1和第2阶段上调编码的mRNA含有BMP 1结合位点，在基因表达的激增不能仅仅归因于稳定的mRNA在BMP 1的情况下。(v)最后，耗尽的p272不会导致1期或2期基因的上调。这里提出的研究结果表明，LGP 1是LGP 2的负调节因子，LGP 2是以级联方式表达的先天免疫基因的主调节因子。
Significance We report that PUM1, a protein linked to control of translation of mRNAs carrying a cognate sequence, is a negative regulator of LGP2. In turn LGP2 emerged as a biphasic master activator of numerous innate immunity genes leading to production of interferon. The studies traced in real-time the changes in innate immune responses following transfection of siPUM1 RNA. This approach enabled the discovery that innate immune genes analyzed in this report were activated sequentially in a cascade fashion. The studies were done in uninfected cells in the absence of viral gene products that could affect the expression of cellular genes. This report seeds the possibility of systemic engagement of innate immune responses following life-threatening viral infections by suppressing PUM1 function. PUM1 is an RNA binding protein shown to regulate the stability and function of mRNAs bearing a specific sequence. We report the following: (i) A key function of PUM1 is that of a repressor of key innate immunity genes by repressing the expression of LGP2. Thus, between 12 and 48 hours after transfection of human cells with siPUM1 RNA there was an initial (phase 1) upsurge of transcripts encoding LGP2, CXCL10, IL6, and PKR. This was followed 24 hours later (phase 2) by a significant accumulation of mRNAs encoding RIG-I, SP100, MDA5, IFIT1, PML, STING, and IFNβ. The genes that were not activated encoded HDAC4 and NF-κB1. (ii) Simultaneous depletion of PUM1 and LGP2, CXCL10, or IL6 revealed that up-regulation of phase 1 and phase 2 genes was the consequence of up-regulation of LGP2. (iii) IFNβ produced 48–72 hours after transfection of siPUM1 was effective in up-regulating LGP2 and phase 2 genes and reducing the replication of HSV-1 in untreated cells. (iv) Because only half of genes up-regulated in phase 1 and 2 encode mRNAs containing PUM1 binding sites, the upsurge in gene expression could not be attributed solely to stabilization of mRNAs in the absence of PUM1. (v) Lastly, depletion of PUM2 does not result in up-regulation of phase 1 or phase 2 genes. The results of the studies presented here indicate that PUM1 is a negative regulator of LGP2, a master regulator of innate immunity genes expressed in a cascade fashion.