Positive role of promyelocytic leukemia protein in type I interferon response and its regulation by human cytomegalovirus.
Positive role of promyelocytic leukemia protein in type I interferon response and its regulation by human cytomegalovirus.
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DOI：
10.1371/journal.ppat.1004785
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Ahn JH
中科院分区：
文献类型：
--
作者：
Kim YE;Ahn JH
早幼粒细胞白血病蛋白（PML）是PML核体（也称为核结构域10）的主要组分，参与多种细胞过程，如细胞增殖、凋亡、基因调控和DNA损伤反应。PML还作为抑制传入病毒基因组的限制因子，因此在内在防御中发挥重要作用。在这里，我们表明，PML积极调节I型干扰素反应，通过促进干扰素刺激基因（ISGs）的转录，这种调节由PML抵消了人巨细胞病毒（HCMV）IE 1蛋白。人成纤维细胞中小发夹RNA介导的PML敲低减少了干扰素-β治疗或UV灭活HCMV感染引起的ISG诱导。PML是激活的STAT 1和STAT 2积累所必需的，与它们和HDAC 1和HDAC 2相互作用，并与HCMV感染后的ISG启动子相关。在HCMV感染过程中，病毒IE 1蛋白与PML、STAT 1、STAT 2和HDAC相互作用。对IE 1突变病毒的分析表明，除了STAT 2结合结构域之外，IE 1的PML结合结构域对于抑制干扰素-β介导的ISG转录也是必需的，并且IE 1通过隔离干扰素刺激的基因因子3（ISGF 3）来抑制ISG转录，其方式需要结合PML和STAT 2，但不需要结合HDAC。总之，我们的研究结果表明，PML通过调节ISGF 3参与I型干扰素诱导的ISG表达，并且这种由PML进行的调节被HCMV IE 1抵消，突出了针对PML的广泛共享的病毒策略，以逃避内在和先天防御机制。为了进行有效的病毒感染，病毒需要克服宿主的连续防御，包括内在防御和先天性和获得性免疫。早幼粒细胞白血病蛋白（PML）已被证明在内在防御中发挥重要作用，作为一个核限制因子，抑制传入的病毒基因组。在这项研究中，我们证明，PML也积极调节I型干扰素反应，通过促进干扰素刺激基因（ISGs）的转录。因此，PML是内在和先天宿主防御的关键参与者。我们进一步表明，在I型干扰素应答中PML的这种调节被人巨细胞病毒（HCMV）IE 1蛋白抑制，该蛋白在病毒感染的细胞中与PML，STAT 1，STAT 2和HDAC形成复合物。通过分析突变病毒，我们证明IE 1抑制ISG转录的方式需要其结合的PML和STAT 2，但不是HDACs的干扰素刺激的基因因子3（ISGF 3）的隔离。我们的研究结果表明，PML是I型干扰素反应中ISGF 3的调节剂，并且这种PML活性被HCMV IE 1抵消。我们的研究解释了为什么PML靶向活性在许多病毒中广泛保守。
Promyelocytic leukemia protein (PML), a major component of PML nuclear bodies (also known as nuclear domain 10), is involved in diverse cellular processes such as cell proliferation, apoptosis, gene regulation, and DNA damage response. PML also acts as a restriction factor that suppresses incoming viral genomes, therefore playing an important role in intrinsic defense. Here, we show that PML positively regulates type I interferon response by promoting transcription of interferon-stimulated genes (ISGs) and that this regulation by PML is counteracted by human cytomegalovirus (HCMV) IE1 protein. Small hairpin RNA-mediated PML knockdown in human fibroblasts reduced ISG induction by treatment of interferon-β or infection with UV-inactivated HCMV. PML was required for accumulation of activated STAT1 and STAT2, interacted with them and HDAC1 and HDAC2, and was associated with ISG promoters after HCMV infection. During HCMV infection, viral IE1 protein interacted with PML, STAT1, STAT2, and HDACs. Analysis of IE1 mutant viruses revealed that, in addition to the STAT2-binding domain, the PML-binding domain of IE1 was necessary for suppression of interferon-β-mediated ISG transcription, and that IE1 inhibited ISG transcription by sequestering interferon-stimulated gene factor 3 (ISGF3) in a manner requiring its binding of PML and STAT2, but not of HDACs. In conclusion, our results demonstrate that PML participates in type I interferon-induced ISG expression by regulating ISGF3, and that this regulation by PML is counteracted by HCMV IE1, highlighting a widely shared viral strategy targeting PML to evade intrinsic and innate defense mechanisms. For productive viral infection, virus needs to overcome successive host defenses including intrinsic defense and innate and acquired immunity. Promyelocytic leukemia protein (PML) has been shown to play an important role in intrinsic defense by acting as a nuclear restriction factor that suppresses incoming viral genomes. In this study, we demonstrate that PML also positively regulates type I interferon response by promoting transcription of interferon-stimulated genes (ISGs). Therefore, PML is a key player in both intrinsic and innate host defenses. We further show that this regulation by PML in type I interferon response is inhibited by human cytomegalovirus (HCMV) IE1 protein, which forms a complex with PML, STAT1, STAT2, and HDACs in virus-infected cells. By analyzing mutant viruses, we demonstrate that IE1 inhibits ISG transcription by sequestering interferon-stimulated gene factor 3 (ISGF3) in a manner requiring its binding of PML and STAT2, but not of HDACs. Our findings reveal that PML is a regulator of ISGF3 in type I interferon response and that this PML activity is counteracted by HCMV IE1. Our study explains why PML targeting activity is widely conserved among many viruses.
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