The interferon-induced antiviral protein PML (TRIM19) promotes the restriction and transcriptional silencing of lentiviruses in a context-specific, isoform-specific fashion.
The interferon-induced antiviral protein PML (TRIM19) promotes the restriction and transcriptional silencing of lentiviruses in a context-specific, isoform-specific fashion.
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DOI：
10.1186/s12977-016-0253-1
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发表时间：
2016-03-22
期刊：
影响因子：
3.3
通讯作者：
Berthoux L
中科院分区：
文献类型：
--
作者：
Masroori N;Merindol N;Berthoux L
早幼粒细胞白血病（PML）蛋白是I型干扰素（IFN-I）诱导的基因产物，并且是三重基序（TRIM）家族的成员，其调节属于不同家族的病毒的转录活性。PML是否对HIV-1的复制有影响尚未完全解决，但最近的研究指出，它可能参与限制HIV-1在人类细胞中的表达，以及维持HIV-1被组成性抑制的人类细胞系中的转录潜伏期。我们进一步研究了PML在小鼠细胞和淋巴细胞人类细胞系中对HIV-1和相关慢病毒SIVmac的限制。特别是，我们研究了PML与IFN-I介导的抑制的相关性以及个体人类亚型的作用。我们证明，人类PML（hPML）和小鼠PML（mPML）抑制HIV-1和相关慢病毒SIVmac复制的早期进入后阶段。此外，HIV-1在MEF中被mPML和hPML亚型I、II、IV和VI转录沉默。在组蛋白去乙酰化酶抑制剂SAHA的存在下，这种PML介导的转录抑制被减弱。相反，PML的耗竭对人类T细胞系中HIV-1基因的表达没有影响。发现PML有助于IFN-I抑制HIV-1。特别是，IFN-α和IFN-β处理MEFs增强了HIV-1早期复制阶段的PML依赖性抑制。我们表明，PML可以抑制HIV-1和其他慢病毒作为IFN-I介导的反应的一部分。限制发生在两个不同的步骤，即逆转录和转录，并以同种型特异性，细胞环境特异性的方式。我们的研究结果支持PML激活先天免疫抗慢病毒效应子的模型。这些数据与潜伏期逆转诱导药理学药物的开发相关，因为先前提出PML作为此类抑制剂的药理学靶点。这项研究也对HIV-1小鼠模型的发展有影响。本文的在线版本（doi：10.1186/s12977-016-0253-1）包含补充材料，可供授权用户使用。
The promyelocytic leukemia (PML) protein, a type I interferon (IFN-I)-induced gene product and a member of the tripartite motif (TRIM) family, modulates the transcriptional activity of viruses belonging to various families. Whether PML has an impact on the replication of HIV-1 has not been fully addressed, but recent studies point to its possible involvement in the restriction of HIV-1 in human cells and in the maintenance of transcriptional latency in human cell lines in which HIV-1 is constitutively repressed. We investigated further the restriction of HIV-1 and a related lentivirus, SIVmac, by PML in murine cells and in a lymphocytic human cell line. In particular, we studied the relevance of PML to IFN-I-mediated inhibition and the role of individual human isoforms. We demonstrate that both human PML (hPML) and murine PML (mPML) inhibit the early post-entry stages of the replication of HIV-1 and a related lentivirus, SIVmac. In addition, HIV-1 was transcriptionally silenced by mPML and by hPML isoforms I, II, IV and VI in MEFs. This PML-mediated transcriptional repression was attenuated in presence of the histone deacetylase inhibitor SAHA. In contrast, depletion of PML had no effect on HIV-1 gene expression in a human T cell line. PML was found to contribute to the inhibition of HIV-1 by IFN-I. Specifically, IFN-α and IFN-β treatments of MEFs enhanced the PML-dependent inhibition of HIV-1 early replication stages. We show that PML can inhibit HIV-1 and other lentiviruses as part of the IFN-I-mediated response. The restriction takes place at two distinct steps, i.e. reverse transcription and transcription, and in an isoform-specific, cellular context-specific fashion. Our results support a model in which PML activates innate immune antilentiviral effectors. These data are relevant to the development of latency reversal-inducing pharmacological agents, since PML was previously proposed as a pharmacological target for such inhibitors. This study also has implications for the development of murine models of HIV-1. The online version of this article (doi:10.1186/s12977-016-0253-1) contains supplementary material, which is available to authorized users.