Proximity to PML Nuclear Bodies Regulates HIV-1 Latency in CD4+T Cells
Proximity to PML Nuclear Bodies Regulates HIV-1 Latency in CD4+T Cells
复制标题
DOI：
10.1016/j.chom.2013.05.006
复制
发表时间：
2013-06-12
影响因子：
30.3
通讯作者：
Giacca, Mauro
中科院分区：
文献类型：
--
作者：
Lusic, Marina;Marini, Bruna;Giacca, Mauro
核小体（NB），其特征在于存在早幼粒细胞白血病（PML）蛋白，是核结构的重要组成部分，有助于基因表达的遗传和表观遗传控制。在研究介导HIV-1潜伏期的机制时，我们确定沉默但具有转录能力的HIV-1前病毒与PML NB非常接近，并且这种关联抑制HIV-1基因表达。PML与潜伏的HIV-1启动子结合，该启动子与病毒基因组上的转录失活兼性异染色质标记（特别是H3 K9 me 2）相一致。PML降解和NB破坏导致病毒转录的强烈激活以及G9 a（负责H3 K9 me 2的主要甲基转移酶）的释放，以及兼性异染色质标记从前病毒DNA的丢失。此外，HIV-1转录激活需要通过活性核肌动蛋白聚合从PML NB置换前病毒。因此，核拓扑结构和活跃的基因运动介导HIV-1的转录调控，并对控制HIV-1潜伏期和根除有影响。
Nuclear bodies (NBs), characterized by the presence of the promyelocytic leukemia (PML) protein, are important components of the nuclear architecture, contributing to genetic and epigenetic control of gene expression. In investigating the mechanisms mediating HIV-1 latency, we determined that silenced but transcriptionally competent HIV-1 proviruses reside in close proximity to PML NBs and that this association inhibits HIV-1 gene expression. PML binds to the latent HIV-1 promoter, which coincides with transcriptionally inactive facultative heterochromatic marks, notably H3K9me2, at the viral genome. PML degradation and NB disruption result in strong activation of viral transcription as well as release of G9a, the major methyltransferase responsible for H3K9me2, and loss of facultative heterochromatin marks from the proviral DNA. Additionally, HIV-1 transcriptional activation requires proviral displacement from PML NBs by active nuclear actin polymerization. Thus, nuclear topology and active gene movement mediate HIV-1 transcriptional regulation and have implications for controlling HIV-1 latency and eradication.