Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, PO Box 1709, Newark, NJ 07101-1709, USA.
J Mol Biol. 2011 Jul 29;410(5):917-32. doi: 10.1016/j.jmb.2011.03.060.
Human immunodeficiency virus (HIV) exploits cellular proteins during its replicative cycle and latent infection. The positive transcription elongation factor b (P-TEFb) is a key cellular transcription factor critical for these viral processes and is a drug target. During viral replication, P-TEFb is recruited via interactions of its cyclin T1 subunit with the HIV Tat (transactivator of transcription) protein and TAR (transactivation response) element. Through RNA silencing and over-expression experiments, we discovered that nuclear factor 90 (NF90), a cellular RNA binding protein, regulates P-TEFb expression. NF90 depletion reduced cyclin T1 protein levels by inhibiting translation initiation. Regulation was mediated by the 3' untranslated region of cyclin T1 mRNA independently of microRNAs. Cyclin T1 induction is involved in the escape of HIV-1 from latency. We show that the activation of viral replication by phorbol ester in latently infected monocytic cells requires the posttranscriptional induction of NF90 and cyclin T1, implicating NF90 in protein kinase C signaling pathways. This investigation reveals a novel mechanism of cyclin T1 regulation and establishes NF90 as a regulator of HIV-1 replication during both productive infection and induction from latency.
人类免疫缺陷病毒 (HIV) 在其复制周期和潜伏感染期间利用细胞蛋白。正转录延伸因子 b (P-TEFb) 是一种关键的细胞转录因子，对这些病毒过程至关重要，是一种药物靶点。在病毒复制过程中，P-TEFb 通过其细胞周期蛋白 T1 亚基与 HIV Tat（转录激活物）蛋白和 TAR（转录激活反应）元件的相互作用被募集。通过 RNA 沉默和过表达实验，我们发现核因子 90 (NF90)，一种细胞 RNA 结合蛋白，调节 P-TEFb 的表达。NF90 耗竭通过抑制翻译起始来降低细胞周期蛋白 T1 蛋白水平。调节是通过细胞周期蛋白 T1 mRNA 的 3'非翻译区介导的，而不依赖于 microRNAs。细胞周期蛋白 T1 的诱导参与了 HIV-1 从潜伏状态中逃逸。我们表明，佛波酯在潜伏感染的单核细胞中激活病毒复制需要 NF90 和细胞周期蛋白 T1 的转录后诱导，这表明 NF90 参与了蛋白激酶 C 信号通路。这项研究揭示了细胞周期蛋白 T1 调节的一种新机制，并确立了 NF90 作为 HIV-1 复制的调节剂，无论是在有性感染期间还是从潜伏状态诱导期间。
