LANA and hnRNP A1 Regulate the Translation of LANA mRNA through G-Quadruplexes
LANA and hnRNP A1 Regulate the Translation of LANA mRNA through G-Quadruplexes
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DOI：
10.1128/jvi.01508-19
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发表时间：
2020-02-01
影响因子：
5.4
通讯作者：
Verma, Subhash C.
中科院分区：
文献类型：
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作者：
Dabral, Prerna;Babu, Jay;Verma, Subhash C.
在潜伏期，卡波西肉瘤相关疱疹病毒（KSHV）通过限制蛋白质表达逃避宿主免疫监视机制而在宿主体内维持自身。潜伏相关核抗原（拉娜）是表达最丰富的蛋白质，它在病毒DNA的潜伏复制和病毒基因组在细胞分裂后向子代细胞的有效分离中起重要作用，是病毒持续存在的关键。KSHV通过维持拉娜蛋白的水平低于宿主免疫系统检测所需的阈值但足以维持病毒基因组来逃避免疫检测。拉娜通过调节其启动子控制其表达并通过与I类和II类主要组织相容性复合体（MHC）途径的蛋白质相互作用抑制其呈递来实现这一点。在这项研究中，我们确定了拉娜表达的机制，并通过在拉娜mRNA中形成G-四链体来限制免疫识别。我们表明，这些稳定的结构在拉娜mRNA的形成抑制其翻译控制抗原呈递，这是支持与TMPyP 4，一个G-四链体稳定配体处理细胞。我们鉴定了异源核糖核蛋白A1（hnRNP A1）作为一种G-四链体解旋酶，它解旋这些稳定的二级结构以调节拉娜的翻译。重要的是拉娜是KSHV在宿主细胞中持续存在所必需的多功能蛋白，是潜伏期表达最丰富的蛋白。尽管拉娜在协助病毒致病中的功能已被广泛研究，但拉娜如何逃避宿主免疫监视的机制尚未完全了解。本研究揭示了拉娜通过在其mRNA中形成G-四链体来调节其表达和免疫逃避的自身调节作用。我们使用G-四链体稳定配体来定义通过MHC I类在细胞表面上的拉娜表达和呈递的抑制。我们定义了拉娜的自身调节作用，并鉴定了一种细胞RNA解旋酶hnRNP A1，其调节拉娜mRNA的翻译。hnRNPA 1与拉娜mRNA的相互作用可用于控制KSHV潜伏期。
During the latent phase, Kaposi's sarcoma- associated herpes virus (KSHV) maintains itself inside the host by escaping the host immune surveillance mechanism through restricted protein expression. Latency-associated nuclear antigen (LANA), the most abundantly expressed protein, is essential for viral persistence, as it plays important roles in latent viral DNA replication and efficient segregation of the viral genome to the daughter cells following cell division. KSHV evades immune detection by maintaining the levels of LANA protein below a threshold required for detection by the host immune system but sufficient to maintain the viral genome. LANA achieves this by controlling its expression through regulation of its promoters and by inhibiting its presentation through interaction with the proteins of class I and class II major histocompatibility complex (MHC) pathways. In this study, we identified a mechanism of LANA expression and restricted immune recognition through formation of G-quadruplexes in LANA mRNA. We show that the formation of these stable structures in LANA mRNA inhibits its translation to control antigen presentation, which was supported by treatment of cells with TMPyP4, a G-quadruplex-stabilizing ligand. We identified heterogenous ribonucleoprotein A1 (hnRNP A1) as a G-quadruplex-unwinding helicase, which unfolds these stable secondary structures to regulate LANA translation.IMPORTANCE LANA, the most abundantly expressed protein during latency, is a multifunctional protein which is absolutely required for the persistence of KSHV in the host cell. Even though the functions of LANA in aiding pathogenesis of the virus have been extensively studied, the mechanism of how LANA escapes host's immune surveillance is not fully understood. This study sheds light on the autoregulatory role of LANA to modulate its expression and immune evasion through formation of G-quadruplexes in its mRNA. We used G-quadruplex-stabilizing ligand to define the inhibition in LANA expression and presentation on the cell surface through MHC class I. We defined the autoregulatory role of LANA and identified a cellular RNA helicase, hnRNP A1, regulating the translation of LANA mRNA. This interaction of hnRNP A1 with LANA mRNA could be exploited for controlling KSHV latency.