Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, 1664 N Virginia Street, Reno, NV 89557, USA.
Viruses. 2023 Dec 15;15(12):2438. doi: 10.3390/v15122438.
Kaposi's sarcoma-associated herpesvirus (KSHV) establishes life-long latent infection and is linked to several human malignancies. Latency-associated nuclear antigen (LANA) is highly expressed during latency, and is responsible for the replication and maintenance of the viral genome. The expression of LANA is regulated at transcriptional/translational levels through multiple mechanisms, including the secondary structures in the mRNA sequence. LANA mRNA has multiple G-quadruplexes (G4s) that are bound by multiple proteins to stabilize/destabilize these secondary structures for regulating LANA. In this manuscript, we demonstrate the role of Nucleolin (NCL) in regulating LANA expression through its interaction with G-quadruplexes of LANA mRNA. This interaction reduced LANA's protein expression through the sequestration of mRNA into the nucleus, demonstrated by the colocalization of G4-carrying mRNA with NCL. Furthermore, the downregulation of NCL, by way of a short hairpin, showed an increase in LANA translation following an alteration in the levels of LANA mRNA in the cytoplasm. Overall, the data presented in this manuscript showed that G-quadruplexes-mediated translational control could be regulated by NCL, which can be exploited for controlling KSHV latency.
卡波济肉瘤相关疱疹病毒（KSHV）建立终身潜伏感染，并与几种人类恶性肿瘤有关。潜伏相关核抗原（LANA）在潜伏期间高度表达，负责病毒基因组的复制和维持。LANA 的表达通过多种机制在转录/翻译水平上受到调节，包括 mRNA 序列中的二级结构。LANA mRNA 具有多个 G-四联体（G4s），这些 G4s 被多种蛋白质结合，以稳定/破坏这些二级结构来调节 LANA。在本文中，我们通过与 LANA mRNA 的 G-四联体相互作用，证明了核仁素（NCL）在调节 LANA 表达中的作用。这种相互作用通过将 mRNA 隔离到核内来减少 LANA 的蛋白表达，这通过携带 G4 的 mRNA 与 NCL 的共定位来证明。此外，通过短发夹，下调 NCL 显示在细胞质中 LANA mRNA 水平改变后 LANA 翻译增加。总的来说，本文提供的数据表明，G-四联体介导的翻译控制可以通过 NCL 调节，这可以用于控制 KSHV 潜伏期。
