School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, People's Republic of China.
Affiliated Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, People's Republic of China.
Virology. 2019 May;531:69-78. doi: 10.1016/j.virol.2019.02.019. Epub 2019 Feb 27.
Latency-associated nuclear antigen (LANA) is the key factor in the establishment and maintenance of latency of Kaposi's sarcoma-associated herpesvirus (KSHV). A cellular protein, recombination signal binding protein for immunoglobulin kappa J region (RBPJ), is essential for the lytic reactivation of KSHV. However, whether RBPJ expression is regulated by KSHV is not clear. Here, we show that LANA upregulates let-7a and its primary transcripts in parallel with its reduction of RBPJ expression. An increase in notch intracellular domain (NICD) and the downregulation of NF-κB and LIN28B contribute to the upregulation of let-7a by LANA. Let-7a represses RBPJ expression by directly binding the 3' untranslated region of RBPJ. Let-7a overexpression or RBPJ knockdown led to a dose- and time-dependent inhibition of lytic reactivation of KSHV. Collectively, these findings support a model wherein LANA inhibits the lytic replication of KSHV by regulating let-7a/RBPJ signaling.
潜伏相关核抗原（LANA）是卡波西肉瘤相关疱疹病毒（KSHV）建立和维持潜伏的关键因素。一种细胞蛋白，免疫球蛋白 kappa J 区重组信号结合蛋白（RBPJ），对于 KSHV 的裂解性再激活是必需的。然而，RBPJ 的表达是否受 KSHV 调节尚不清楚。在这里，我们表明 LANA 与 RBPJ 表达的减少平行地上调 let-7a 和其初级转录物。Notch 细胞内结构域（NICD）的增加和 NF-κB 和 LIN28B 的下调有助于 LANA 上调 let-7a。Let-7a 通过直接结合 RBPJ 的 3'非翻译区来抑制 RBPJ 的表达。Let-7a 的过表达或 RBPJ 的敲低导致 KSHV 的裂解性再激活呈剂量和时间依赖性抑制。总之，这些发现支持了一种模型，其中 LANA 通过调节 let-7a/RBPJ 信号抑制 KSHV 的裂解性复制。
