School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, LS2 9JT Leeds, UK.
School of Pharmacy, University of Reading, RG6 6AP Reading, UK.
Sci Signal. 2024 Jul 16;17(845):eadg4124. doi: 10.1126/scisignal.adg4124.
Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus that is linked directly to the development of Kaposi's sarcoma. KSHV establishes a latent infection in B cells, which can be reactivated to initiate lytic replication, producing infectious virions. Using pharmacological and genetic silencing approaches, we showed that the voltage-gated K channel K1.3 in B cells enhanced KSHV lytic replication. The KSHV replication and transcription activator (RTA) protein increased the abundance of K1.3 and led to enhanced K channel activity and hyperpolarization of the B cell membrane. Enhanced K1.3 activity promoted intracellular Ca influx, leading to the Ca-driven nuclear localization of KSHV RTA and host nuclear factor of activated T cells (NFAT) proteins and subsequently increased the expression of NFAT1 target genes. KSHV lytic replication and infectious virion production were inhibited by K1.3 blockers or silencing. These findings highlight K1.3 as a druggable host factor that is key to the successful completion of KSHV lytic replication.
卡波济肉瘤相关疱疹病毒（KSHV）是一种致癌性疱疹病毒，与卡波济肉瘤的发展直接相关。KSHV 在 B 细胞中建立潜伏感染，B 细胞可以被重新激活以启动裂解复制，产生感染性病毒粒子。使用药理学和基因沉默方法，我们表明 B 细胞中的电压门控钾通道 K1.3 增强了 KSHV 的裂解复制。KSHV 复制和转录激活剂（RTA）蛋白增加了 K1.3 的丰度，并导致增强的 K 通道活性和 B 细胞膜的超极化。增强的 K1.3 活性促进细胞内 Ca 流入，导致 KSHV RTA 和宿主激活 T 细胞核因子（NFAT）蛋白的 Ca 驱动核定位，随后增加 NFAT1 靶基因的表达。K1.3 阻断剂或沉默抑制了 KSHV 的裂解复制和感染性病毒粒子的产生。这些发现强调了 K1.3 作为一种可成药的宿主因子，是 KSHV 裂解复制成功完成的关键。
