Kv1.3-induced Hyperpolarization is Required for Efficient Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication

Holli Carden,Katherine L. Harper,Timothy J. Mottram,Oliver Manners, Katie L. Allott,Mark L. Dallas,David J. Hughes,Jonathan D. Lippiat,Jamel Mankouri,Adrian Whitehouse

SCIENCE SIGNALING（2024）

Univ Leeds | Univ Reading | Univ St Andrews

Cited 0|Views14

Abstract

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 Kv1.3 in B cells enhanced KSHV lytic replication. The KSHV replication and transcription activator (RTA) protein increased the abundance of Kv1.3 and led to enhanced K+ channel activity and hyperpolarization of the B cell membrane. Enhanced Kv1.3 activity promoted intracellular Ca2+ influx, leading to the Ca2+-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 Kv1.3 blockers or silencing. These findings highlight Kv1.3 as a druggable host factor that is key to the successful completion of KSHV lytic replication.

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【要点】：本研究揭示了电压门控K+通道Kv1.3在B细胞中通过促进Kaposi’s sarcoma–associated herpesvirus (KSHV)的即时复制，是完成KSHV复制的关键宿主因子，并可作为潜在的治疗靶点。

【方法】：采用药理学和遗传沉默手段，研究了Kv1.3对KSHV即时复制的影响。

【实验】：通过实验发现，使用Kv1.3阻断剂或沉默Kv1.3可以抑制KSHV的即时复制和感染性病毒粒子的产生，实验使用的数据集未在文中明确提及。