K_v1.3 induced hyperpolarisation and Ca_v3.2-mediated calcium entry are required for efficient Kaposi’s sarcoma-associated herpesvirus lytic replication

Abstract

Understanding the host factors critical for Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication can identify new targets for therapeutic intervention. Using pharmacological and genetic silencing approaches, we reveal for the first time that KSHV requires a B cell expressed voltage-gated K+ channel, Kv1.3, to enhance lytic replication. We show that the KSHV replication and transcription activator (RTA) protein upregulates Kv1.3 expression, leading to enhanced K+ channel activity and hyperpolarisation of the B cell membrane. Enhanced Kv1.3 activity then promotes intracellular Ca2+ influx through Cav3.2, a T-type Ca2+ channel, leading to the Ca2+ driven nuclear localisation of NFAT and the subsequent NFAT1-responsive gene expression. Importantly, KSHV lytic replication and infectious virion production could be inhibited by both Kv1.3 and Cav3.2 blockers or through Kv1.3 silencing. These findings provide new mechanistic insight into the essential role of host ion channels during KSHV infection and highlight Kv1.3 and Cav3.2 as new druggable host factors that are key to the successful completion of KSHV lytic replication.

Exploitation of ATP-sensitive potassium ion (KATP) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling

“…Together, this underlines the importance of regulating host ion channel homeostasis during infection. Until recently however, much research in this field had focussed on RNA viruses, but recent work in our laboratories have highlighted roles for host chloride, potassium and calcium ion channels during BK polyomavirus (BKPyV), Merkel cell polyomavirus (MCPyV) and Kaposi's sarcoma-associated herpesvirus (KSHV) infection [60][61][62]. Importantly, this study is the first to our knowledge to explicitly demonstrate modulation of ion channel activity by HPV, and that this can contribute to host cell transformation.…”