Kv 1.3-induced hyperpolarization is required for efficient Kaposi’s sarcoma–associated herpesvirus lytic replication

Carden, H., Harper, K. L., Mottram, T. J., Manners, O., Allott, K. L., Dallas, M. L. ORCID: https://orcid.org/0000-0002-5190-0522, Hughes, D. J., Lippiat, J. D., Mankouri, J. and Whitehouse, A. (2024) Kv 1.3-induced hyperpolarization is required for efficient Kaposi’s sarcoma–associated herpesvirus lytic replication. Science Signaling, 17 (845). eadg4124. ISSN 1937-9145 doi: 10.1126/scisignal.adg4124

Abstract/Summary

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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/117368
Identification Number/DOI	10.1126/scisignal.adg4124
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	AAAS
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