by Guillaume N. Fiches, Zhenyu Wu, Dawei Zhou, Ayan Biswas, Tai-Wei Li, Weili Kong, Maxime Jean, Netty G. Santoso, Jian Zhu
Polyamines are critical metabolites involved in various cellular processes and often dysregulated in cancers. Kaposi’s sarcoma-associated Herpesvirus (KSHV), a defined human oncogenic virus, leads to profound alterations of host metabolic landscape to favor development of KSHV-associated malignancies. In our studies, we identified that polyamine biosynthesis and eIF5A hypusination are dynamically regulated by KSHV infection through modulation of key enzymes (ODC1 and DHPS) of these pathways. During KSHV latency, ODC1 and DHPS are upregulated along with increase of hypusinated eIF5A (hyp-eIF5A), while hyp-eIF5A is further induced along with reduction of ODC1 and intracellular polyamines during KSHV lytic reactivation. In return these metabolic pathways are required for both KSHV lytic reactivation and de novo infection. Further analysis unraveled that synthesis of critical KSHV latent and lytic proteins (LANA, RTA) depends on hypusinated-eIF5A. We also demonstrated that KSHV infection can be efficiently and specifically suppressed by inhibitors targeting these pathways. Collectively, our results illustrated that the dynamic and profound interaction of a DNA tumor virus (KSHV) with host polyamine biosynthesis and eIF5A hypusination pathways promote viral propagation, thus defining new therapeutic targets to treat KSHV-associated malignancies.
Unless otherwise indicated, articles and accompanying materials published by PLOS on the PLOS Sites, including peer reviews, are licensed by the respective authors for use and distribution by you subject to citation of the original source in accordance with the Creative Commons Attribution (CC BY) license.