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Cleveland Clinic

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Cell Reports, 2022 Aug 16;40(7):111234 | https://doi.org/10.1016/j.celrep.2022.111234 Herpesvirus-induced spermidine synthesis and eIF5A hypusination for viral episomal maintenance

Un Yung Choi ¹, Jae Jin Lee ², Angela Park ², Kyle L Jung ³, Shin-Ae Lee ^3, Youn Jung Choi ³, Hye-Ra Lee⁴, Chih-Jen Lai ³, Hyungjin Eoh ², Jae U Jung ⁵

¹Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
²Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
³Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
⁴Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong 30019, Republic of Korea.
⁵Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Corresponding author: Un Yung Choi, Jae U. Jung

Abstract

Spermidine is essential for cellular growth and acts as a prerequisite of hypusination, a post-translational modification of eukaryotic initiation factor 5A (eIF5A), allowing the translation of polyproline-containing proteins. Here, we show that oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) increases spermidine synthesis and eIF5A hypusination to enhance expression of polyproline-containing latency-associated nuclear antigen (LANA) for viral episomal maintenance. KSHV upregulates intracellular spermidine levels by dysregulating polyamine metabolic pathways in three-dimensional (3D) culture and 2D de novo infection conditions. Increased intracellular spermidine leads to increased eIF5A hypusination, ultimately enhancing LANA expression. In contrast, inhibition of spermidine synthesis or eIF5A hypusination alleviates LANA expression, decreasing viral episomal maintenance and KSHV-infected cell proliferation in vitro and in vivo, which is reversed by spermidine supplement. This demonstrates that KSHV hijacks spermidine synthesis and eIF5A hypusination pathways to enhance LANA expression for viral episomal maintenance, suggesting polyamine metabolism and eIF5A hypusination as therapeutic targets for KSHV-induced tumorigenesis.

논문정보

형식Research article
게재일2022년 08월 (BRIC 등록일 2022-10-18)
연구진국내+국외 연구진
분야 생명과학 > 미생물학

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