Interferon-Induced Spermidine-Spermine Acetyltransferase and Polyamine Depletion Restrict Zika and Chikungunya Viruses

Bryan C. Mounce, Enzo Z. Poirier, Gabriella Passoni, Etienne Simon-Loriere, Teresa Cesaro, Matthieu Prot, Kenneth A. Stapleford, Gonzalo Moratorio, Anavaj Sakuntabhai, Jean-Pierre Levraud, and Marco Vignuzzi

Cell host & microbe 20, 167-177, (2016)

Speaker: Po-Chun Chang (張博淳)                                      Time: 14:00~15:00 Nov. 2, 2016

Commentator: Dr. Shun-Hua Chen (陳舜華 老師)            Place: Room 601

Abstract:

Spermidine and spermine are two polyamines derived from ornithine, a critical amino acid involved in urea cycle for nitrogen metabolism. Polyamines are abundant within cells and involved in several cellular processes like apoptosis, transcription, and translation. Some previous studies reported that several DNA, even RNA viruses incorporate polyamines into virion to neutralize charges on nucleic acids. In addition, polyamines are also known to promote viral RNA synthesis.¹ Several transcriptomics studies revealed that polyamine biosynthetic gene expression is able to regulate by type I interferon (IFN) stimulation, including spermidine/spermine N1-acetyltransferase (SAT1).² SAT1 is a key catabolic enzyme to reduce cellular spermidine and spermin by acetylation to matain polyamine pool. According to these previous findings, authors tried to understand whether IFN-dependent SAT1 expression is involved in viral replication. Zika (ZIKV) and Chikungunya (CHIKV) viruses, two positive single-strand RNA arboviruses which gained notoriety for their swiftly spreading ability to be global infectious diseases in recent years, where tested in this study. First, they revealed that CRISPR/Cas9-mediated knockout of SAT1 restore CHIKV replication under IFN treatment. They further confirmed that restriction of CHIKV and ZIKV replication by SAT1 was dependent on its enzymatic activity via over-expression system by constructs-transfection and inducible-transgenes systems. They used a polyamine depletion model to investigate the impact of polyamines on viral RNA replication. Results indicated that transcription and translation of viral RNA relied on biogenic polyamines. Finally, they employed Drosophila melanogaster and Danio rerio (zebrafish) as their in vivo models to confirm the requirent of polyamines in virus replication in vivo. According to their findings, polyamine depletion whether via SAT1-dependent or broadly other ways may consider as an antiviral therapy avenue to restrict viral replication.

References:

1     Raina, A., Tuomi, K. & Mantyjarvi, R. Roles of polyamines in the replication of animal viruses. Medical biology 59, 428-432 (1981).

2     Izmailova, E. et al. HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nature medicine 9, 191-197, (2003).