Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral infection.
Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral infection.
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DOI：
10.1371/journal.ppat.1010503
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发表时间：
2022-04
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
多胺是参与各种细胞过程的关键代谢物，并且通常在癌症中失调。卡波西肉瘤相关疱疹病毒（KSHV）是一种明确的人类致癌病毒，可导致宿主代谢格局发生深刻变化，从而有利于KSHV相关恶性肿瘤的发展。在我们的研究中，我们确定了多胺的生物合成和eIF 5A hypusination的动态调节KSHV感染通过调节这些途径的关键酶（ODC 1和DHPS）。在KSHV潜伏期，ODC 1和DHPS沿着hypusinated eIF 5A（hyp-eIF 5A）的增加而上调，而hyp-eIF 5A在KSHV裂解性再激活期间沿着ODC 1和细胞内多胺的减少而被进一步诱导。反过来，这些代谢途径是KSHV裂解再活化和从头感染所必需的。进一步的分析揭示了关键的KSHV潜伏蛋白和裂解蛋白（拉娜，RTA）的合成依赖于羟腐殖酸化的eIF 5A。我们还证明，KSHV感染可以有效地和特异性抑制针对这些途径的抑制剂。总的来说，我们的研究结果表明，DNA肿瘤病毒（KSHV）与宿主多胺生物合成和eIF 5A hypusination途径的动态和深刻的相互作用促进了病毒的繁殖，从而定义了新的治疗靶点来治疗KSHV相关的恶性肿瘤。了解病毒-宿主相互作用对于开发和改进治疗至关重要。卡波西肉瘤相关疱疹病毒（KSHV）是一种人类γ-疱疹病毒，可深度调节宿主代谢，并与内皮和淋巴起源的各种癌症相关。多胺是癌症中经常失调的关键代谢物。在这项研究中，我们证明了KSHV动态调节多胺代谢，有利于eIF 5A hypusination和关键KSHV潜伏和裂解蛋白（拉娜，RTA）的翻译。因此，我们发现，KSHV从潜伏期和从头感染的裂解开关依赖于多胺和羟腐胺酸和药物抑制有效和特异性地限制KSHV感染。我们的研究为KSHV改变宿主代谢提供了新的见解，并描述了治疗KSHV相关恶性肿瘤的新治疗靶点。
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. Understanding virus-host interactions is crucial to develop and improve therapies. Kaposi’s sarcoma associated Herpesvirus (KSHV) is a human gamma-herpesvirus which deeply modulates the host metabolism and is associated with various cancers of endothelial and lymphoid origin. Polyamines are critical metabolites often dysregulated in cancers. In this study we demonstrated KSHV dynamically modulates polyamine metabolism to favor eIF5A hypusination and translation of critical KSHV latent and lytic proteins (LANA, RTA). Consequently, we found KSHV lytic switch from latency and de novo infection were dependent on polyamines and hypusination and pharmacological inhibition efficiently and specifically restricted KSHV infection. Our study provides new insights into KSHV alteration of the host metabolism and describe new therapeutic targets to treat KSHV-associated malignancies.
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DOI：
10.1016/s1056-8719(01)00157-5
发表时间：
2001-05-01
影响因子：
1.9
作者：
Bartzatt, R
通讯作者：
Bartzatt, R
癌症发动机的油：致癌信号传导和多胺代谢之间的串扰。
影响因子：
13.6
作者：
Arruabarrena-Aristorena A;Zabala-Letona A;Carracedo A
通讯作者：
Carracedo A
影响因子：
6.7
作者：
Balistreri G;Viiliäinen J;Turunen M;Diaz R;Lyly L;Pekkonen P;Rantala J;Ojala K;Sarek G;Teesalu M;Denisova O;Peltonen K;Julkunen I;Varjosalo M;Kainov D;Kallioniemi O;Laiho M;Taipale J;Hautaniemi S;Ojala PM
通讯作者：
Ojala PM
DOI：
10.1038/s41568-018-0050-3
发表时间：
2018-11
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Casero RA Jr;Murray Stewart T;Pegg AE
通讯作者：
Pegg AE
影响因子：
14.9
作者：
FRUGIER, M;FLORENTZ, C;GIEGE, R
通讯作者：
GIEGE, R