Polyamine-Linked Cholesterol Incorporation in Rift Valley Fever Virus Particles Promotes Infectivity.
Polyamine-Linked Cholesterol Incorporation in Rift Valley Fever Virus Particles Promotes Infectivity.
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DOI：
10.1021/acsinfecdis.2c00071
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发表时间：
2022-08-12
影响因子：
5.3
通讯作者：
Mounce, Bryan C.
中科院分区：
文献类型：
--
作者：
Mastrodomenico, Vincent;LoMascolo, Natalie J.;Cruz-Pulido, Yazmin E.;Cunha, Christina R.;Mounce, Bryan C.
病毒依靠一系列细胞代谢物来复制并形成子代病毒粒子。其中一组分子，多胺，是小的脂肪族分子，在大多数细胞中含量丰富，支持病毒感染；然而，多胺在病毒感染中的确切作用仍不完全清楚。最近的研究表明，多胺代谢通过关键转录因子 SREBP2 的翻译支持细胞胆固醇合成。在这里，我们证明布尼亚病毒裂谷热病毒（RVFV）依赖胆固醇和多胺进行病毒感染。细胞胆固醇的消耗或胆固醇运输的中断会对 RVFV 感染产生负面影响。胆固醇掺入 RVFV 病毒体中，并以多胺依赖性方式介导其感染性；我们发现源自多胺耗尽细胞的病毒病毒颗粒膜内缺乏胆固醇。相反，我们发现病毒颗粒相关胆固醇与病毒颗粒内亚精胺的掺入有关。我们之前的工作表明，多胺促进 pH 介导的融合和基因组释放，这可能是病毒粒子内胆固醇消耗的结果。因此，我们的工作强调了多胺和胆固醇合成之间的代谢联系，以影响布尼亚病毒感染。这些数据证明了细胞代谢途径之间的联系，并揭示了治疗干预的潜在途径。
Viruses rely on an array of cellular metabolites to replicate and form progeny virions. One set of these molecules, polyamines, are small aliphatic molecules, which are abundant in most cells, that support virus infection; however, the precise roles of polyamines in virus infection remain incompletely understood. Recent work demonstrated that polyamine metabolism supports cellular cholesterol synthesis through translation of the key transcription factor SREBP2. Here, we show that the bunyavirus Rift Valley fever virus (RVFV) relies on both cholesterol and polyamines for virus infection. Depletion of cellular cholesterol or interruption of cholesterol trafficking negatively impacts RVFV infection. Cholesterol is incorporated into RVFV virions and mediates their infectivity in a polyamine-dependent manner; we find that the virus derived from polyamine-depleted cells lacks cholesterol within the virion membrane. Conversely, we find that virion-associated cholesterol is linked to the incorporation of spermidine within the virion. Our prior work demonstrated that polyamines facilitate pH-mediated fusion and genome release, which may be a consequence of cholesterol depletion within virions. Thus, our work highlights the metabolic connection between polyamines and cholesterol synthesis to impact bunyavirus infection. These data demonstrate the connectedness between cellular metabolic pathways and reveal potential avenues of therapeutic intervention.
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