Inhibition of Arenavirus Entry and Replication by the Cell-Intrinsic Restriction Factor ZMPSTE24 Is Enhanced by IFITM Antiviral Activity.
Inhibition of Arenavirus Entry and Replication by the Cell-Intrinsic Restriction Factor ZMPSTE24 Is Enhanced by IFITM Antiviral Activity.
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DOI：
10.3389/fmicb.2022.840885
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发表时间：
2022
影响因子：
5.2
通讯作者：
Foster TL
中科院分区：
文献类型：
--
作者：
Stott-Marshall RJ;Foster TL
在缺乏有效疫苗和治疗的情况下，每年由沙病毒（如拉沙病毒）引起的严重人类出血热疫情继续对人类健康构成重大威胁。了解抑制或促进沙粒病毒感染的细胞因子的平衡可能对开发有效的抗病毒策略具有重要意义。在这里，我们确定了细胞内禀锌跨膜金属蛋白酶ZMPSTE24作为沙粒病毒的限制因子。值得注意的是，在假颗粒实验和活病毒感染模型中，crispr - cas9介导的敲除人肺泡上皮A549细胞中的ZMPSTE24增加了沙粒病毒糖蛋白介导的病毒进入。作为病毒进入和复制的屏障，ZMPSTE24可能作为干扰素诱导跨膜蛋白（IFITM）抗病毒功能的下游效应物；尽管通过一种尚不清楚的机制。IFITM1、IFITM2和IFITM3蛋白的过表达不限制携带沙粒病毒包膜糖蛋白的假颗粒的进入和活病毒感染。此外，功能获得性研究表明，IFITMs增强了ZMPSTE24对沙粒病毒的抗病毒活性，表明病毒限制的协同作用。我们发现ZMPSTE24和ifitm影响细胞内吞动力学，表明膜结构和稳定性的扰动可能是ZMPSTE24介导的限制和ZMPSTE24- ifitm协同抗病毒活性的机制。总的来说，我们的研究结果确定了ZMPSTE24宿主限制性活性在沙粒病毒感染早期阶段的作用。此外，我们还提供了细胞膜完整性对沙粒病毒有效融合的重要性的见解，并强调了治疗发展的新途径。
In the absence of effective vaccines and treatments, annual outbreaks of severe human haemorrhagic fever caused by arenaviruses, such as Lassa virus, continue to pose a significant human health threat. Understanding the balance of cellular factors that inhibit or promote arenavirus infection may have important implications for the development of effective antiviral strategies. Here, we identified the cell-intrinsic zinc transmembrane metalloprotease, ZMPSTE24, as a restriction factor against arenaviruses. Notably, CRISPR-Cas9-mediated knockout of ZMPSTE24 in human alveolar epithelial A549 cells increased arenavirus glycoprotein-mediated viral entry in pseudoparticle assays and live virus infection models. As a barrier to viral entry and replication, ZMPSTE24 may act as a downstream effector of interferon-induced transmembrane protein (IFITM) antiviral function; though through a yet poorly understood mechanism. Overexpression of IFITM1, IFITM2, and IFITM3 proteins did not restrict the entry of pseudoparticles carrying arenavirus envelope glycoproteins and live virus infection. Furthermore, gain-of-function studies revealed that IFITMs augment the antiviral activity of ZMPSTE24 against arenaviruses, suggesting a cooperative effect of viral restriction. We show that ZMPSTE24 and IFITMs affect the kinetics of cellular endocytosis, suggesting that perturbation of membrane structure and stability is likely the mechanism of ZMPSTE24-mediated restriction and cooperative ZMPSTE24-IFITM antiviral activity. Collectively, our findings define the role of ZMPSTE24 host restriction activity in the early stages of arenavirus infection. Moreover, we provide insight into the importance of cellular membrane integrity for productive fusion of arenaviruses and highlight a novel avenue for therapeutic development.
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