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细胞 N-豆蔻酰转移酶是哺乳动物正黏液病毒复制所必需的。

Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication.

机构信息

Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Center for Medical Biochemistry, Max F. Perutz Laboratories (MFPL), Medical University of Vienna, Vienna Biocenter (VBC), 1030 Vienna, Austria.

出版信息

Viruses. 2024 Aug 26;16(9):1362. doi: 10.3390/v16091362.

DOI:10.3390/v16091362
PMID:39339839
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11436053/
Abstract

The mammarenavirus matrix Z protein plays critical roles in virus assembly and cell egress. Meanwhile, heterotrimer complexes of a stable signal peptide (SSP) together with glycoprotein subunits GP1 and GP2, generated via co-and post-translational processing of the surface glycoprotein precursor GPC, form the spikes that decorate the virion surface and mediate virus cell entry via receptor-mediated endocytosis. The Z protein and the SSP undergo N-terminal myristoylation by host cell N-myristoyltransferases (NMT1 and NMT2), and G2A mutations that prevent myristoylation of Z or SSP have been shown to affect the Z-mediated virus budding and GP2-mediated fusion activity that is required to complete the virus cell entry process. In the present work, we present evidence that the validated on-target specific pan-NMT inhibitor DDD85646 exerts a potent antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV) that correlates with reduced Z budding activity and GP2-mediated fusion activity as well as with proteasome-mediated degradation of the Z protein. The potent anti-mammarenaviral activity of DDD85646 was also observed with the hemorrhagic-fever-causing Junin (JUNV) and Lassa (LASV) mammarenaviruses. Our results support the exploration of NMT inhibition as a broad-spectrum antiviral against human pathogenic mammarenaviruses.

摘要

基质 Z 蛋白在病毒组装和细胞出芽过程中发挥着关键作用。同时，通过表面糖蛋白前体 GPC 的共翻译和翻译后加工，稳定信号肽 (SSP) 与糖蛋白亚基 GP1 和 GP2 形成三聚体复合物，这些复合物形成装饰在病毒表面的刺突，并通过受体介导的内吞作用介导病毒进入细胞。Z 蛋白和 SSP 被宿主细胞 N-豆蔻酰转移酶 (NMT1 和 NMT2) 进行 N 端豆蔻酰化，并且已经表明，阻止 Z 或 SSP 豆蔻酰化的 G2A 突变会影响 Z 介导的病毒出芽和 GP2 介导的融合活性，这是完成病毒进入细胞过程所必需的。在本工作中，我们提供了证据表明，经验证的针对靶标的泛 NMT 抑制剂 DDD85646 对原型哺乳动物正粘病毒淋巴细胞性脉络丛脑膜炎病毒 (LCMV) 表现出强大的抗病毒活性，这与降低的 Z 出芽活性和 GP2 介导的融合活性以及蛋白酶体介导的 Z 蛋白降解相关。DDD85646 对引起出血热的 Junin (JUNV) 和 Lassa (LASV) 哺乳动物正粘病毒也表现出强烈的抗哺乳动物病毒活性。我们的结果支持探索 NMT 抑制作为针对人类致病性哺乳动物正粘病毒的广谱抗病毒药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/f75dc6664540/viruses-16-01362-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/3480c82ebc9a/viruses-16-01362-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/baf80c9f7948/viruses-16-01362-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/8634ba7a2f05/viruses-16-01362-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/b23103a915dc/viruses-16-01362-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/f8d4431ab059/viruses-16-01362-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/5a51daecdaf6/viruses-16-01362-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/b4a1dbbe32e5/viruses-16-01362-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/f75dc6664540/viruses-16-01362-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/3480c82ebc9a/viruses-16-01362-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/baf80c9f7948/viruses-16-01362-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/8634ba7a2f05/viruses-16-01362-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/b23103a915dc/viruses-16-01362-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/f8d4431ab059/viruses-16-01362-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/5a51daecdaf6/viruses-16-01362-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/b4a1dbbe32e5/viruses-16-01362-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/23d1/11436053/f75dc6664540/viruses-16-01362-g008.jpg

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