NFAT5 Restricts Bovine Herpesvirus 1 Productive Infection in MDBK Cell Cultures.
NFAT5 Restricts Bovine Herpesvirus 1 Productive Infection in MDBK Cell Cultures.
复制标题
DOI：
10.1128/spectrum.00117-23
复制
发表时间：
2023-08-17
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
牛疱疹病毒1（BoHV-1）是一种重要的牛病毒病原体，可引起上呼吸道和生殖系统的严重疾病。张力反应增强子结合蛋白 (TonEBP)，也称为活化 T 细胞核因子 5 (NFAT5)，是一种参与一系列细胞过程的多效性应激蛋白。在这项研究中，我们发现通过 siRNA 敲低 NFAT5 会增加 BoHV-1 的生产性感染，而通过质粒转染过度表达 NFAT5 会减少牛肾 (MDBK) 细胞中的病毒产量。后期阶段的病毒产生性感染显着增加了 NFAT5 的转录，但没有明显改变可测量的 NFAT5 蛋白水平。病毒感染使 NFAT5 蛋白重新定位并减少细胞质积累。重要的是，我们发现 NFAT5 的一个子集存在于线粒体中，病毒感染导致线粒体 NFAT5 的消耗。除了全长 NFAT5 之外，还专门在细胞核中检测到了另外两种具有不同分子量的亚型，病毒感染后细胞核中的积累受到不同的影响。此外，病毒感染差异性地改变了 PGK1、SMIT 和 BGT-1（受 NFAT5 调节的典型下游靶标）的 mRNA 水平。综上所述，NFAT5是限制BoHV-1生产性感染的潜在宿主因子，病毒感染通过NFAT5分子在细胞质、细胞核和线粒体中的重新定位以及其下游靶标的表达改变来劫持NFAT5信号转导。重要性 越来越多的研究表明，NFAT5 调节多种病毒感染引起的疾病发展，这表明了宿主因素在病毒发病机制中的重要性。在此，我们报告 NFAT5 具有在体外限制 BoHV-1 生产性感染的能力。通过 NFAT5 蛋白的重新定位、NFAT5 在细胞质中的积累减少以及 NFAT5 下游靶标的差异表达，可以观察到后期的病毒生产性感染可能会改变 NFAT5 信号通路。重要的是，我们首次发现NFAT5的一个子集存在于线粒体中，这意味着NFAT5可能调节线粒体功能，这将扩展我们对NFAT5生物活性的认识。此外，我们发现两种具有不同分子量的 NFAT5 亚型仅在细胞核中检测到，病毒感染后细胞核中的积累受到不同的影响，这代表了 NFAT5 功能响应 BoHV-1 感染的一种新的调节机制。
Bovine herpesvirus 1 (BoHV-1), an important bovine viral pathogen, causes severe disease in the upper respiratory tract and reproductive system. Tonicity-responsive enhancer-binding protein (TonEBP), also known as nuclear factor of activated T cells 5 (NFAT5), is a pleiotropic stress protein involved in a range of cellular processes. In this study, we showed that the knockdown of NFAT5 by siRNA increased BoHV-1 productive infection and overexpression of NFAT5 via plasmid transfection decreased virus production in bovine kidney (MDBK) cells. Virus productive infection at later stages significantly increased transcription of NFAT5 but not appreciably alter measurable NFAT5 protein levels. Virus infection relocalized NFAT5 protein and decreased the cytosol accumulation. Importantly, we found a subset of NFAT5 resides in mitochondria, and virus infection led to the depletion of mitochondrial NFAT5. In addition to full-length NFAT5, another two isoforms with distinct molecular weights were exclusively detected in the nucleus, where the accumulation was differentially affected following virus infection. In addition, virus infection differentially altered mRNA levels of PGK1, SMIT, and BGT-1, the canonical downstream targets regulated by NFAT5. Taken together, NFAT5 is a potential host factor that restricts BoHV-1 productive infection, and virus infection hijacks NFAT5 signaling transduction by relocalization of NFAT5 molecules in cytoplasm, nucleus, and mitochondria, as well as altered expression of its downstream targets. IMPORTANCE Accumulating studies have revealed that NFAT5 regulates disease development due to infection of numerous viruses, underlying the importance of the host factor in virus pathogenesis. Here, we report that NFAT5 has capacity to restrict BoHV-1 productive infection in vitro. And virus productive infection at later stages may alter NFAT5 signaling pathway as observed by relocalization of NFAT5 protein, reduced accumulation of NFAT5 in cytosol, and differential expression of NFAT5 downstream targets. Importantly, for the first time, we found that a subset of NFAT5 resides in mitochondria, implying that NFAT5 may regulate mitochondrial functions, which will extend our knowledge on NFAT5 biological activities. Moreover, we found two NFAT5 isoforms with distinct molecular weights were exclusively detected in the nucleus, where the accumulation was differentially affected following virus infection, representing a novel regulation mechanism on NFAT5 function in response to BoHV-1infection.
登录
查看更多内容
影响因子：
7.2
作者：
Fiorito, Filomena;Marfe, Gabriella;Pagnini, Ugo
通讯作者：
Pagnini, Ugo
影响因子：
16.6
作者：
Lee, Hwan Hee;An, Seung Min;Kwon, Hyug Moo
通讯作者：
Kwon, Hyug Moo
DOI：
10.1007/s00018-022-04406-y
发表时间：
2022-06-22
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
通讯作者：
--
影响因子：
5
作者：
Gaudreault, Natasha;Jones, Clinton
通讯作者：
Jones, Clinton
影响因子：
64.8
作者：
Kleinewietfeld, Markus;Manzel, Arndt;Titze, Jens;Kvakan, Heda;Yosef, Nir;Linker, Ralf A.;Muller, Dominik N.;Hafler, David A.
通讯作者：
Hafler, David A.