Complex Interplay of the UL136 Isoforms Balances Cytomegalovirus Replication and Latency.
Complex Interplay of the UL136 Isoforms Balances Cytomegalovirus Replication and Latency.
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DOI：
10.1128/mbio.01986-15
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发表时间：
2016-03-01
期刊：
影响因子：
6.4
通讯作者：
Goodrum F
中科院分区：
文献类型：
--
作者：
Caviness K;Bughio F;Crawford LB;Streblow DN;Nelson JA;Caposio P;Goodrum F
人巨细胞病毒(HCMV)是一种β疱疹病毒，通过鲜为人知的机制在人体内无限期存活。UL136基因携带在一个对HCMV潜伏期很重要的遗传基因座中，称为UL133/8基因座，它还携带UL133、UL135和UL138。以前，我们证明UL136表达为5种蛋白质亚型，从33-kDa到19-kDa，产生于选择性转录和可能的翻译启动机制。我们之前已经证明，UL136亚型对于病毒在成纤维细胞中的感染是必不可少的，成纤维细胞是一种高效的病毒复制模型。在我们目前的工作中，UL136已经成为与巨细胞病毒持续感染相关的多种感染环境中的复杂调节因子：在慢性感染的内皮细胞模型中，在CD34+造血祖细胞潜伏期的模型中，以及在体内NOD-SCID IL2Rγ裸人化(HuNSG)小鼠模型中。33 kDa和26 kDa的亚型促进复制，而23 kDa和19 kDa的亚型抑制ECs、CD34+HPC和huNSG小鼠的复制。25 kDa异构体的作用依赖于环境，并影响其他异构体的活性。这些异构体分布于整个分泌途径，33-和26-kDa UL136亚型的缺失会导致内皮细胞中病毒成熟缺陷。这项工作揭示了影响病毒复制、潜伏和传播的蛋白质亚型之间有趣的功能相互作用，有助于UL133/8基因座在HCMV感染中的总体作用。DNA病毒，尤其是疱疹病毒的持久性仍然是一个谜，因为我们还没有完全定义对持久性重要的病毒和宿主因素。人类巨细胞病毒是一种疱疹病毒，在具有免疫能力的人中持续存在，但对移植患者和发育中的胎儿构成严重的疾病威胁。目前还没有疫苗，目前的治疗方法也不针对潜伏的储蓄者。为了确定对持久性重要的病毒因素，我们研究了对HCMV持久性重要的背景下未知病毒复制功能的病毒基因。使用与病毒持久性相关的模型，我们证明了UL136基因编码的蛋白质异构体在调节感染的潜伏和复制状态中的相反作用。我们的发现揭示了UL136蛋白亚型之间有趣的相互作用，并将UL136定义为HCMV持久性的重要调节因子。
Human cytomegalovirus (HCMV), a betaherpesvirus, persists indefinitely in the human host through poorly understood mechanisms. The UL136 gene is carried within a genetic locus important to HCMV latency termed the UL133/8 locus, which also carries UL133, UL135, and UL138. Previously, we demonstrated that UL136 is expressed as five protein isoforms ranging from 33-kDa to 19-kDa, arising from alternative transcription and, likely, translation initiation mechanisms. We previously showed that the UL136 isoforms are largely dispensable for virus infection in fibroblasts, a model for productive virus replication. In our current work, UL136 has emerged as a complex regulator of HCMV infection in multiple contexts of infection relevant to HCMV persistence: in an endothelial cell (EC) model of chronic infection, in a CD34+ hematopoietic progenitor cell (HPC) model of latency, and in an in vivo NOD-scid IL2Rγcnull humanized (huNSG) mouse model for latency. The 33- and 26-kDa isoforms promote replication, while the 23- and 19-kDa isoforms suppress replication in ECs, in CD34+ HPCs, and in huNSG mice. The role of the 25-kDa isoform is context dependent and influences the activity of the other isoforms. These isoforms localize throughout the secretory pathway, and loss of the 33- and 26-kDa UL136 isoforms results in virus maturation defects in ECs. This work reveals an intriguing functional interplay between protein isoforms that impacts virus replication, latency, and dissemination, contributing to the overall role of the UL133/8 locus in HCMV infection. The persistence of DNA viruses, and particularly of herpesviruses, remains an enigma because we have not completely defined the viral and host factors important to persistence. Human cytomegalovirus, a herpesvirus, persists in the absence of disease in immunocompetent individuals but poses a serious disease threat to transplant patients and the developing fetus. There is no vaccine, and current therapies do not target latent reservoirs. In an effort to define the viral factors important to persistence, we have studied viral genes with no known viral replication function in contexts important to HCMV persistence. Using models relevant to viral persistence, we demonstrate opposing roles of protein isoforms encoded by the UL136 gene in regulating latent and replicative states of infection. Our findings reveal an intriguing interplay between UL136 protein isoforms and define UL136 as an important regulator of HCMV persistence.