五聚体糖蛋白复合物在人类巨细胞病毒感染过程中抑制病毒即刻早期转录。

The Pentamer glycoprotein complex inhibits viral Immediate Early transcription during Human Cytomegalovirus infections.

机构信息

Institute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706.

出版信息

Proc Natl Acad Sci U S A. 2024 Sep 24;121(39):e2408078121. doi: 10.1073/pnas.2408078121. Epub 2024 Sep 18.

Abstract

The Pentamer complex of Human Cytomegalovirus (HCMV) consists of the viral glycoproteins gH, gL, UL128, UL130, and UL131 and is incorporated into infectious virions. HCMV strains propagated extensively in vitro in fibroblasts carry UL128, UL130, or UL131 alleles that do not make a functional complex and thus lack Pentamer function. Adding functional Pentamer to such strains decreases virus growth in fibroblasts. Here, we show that the Pentamer inhibits productive HCMV replication in fibroblasts by repressing viral Immediate Early (IE) transcription. We show that ectopic expression of the viral IE1 protein, a target of Pentamer-mediated transcriptional repression, complements the growth defect of a Pentamer-positive virus. Furthermore, we show that the Pentamer also represses viral IE transcription in cell types where HCMV in vitro latency is studied. Finally, we identify UL130 as a functional subunit of the Pentamer for IE transcriptional repression and demonstrate that cyclic AMP Response Element (CRE) and NFkB sites within the Major Immediate Early Promoter that drives IE1 transcription contribute to this repression. We conclude that the HCMV Pentamer represses viral IE transcription.

摘要

人巨细胞病毒 (HCMV) 的五聚体复合物由病毒糖蛋白 gH、gL、UL128、UL130 和 UL131 组成,并整合到感染性病毒粒子中。在成纤维细胞中广泛体外繁殖的 HCMV 株携带不形成功能复合物的 UL128、UL130 或 UL131 等位基因,因此缺乏五聚体功能。向这些菌株中添加功能性五聚体可降低病毒在成纤维细胞中的生长。在这里,我们表明五聚体通过抑制病毒立即早期 (IE) 转录来抑制成纤维细胞中有效的 HCMV 复制。我们表明,五聚体介导的转录抑制的靶标病毒 IE1 蛋白的异位表达可弥补五聚体阳性病毒的生长缺陷。此外,我们表明五聚体还可抑制在研究 HCMV 体外潜伏期的细胞类型中的病毒 IE 转录。最后,我们确定 UL130 是用于 IE 转录抑制的五聚体的功能性亚基,并证明驱动 IE1 转录的主要立即早期启动子内的环 AMP 反应元件 (CRE) 和 NFkB 位点有助于这种抑制。我们得出结论,HCMV 五聚体抑制病毒 IE 转录。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec68/11441559/565c3a10556b/pnas.2408078121fig01.jpg

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