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首页> 外文期刊>MBio >Human Cytomegalovirus-Encoded pUL7 Is a Novel CEACAM1-Like Molecule Responsible for Promotion of Angiogenesis
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Human Cytomegalovirus-Encoded pUL7 Is a Novel CEACAM1-Like Molecule Responsible for Promotion of Angiogenesis

机译：人巨细胞病毒编码的pUL7是负责促进血管生成的新型CEACAM1分子。

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Persistent human cytomegalovirus (HCMV) infection has been linked to several diseases, including atherosclerosis, transplant vascular sclerosis (TVS), restenosis, and glioblastoma. We have previously shown that factors secreted from HCMV-infected cells induce angiogenesis and that this process is due, at least in part, to increased secretion of interleukin-6 (IL-6). In order to identify the HCMV gene(s) responsible for angiogenesis promotion, we constructed a large panel of replication-competent HCMV recombinants. One HCMV recombinant deleted for UL1 to UL10 was unable to induce secretion of factors necessary for angiogenesis. Fine mapping using additional HCMV recombinants identified UL7 as a viral gene required for production of angiogenic factors from HCMV-infected cells. Transient expression of pUL7 induced phosphorylation of STAT3 and ERK1/2 MAP kinases and production of proangiogenic factors, including IL-6. Addition of recombinant pUL7 to cells was sufficient for angiogenesis and was again associated with increased IL-6 expression. Analysis of the UL7 structure revealed a conserved domain similar to the immunoglobulin superfamily domain and related to the N-terminal V-like domain of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). Our report therefore identifies UL7 as a novel HCMV-encoded molecule that is both structurally and functionally related to cellular CEACAM1, a proangiogenic factor highly expressed during vasculogenesis. >IMPORTANCE A hallmark of cytomegalovirus (CMV) infection is its ability to modulate the host cellular machinery, resulting in the secretion of factors associated with long-term diseases such as vascular disorders and cancer. We previously demonstrated that HCMV infection alters the types and quantities of bioactive proteins released from cells (designated the HCMV secretome) that are involved in the promotion of angiogenesis and wound healing. A key proangiogenic and antiapoptotic factor identified from a proteomic-based approach was IL-6. In the present report, we show for the first time that HCMV UL7 encodes a soluble molecule that is a structural and functional homologue of the CEACAM1 proangiogenic cellular factor. This report thereby identifies a critical component of the HCMV secretome that may be responsible, at least in part, for the vascular dysregulation associated with persistent HCMV infection.
机译：持续性人类巨细胞病毒（HCMV）感染与多种疾病有关，包括动脉粥样硬化，移植血管硬化（TVS），再狭窄和成胶质细胞瘤。先前我们已经表明，从HCMV感染的细胞中分泌的因子诱导血管生成，并且该过程至少部分是由于白介素6（IL-6）分泌增加所致。为了鉴定负责促进血管生成的HCMV基因，我们构建了一大批具有复制能力的HCMV重组子。从UL1至UL10缺失的一种HCMV重组体不能诱导血管生成必需因子的分泌。使用其他HCMV重组子的精细定位将UL7视为从HCMV感染的细胞中产生血管生成因子所需的病毒基因。 pUL7的瞬时表达诱导STAT3和ERK1 / 2 MAP激酶的磷酸化和促血管生成因子（包括IL-6）的产生。向细胞中添加重组pUL7足以进行血管生成，并再次与IL-6表达增加相关。对UL7结构的分析显示了一个保守域，类似于免疫球蛋白超家族域，并且与癌胚抗原相关细胞粘附分子1（CEACAM1）的N端V样域相关。因此，我们的报告将UL7鉴定为一种新型HCMV编码分子，其在结构和功能上均与细胞CEACAM1（一种在血管生成过程中高度表达的促血管生成因子）相关。 >重要巨细胞病毒（CMV）感染的标志是其调节宿主细胞机制的能力，导致与长期疾病（如血管疾病和癌症）有关的因子的分泌。我们以前证明了HCMV感染会改变从细胞（称为HCMV分泌组）释放的生物活性蛋白的类型和数量，这些蛋白与促进血管生成和伤口愈合有关。从基于蛋白质组学的方法中鉴定出的关键促血管生成和抗凋亡因子是IL-6。在本报告中，我们首次显示HCMV UL7编码的可溶性分子是CEACAM1促血管生成细胞因子的结构和功能同源物。因此，该报告确定了HCMV分泌组的关键成分，该成分可能至少部分负责与持续性HCMV感染相关的血管失调。

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