Analysis of Host Gene Expression Changes Reveals Distinct Roles for the Cytoplasmic Domain of the Epstein-Barr Virus Receptor/CD21 in B-Cell Maturation, Activation, and Initiation of Virus Infection
Analysis of Host Gene Expression Changes Reveals Distinct Roles for the Cytoplasmic Domain of the Epstein-Barr Virus Receptor/CD21 in B-Cell Maturation, Activation, and Initiation of Virus Infection
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DOI：
10.1128/jvi.03099-13
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发表时间：
2014-05-01
影响因子：
5.4
通讯作者：
Fingeroth, Joyce D.
中科院分区：
文献类型：
--
作者：
Arredouani, Mohamed S.;Bhasin, Manoj K.;Fingeroth, Joyce D.
EB病毒(Epstein-Barr Virus，EBV)附着在B细胞表面的人CD21上，引发感染。CD21是一条简单的系绳，还是将重要信息传递到细胞内部，从而产生促进原代B细胞感染的宿主因子，目前仍存在争议，因为CD21的细胞质片段很短，尽管高度保守。CD21在正常B细胞上的普遍存在，这一群体的多样性，以及众所周知的原代B细胞对基因转移技术的抵抗力，都阻碍了这个问题的解决。为了揭示CD21胞浆结构域在感染起始过程中的作用(S)，在两个缺乏内源性受体的前B细胞系中稳定表达了全长受体(CD21=CR)和对照载体(NEO)。全基因组转录分析表明，稳定的CD21表面表达(无论是CR还是CT)单独产生了多种独立的基因表达变化，尽管两者都显著降低了I类黑色素瘤相关抗原(MAGE)家族的RNA，并上调了与B细胞分化相关的基因(如C2TA、HLA-II、IL21R、MIC2、CD48和PTPRCAP/CD45相关蛋白)。跨越72小时的时间分析表明，不仅是CR表达的线路，而且CT表达的线路也开始了潜伏期。尽管如此，在感染后1h，CR和CT转录本的数量和谱带发生了进一步的分化。即时早期细胞转录本(例如，c-jun和多个组蛋白)的差异调制，既是新的，也是先前与CD21启动的信号有关的，以及来自途径分析的不同结果支持细胞质结构域在启动细胞内信号中的单独作用。
Epstein-Barr virus (EBV) attachment to human CD21 on the B-cell surface initiates infection. Whether CD21 is a simple tether or conveys vital information to the cell interior for production of host factors that promote infection of primary B cells is controversial, as the cytoplasmic fragment of CD21 is short, though highly conserved. The ubiquity of CD21 on normal B cells, the diversity of this population, and the well-known resistance of primary B cells to gene transfer technologies have all impeded resolution of this question. To uncover the role(s) of the CD21 cytoplasmic domain during infection initiation, the full-length receptor (CD21 = CR), a mutant lacking the entire cytoplasmic tail (CT), and a control vector (NEO) were stably expressed in two pre-B-cell lines that lack endogenous receptor. Genome-wide transcriptional analysis demonstrated that stable CD21 surface expression alone (either CR or CT) produced multiple independent changes in gene expression, though both dramatically decreased class I melanoma-associated antigen (MAGE) family RNAs and upregulated genes associated with B-cell differentiation (e. g., C2TA, HLA-II, IL21R, MIC2, CD48, and PTPRCAP/CD45-associated protein). Temporal analysis spanning 72 h revealed that not only CR-but also CT-expressing lines initiated latency. In spite of this, the number and spectrum of transcripts altered in CR-compared with CT-bearing lines at 1 h after infection further diverged. Differential modulation of immediate early cellular transcripts (e.g., c-Jun and multiple histones), both novel and previously linked to CD21-initiated signaling, as well as distinct results from pathway analyses support a separate role for the cytoplasmic domain in initiation of intracellular signals.