Inhibition of heavy chain and β2-microglobulin synthesis as a mechanism of major histocompatibility complex class I downregulation during Epstein-Barr virus replication
Inhibition of heavy chain and β2-microglobulin synthesis as a mechanism of major histocompatibility complex class I downregulation during Epstein-Barr virus replication
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DOI：
10.1128/jvi.01999-06
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发表时间：
2007-02-01
影响因子：
5.4
通讯作者：
Levitsky, Victor
中科院分区：
文献类型：
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作者：
Guerreiro-Cacais, Andre Ortlieb;Uzunel, Mehmet;Levitsky, Victor
EB病毒复制过程中主要组织相容性复合体（MHC）I类下调的机制还没有得到很好的表征。在这里，我们表明，在几个细胞系感染的重组EBV株编码绿色荧光蛋白（GFP），病毒裂解周期与GFP的表达，从而可以作为一个标志物的病毒复制。EBV复制导致MHC II类和所有经典的MHC I类等位基因的下调，独立于病毒DNA合成或晚期基因表达。尽管组装的MHC I类复合物、总重链库和β 2-微球蛋白（β 2 m）显著下调，但游离的I类重链在复制EBV的细胞表面稳定。钙连接蛋白在GFP（+）细胞中表达增加，并且钙连接蛋白和钙网蛋白在细胞表面积累，这可能有助于I类重链的稳定。另一种分子伴侣ERp 57和TAP 2（一种与抗原加工和呈递相关的转运蛋白）表达水平的降低与MHC I类成熟的延迟动力学相关。I类重链和β（2）m mRNA的水平均降低，代谢标记实验表明裂解感染细胞中I类重链合成速率非常低。通过药理学抑制潜伏感染细胞中的蛋白质合成来模拟MHC I类和MHC II类下调。我们的数据表明，虽然有几种机制可能有助于MHC I类分子在EBV复制过程中的下调，抑制MHC I类分子的合成发挥了主要作用的过程中。
The mechanisms of major histocompatibility complex (MHC) class I downregulation during Epstein-Barr virus (EBV) replication are not well characterized. Here we show that in several cell lines infected with a recombinant EBV strain encoding green fluorescent protein (GFP), the virus lytic cycle coincides with GFP expression, which thus can be used as a marker of virus replication. EBV replication resulted in downregulation of MHC class II and all classical MHC class I alleles independently of viral DNA synthesis or late gene expression. Although assembled MHC class I complexes, the total pool of heavy chains, and beta(2)-microglobulin (beta(2)m) were significantly downregulated, free class I heavy chains were stabilized at the surface of cells replicating EBV. Calnexin expression was increased in GFP(+) cells, and calnexin and calreticulin accumulated at the cell surface that could contribute to the stabilization of class I heavy chains. Decreased expression levels of another chaperone, ERp57, and TAP2, a transporter associated with antigen processing and presentation, correlated with delayed kinetics of MHC class I maturation. Levels of both class I heavy chain and beta(2)m mRNA were reduced, and metabolic labeling experiments demonstrated a very low rate of class I heavy chain synthesis in lytically infected cells. MHC class I and MHC class II downregulation was mimicked by pharmacological inhibition of protein synthesis in latently infected cells. Our data suggest that although several mechanisms may contribute to MHC class I downregulation in the course of EBV replication, inhibition of MHC class I synthesis plays the primary role in the process.