Downregulation of class I major histocompatibility complex surface expression by varicella-zoster virus involves open reading frame 66 protein kinase-dependent and -independent mechanisms
Downregulation of class I major histocompatibility complex surface expression by varicella-zoster virus involves open reading frame 66 protein kinase-dependent and -independent mechanisms
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DOI：
10.1128/jvi.00711-07
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发表时间：
2007-09-01
影响因子：
5.4
通讯作者：
Kinchington, Paul R.
中科院分区：
文献类型：
--
作者：
Eisfeld, Amie J.;Yee, Michael B.;Kinchington, Paul R.
我们在这里表明，水痘带状疱疹病毒（VZV）开放阅读框66（ORF 66）蛋白激酶是一种机制，采用减少I类主要组织相容性复合体（MHC-I）的表面表达VZV感染的细胞。细胞表达增强的绿色荧光蛋白标记的功能性和失活的ORF 66（GFP-66和GFP-66 kd）从复制缺陷型腺病毒载体显示，ORF 66降低MHC-I表面水平依赖于激酶活性的方式。用表达GFP-66的重组VZV感染的细胞表现出比在用GFP-66表达被破坏的VZV感染的细胞中观察到的MHC-I表面表达显著更大的降低。在仅表达GFP-66的腺病毒转导细胞和表达高水平GFP-66的VZV感染细胞中，MHC-I成熟在其从内质网通过高尔基体的运输中被延迟，并且这主要是激酶依赖性的。在VZV感染的细胞中，MHC-I水平降低，并且细胞内MHC-I的分析揭示了在高尔基体区域中折叠的MHC-I的积累，而与ORF 66表达无关。因此，ORF 66激酶对于VZV介导的MHC-I下调是重要的，但也可能涉及其他机制。VZV ORF 9a蛋白（与抗原加工抑制剂UL49.5相关的牛疱疹病毒1型转运蛋白的直系同源物）的分析显示对MHC-I无影响。这些结果确立了病毒蛋白激酶在免疫逃避中的新作用，并表明VZV利用独特的机制来抑制抗原呈递。
We show here that the varicella-zoster virus (VZV) open reading frame 66 (ORF66) protein kinase is one mechanism employed to reduce class I major histocompatibility complex (MHC-I) surface expression in VZV-infected cells. Cells expressing enhanced green fluorescent protein-tagged functional and inactivated ORF66 (GFP-66 and GFP-66kd) from replication-defective adenovirus vectors revealed that ORF66 reduced MHC-I surface levels in a manner dependent on kinase activity. Cells infected with recombinant VZV expressing GFP-66 exhibited a significantly greater reduction in MHC-I surface expression than that observed in cells infected with VZV disrupted in GFP-66 expression. MHC-I maturation was delayed in its transport from the endoplasmic reticulum through the Golgi in both adenovirus-transduced cells expressing only GFP-66 and in VZV-infected cells expressing high levels of GFP-66, and this was predominantly kinase dependent. MHC-I levels were reduced in VZV-infected cells, and analyses of intracellular MHC-I revealed accumulation of folded MHC-I in the Golgi region, irrespective of ORF66 expression. Thus, the ORF66 kinase is important for VZV-mediated MHC-I downregulation, but additional mechanisms also may be involved. Analyses of the VZV ORF9a protein, the ortholog of the bovine herpesvirus 1 transporter associated with antigen processing inhibitor UL49.5 revealed no effects on MHC-I. These results establish a new role for viral protein kinases in immune evasion and suggest that VZV utilizes unique mechanisms to inhibit antigen presentation.