The vaccinia virus K1L gene product inhibits host NF-κB activation by preventing IκBα degradation
The vaccinia virus K1L gene product inhibits host NF-κB activation by preventing IκBα degradation
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DOI：
10.1128/jvi.78.7.3553-3560.2004
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发表时间：
2004-04-01
影响因子：
5.4
通讯作者：
Jin, XL
中科院分区：
文献类型：
--
作者：
Shisler, JL;Jin, XL
牛痘病毒野生型菌株，如Ankara和WR，能够合成能够抑制宿主NF-kappaB激活的蛋白质，NF-kappaB是调节炎症基因表达的转录因子家族。相比之下，由减毒MVA菌株感染，其基因结构缺乏其安卡拉亲本DNA中存在的许多免疫调节基因，诱导NF-kappaB激活。然后，将NF-kappaB抑制基因插入MVA DNA中，将改变MVA表型。通过这种方法，在感染MVA/5.2kb病毒的细胞中，含有K1L基因和MVA基因组中不存在的另外两个基因的5.2kb安卡拉DNA区域被鉴定为NF-kappaB被抑制。为了确定K1L是否起作用，我们检测了含有WR菌株K1L拷贝的重组MVA （MVA/K1L）和缺乏K1L基因的WR缺失突变体（DeltaK1L）的相关生物学特性。事实上，与它的祖先不同，改变的MVA阻止了宿主调节蛋白ikappabα的降解——这是NF-kappaB因子转录激活途径中的关键事件。此外，MVA/K1L获得了分别抑制人工和天然nf - kappab调控的转染荧光素酶和细胞肿瘤坏死因子基因表达的能力。相比之下，尽管这些功能也可以由WR执行，但DeltaK1L病毒失去了这些能力。因此，K1L的一个明显的分子功能是防止IkappaBalpha降解。这种对nf - kappab诱导的宿主促炎基因表达的阻碍反过来可能会提高病毒的存活率。
Vaccinia virus wild-type strains such as Ankara and WR synthesize proteins capable of inhibiting the activation of host NF-kappaB, a family of transcription factors that regulate the expression of inflammatory genes. In contrast, an infection by the attenuated MVA strain, whose gedome lacks many immunoregulatory genes present in the DNA of its Ankara parent, induces NF-kappaB activation. Insertion of NF-kappaB inhibitory genes into the MVA DNA, then, would alter the MVA phenotype. By this method, a 5.2-kb region of Ankara DNA containing the K1L gene and two other genes that are absent in the MVA genome that was identified as NF-kappaB was inhibited in cells infected with the MVA/5.2kb virus. To determine if K1L was responsible, the relevant biological properties of both a recombinant MVA containing a copy of the WR strain's K1L (MVA/K1L) and a WR deletion mutant lacking the K1L gene (DeltaK1L) were examined. Indeed, unlike its progenitor, the altered MVA halted degradation of the host regulatory protein IkappaBalpha-a key event in the pathway of transcriptional activation by NF-kappaB factors. Moreover, MVA/K1L gained the ability to repress artificially contrived and natural NF-kappaB-regulated expression of a transfected luciferase and the cellular tumor necrosis factor gene, respectively. In contrast, although these functions could also be performed by WR, the DeltaK1L virus lost these abilities. Thus, one apparent molecular function of K1L is to prevent IkappaBalpha degradation. This impediment to NF-kappaB-induced host proinflammatory gene expression, in turn, might enhance virus survival.