Mann Elizabeth A, Stanford Sandra, Sherman Kenneth E
Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, 231 Albert B. Sabin Way, OH 55267-0595, USA.
Virus Res. 2006 Oct;121(1):51-7. doi: 10.1016/j.virusres.2006.04.001. Epub 2006 May 24.
The hepatitis C virus (HCV) core protein is a key structural element of the virion but also affects a number of cellular pathways, including nuclear factor kappaB (NF-kappaB) signaling. NF-kappaB is a transcription factor that regulates both anti-apoptotic and pro-inflammatory genes and its activation may contribute to HCV-mediated pathogenesis. Amino acid sequence divergence in core is seen at the genotype level as well as within patient isolates. Recent work has implicated amino acids 9-11 of core in the modulation of NF-kappaB activation. We report that the sequence RKT is highly conserved (93%) at this position across all HCV genotypes, based on sequences collected in the Los Alamos HCV database. Of the 13 types of variants present in the database, the two most prevalent substitutions are RQT and RKP. We further show that core encoding RKP fails to activate NF-kappaB signaling in vitro while NF-kappaB activation by core encoding RQT does not differ from control RKT core. The effect of RKP core is specific to NF-kappaB signaling as activator protein 1 (AP-1) activity is not altered. Further studies are needed to assess potential associations between specific amino acid substitutions at positions 9-11 and liver disease progression and/or response to treatment in individual patients.
丙型肝炎病毒（HCV）核心蛋白是病毒粒子的关键结构元件，但也会影响许多细胞信号通路，包括核因子κB（NF-κB）信号通路。NF-κB是一种转录因子，可调节抗凋亡和促炎基因，其激活可能有助于HCV介导的发病机制。核心蛋白的氨基酸序列差异在基因型水平以及患者分离株中均可见。最近的研究表明，核心蛋白的9-11位氨基酸参与调节NF-κB的激活。基于洛斯阿拉莫斯HCV数据库中收集的序列，我们报告序列RKT在所有HCV基因型的该位置高度保守（93%）。数据库中存在的13种变异类型中，最常见的两种替代是RQT和RKP。我们进一步表明，编码RKP的核心蛋白在体外不能激活NF-κB信号通路，而编码RQT的核心蛋白激活NF-κB的能力与对照RKT核心蛋白无差异。RKP核心蛋白的作用对NF-κB信号通路具有特异性，因为激活蛋白1（AP-1）的活性未改变。需要进一步研究来评估9-11位特定氨基酸替代与个体患者肝病进展和/或治疗反应之间的潜在关联。
