Distinct functional role of hepatitis C virus core protein on NF-κB regulation is linked to genomic variation
Distinct functional role of hepatitis C virus core protein on NF-κB regulation is linked to genomic variation
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DOI：
10.1016/s0168-1702(02)00046-1
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发表时间：
2002-07-01
期刊：
影响因子：
5
通讯作者：
Ray, R
中科院分区：
文献类型：
--
作者：
Ray, RB;Steele, R;Ray, R
丙型肝炎病毒（HCV）通常会导致长期和持续的感染。HCV基因组中的序列差异表明该病毒的几种基因型和一系列亚型。HCV的核心蛋白具有许多有趣的功能特性，并被认为是病毒介导的致病因素。核因子-κ B（NF-κ B）是一种转录因子，响应炎症信号，激活炎症介质的表达，在细胞增殖过程中发挥作用。在这项研究中，我们研究了NF-κ B的调节HCV核心蛋白克隆从三个不同基因型的分离物。我们的研究结果表明，核心蛋白从HCV基因型Ia抑制NF-κ B的激活，不像其他两个核心基因组区域从HCV基因型1b（BK或台湾）。然而，HCV基因型Ia的位置（K-9至R或N-11至T）中的错义突变减轻了核心蛋白对NF-κ B调节的抑制。有趣的是，体外翻译研究表明，HCV基因型Ia中第11位（N -> T）的氨基酸取代产生了类似于17 kDa的初级蛋白产物，小于亲本序列中明显的主要类似于21 kDa的蛋白条带，或者具有携带突变Lit氨基酸第9位（K -> R）的蛋白条带。然而，类似于17 kDa的蛋白似乎不参与NF-κ B的调节。综上所述，我们目前的数据表明，核心蛋白的基因组变异决定了NF-κ B的独特功能调节，NF-κ B可能在病毒感染早期调节免疫调节分子。(C)2002 Elsevier Science B. V.保留所有权利。
Hepatitis C virus (HCV) often causes a prolonged and persistent infection. Sequence divergence in the HCV genome indicates several genotypes and a series of subtypes for this virus. The core protein of HCV has many intriguing functional properties and is implicated as a factor in virus mediated pathogenesis. Nuclear factor kappaB (NF-kappaB), a transcription factor, responds to inflammatory signals, activates the expression of inflammatory mediators, and plays a role in cell proliferation process. In this study, we have investigated NF-kappaB regulation by HCV core protein cloned from three isolates of different genotypes. Our results suggest that core protein from HCV genotype la represses NF-kappaB activation, unlike two other core genomic regions from HCV genotype 1b (BK or Taiwan). However, missense Mutations in positions (K-9 to R or N-11 to T) of HCV genotype la relieve repression of NF-kappaB regulation by core protein. Interestingly, in vitro translation studies suggested that amino acid substitution at position 11 (N --> T) in HCV genotype la generated a primary protein product of similar to 17 kDa, smaller than the major similar to 21 kDa protein band apparent in the parental sequence or with one carrying mutation Lit amino acid position 9 (K --> R). However, the similar to 17 kDa protein did not appear to be involved in NF-kappaB regulation. Taken together, our present data suggest that genomic variation in the core protein determines a distinct functional regulation of NF-kappaB, which may modulate immunnoregulatory molecules early in viral infection. (C) 2002 Elsevier Science B.V. All rights reserved.