Cleavage of the hepatitis C virus NS5A protein by caspase-3 in the interferon sensitivity-determining region in a sequence-dependent manner.
Cleavage of the hepatitis C virus NS5A protein by caspase-3 in the interferon sensitivity-determining region in a sequence-dependent manner.
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发表时间：
2004
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通讯作者：
R. Hidajat;M. Nagano‐Fujii;Lin Deng;H. Hotta
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作者：
R. Hidajat;M. Nagano‐Fujii;Lin Deng;H. Hotta
丙型肝炎病毒（HCV）非结构蛋白5A （NS5A）具有多种功能，并与病毒发病机制有关，包括干扰素（IFN）耐药性和肝癌发生。有报道称，在一定条件下，caspase(s)或caspase样酶(s)可将NS5A切割成几个片段。两个裂解位点被定位到Asp残基的位置154和398 （D154和D398）。然而，到目前为止，其他可能的裂解位点尚未确定。在这项研究中，我们证明了caspase-3介导的NS5A在凋亡刺激下的切割，并确定了一个新的位点作为第三个切割靶点。该位点定位于位于IFN敏感性决定区（ISDR）的D251。虽然D251在所有HCV亚型1b （HCV-1b）测试株中保守，但由于ISDR中248位的序列变异，一致的caspase-3识别序列（D248-X-X-D251）未保守。此外，A252被发现是有效切割NS5A所必需的。HCV毒株依赖性NS5A在该位点裂解的病毒学意义有待进一步研究。
Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) has versatile functions and has been implicated in viral pathogenesis, including interferon (IFN) resistance and hepatocarcinogenesis. It has been reported that NS5A is cleaved into a few fragments by a caspase(s) or caspase-like enzyme(s) under certain conditions. Two cleavage sites have been mapped to the Asp residues at positions 154 and 398 (D154 and D398). However, other possible cleavage sites were not determined yet so far. In this study, we demonstrated caspase-3-mediated NS5A cleavage upon apoptotic stimuli and identified a new site as the third cleavage target. This site was mapped to D251, which lies within IFN sensitivity-determining region (ISDR). Although D251 was conserved among all HCV subtype 1b (HCV-1b) strains tested, the consensus caspase-3 recognition sequence (D248-X-X-D251) was not conserved due to the sequence variation at position 248 in ISDR. Furthermore, A252 was found to be necessary for efficient cleavage of NS5A. The virological significance of the HCV strain-dependent NS5A cleavage at this site awaits further investigation.