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首页> 美国卫生研究院文献>Journal of Virology >Characterization of Hepatitis C Virus Core Protein Multimerization and Membrane Envelopment: Revelation of a Cascade of Core-Membrane Interactions
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Characterization of Hepatitis C Virus Core Protein Multimerization and Membrane Envelopment: Revelation of a Cascade of Core-Membrane Interactions

机译：丙型肝炎病毒核心蛋白多聚化和膜包被的表征：一连串的核心-膜相互作用的启示。

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The molecular basis underlying hepatitis C virus (HCV) core protein maturation and morphogenesis remains elusive. We characterized the concerted events associated with core protein multimerization and interaction with membranes. Analyses of core proteins expressed from a subgenomic system showed that the signal sequence located between the core and envelope glycoprotein E1 is critical for core association with endoplasmic reticula (ER)/late endosomes and the core's envelopment by membranes, which was judged by the core's acquisition of resistance to proteinase K digestion. Despite exerting an inhibitory effect on the core's association with membranes, (Z-LL)2-ketone, a specific inhibitor of signal peptide peptidase (SPP), did not affect core multimeric complex formation, suggesting that oligomeric core complex formation proceeds prior to or upon core attachment to membranes. Protease-resistant core complexes that contained both innate and processed proteins were detected in the presence of (Z-LL)2-ketone, implying that core envelopment occurs after intramembrane cleavage. Mutations of the core that prevent signal peptide cleavage or coexpression with an SPP loss-of-function D219A mutant decreased the core's envelopment, demonstrating that SPP-mediated cleavage is required for core envelopment. Analyses of core mutants with a deletion in domain I revealed that this domain contains sequences crucial for core envelopment. The core proteins expressed by infectious JFH1 and Jc1 RNAs in Huh7 cells also assembled into a multimeric complex, associated with ER/late-endosomal membranes, and were enveloped by membranes. Treatment with (Z-LL)2-ketone or coexpression with D219A mutant SPP interfered with both core envelopment and infectious HCV production, indicating a critical role of core envelopment in HCV morphogenesis. The results provide mechanistic insights into the sequential and coordinated processes during the association of the HCV core protein with membranes in the early phase of virus maturation and morphogenesis.
机译：丙型肝炎病毒（HCV）核心蛋白成熟和形态发生的分子基础仍然难以捉摸。我们表征了与核心蛋白多聚化和与膜相互作用有关的协同事件。从亚基因组系统表达的核心蛋白的分析表明，位于核心和包膜糖蛋白E1之间的信号序列对于核心与内质网（ER）/晚期内体的结合以及核心被膜包被至关重要，这由核心的获取来判断对蛋白酶K消化的抵抗力。尽管对核心与膜的结合有抑制作用，但信号肽肽酶（SPP）的特异性抑制剂（Z-LL）2-酮不会影响核心多聚体复合物的形成，表明寡聚核心复合物的形成先于或在核心附着到膜上。在（Z-LL）2-酮的存在下检测到既含有先天又含有加工蛋白的抗蛋白酶核心复合物，这意味着核心被膜在膜内裂解后发生。防止信号肽裂解或与SPP功能丧失的共表达的核心突变D219A突变体降低了核心的包封，表明核心封装需要SPP介导的裂解。对结构域I中缺失的核心突变体的分析表明，该结构域包含对于核心包被至关重要的序列。 Huh7细胞中由感染性JFH1和Jc1 RNAs表达的核心蛋白也组装成与ER /晚期内体膜相关的多聚体复合物，并被膜包裹。用（Z-LL）2-酮处理或与D219A突变体SPP共表达既干扰核心包膜又感染HCV的产生，表明核心包膜在HCV形态发生中起关键作用。结果为在病毒成熟和形态发生的早期阶段HCV核心蛋白与膜结合过程中的顺序和协调过程提供了机械学见解。

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