Human VAP-C Negatively Regulates Hepatitis C Virus Propagation
Human VAP-C Negatively Regulates Hepatitis C Virus Propagation
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DOI：
10.1128/jvi.00889-09
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发表时间：
2009-08-15
影响因子：
5.4
通讯作者：
Matsuura, Yoshiharu
中科院分区：
文献类型：
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作者：
Kukihara, Hiroshi;Moriishi, Kohji;Matsuura, Yoshiharu
人囊泡相关膜蛋白相关蛋白（VAP）A亚型（VAP-A）和B亚型（VAP-B）参与膜转运、脂质转运和代谢以及未折叠蛋白应答的调节。VAP-A和VAP-B由主要精子蛋白（MSP）结构域、卷曲螺旋基序和C-末端跨膜锚组成，并通过跨膜结构域形成同源和异源二聚体。VAP-A和VAP-B分别通过MSP结构域和卷曲螺旋基序与丙型肝炎病毒（HCV）的NS 5 B和NS 5A相互作用，并参与HCV的复制。VAP-C是VAP-B的剪接变体，其由VAP-B的MSP结构域的N-末端的一半以及随后的亚型特异性移码序列组成，并且其生物学功能尚未被很好地表征。在这项研究中，我们研究了VAP-C在HCV传播中的生物学功能。免疫沉淀分析表明，VAP-C与NS 5 B相互作用，而与VAP-A、VAP-B、NS 5A不相互作用，VAP-C的表达抑制NS 5 B与VAP-A、VAP-B的相互作用。VAP-C的过表达损害了HCV复制子的RNA复制和HCV JFH 1株的繁殖，而VAP-A和VAP-B的过表达增强了复制。此外，在各种组织中观察到VAP-C的表达，而在肝脏中几乎检测不到。这些结果表明，VAP-C作为HCV传播的负调节因子，并且VAP-C的表达可能参与决定HCV传播的组织嗜性。
Human vesicle-associated membrane protein-associated protein (VAP) subtype A (VAP-A) and subtype B (VAP-B) are involved in the regulation of membrane trafficking, lipid transport and metabolism, and the unfolded protein response. VAP-A and VAP-B consist of the major sperm protein (MSP) domain, the coiled-coil motif, and the C-terminal transmembrane anchor and form homo- and heterodimers through the transmembrane domain. VAP-A and VAP-B interact with NS5B and NS5A of hepatitis C virus (HCV) through the MSP domain and the coiled-coil motif, respectively, and participate in the replication of HCV. VAP-C is a splicing variant of VAP-B consisting of the N-terminal half of the MSP domain of VAP-B followed by the subtype-specific frameshift sequences, and its biological function has not been well characterized. In this study, we have examined the biological functions of VAP-C in the propagation of HCV. VAP-C interacted with NS5B but not with VAP-A, VAP-B, or NS5A in immunoprecipitation analyses, and the expression of VAP-C inhibited the interaction of NS5B with VAP-A or VAP-B. Overexpression of VAP-C impaired the RNA replication of the HCV replicon and the propagation of the HCV JFH1 strain, whereas overexpression of VAP-A and VAP-B enhanced the replication. Furthermore, the expression of VAP-C was observed in various tissues, whereas it was barely detected in the liver. These results suggest that VAP-C acts as a negative regulator of HCV propagation and that the expression of VAP-C may participate in the determination of tissue tropism of HCV propagation.