Cochaperone Activity of Human Butyrate-Induced Transcript 1 Facilitates Hepatitis C Virus Replication through an Hsp90-Dependent Pathway
Cochaperone Activity of Human Butyrate-Induced Transcript 1 Facilitates Hepatitis C Virus Replication through an Hsp90-Dependent Pathway
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DOI：
10.1128/jvi.01035-09
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发表时间：
2009-10-15
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：
Taguwa, Shuhei;Kambara, Hiroto;Matsuura, Yoshiharu
丙型肝炎病毒非结构蛋白5A(NS5A)是由多种宿主蛋白和病毒蛋白组成的复制复合体的组成部分。我们先前已经报道，人丁酸诱导转录本1(HB-IND1)通过与NS5A相互作用，将热休克蛋白90(Hsp90)和FK506结合蛋白8(FKBP8)招募到复制复合体中。为了更深入地了解HB-ind1在丙型肝炎病毒复制中的生物学功能，我们评估了HB-ind1的潜在辅助伴侣样活性，因为它与调节Hsp90伴侣活性的辅助伴侣p23有显著的同源性。其中辅伴侣结构域被HB-ind1的p23样结构域取代的嵌合p23显示出与真实p23类似的辅伴侣活性，以Hsp90依赖的方式抑制糖皮质激素受体信号转导。相反，其中p23样结构域被p23的辅伴侣结构域取代的嵌合HB-ind1导致了与在内源性HB-ind1被敲除的细胞中真实的HB-ind1相同水平的丙型肝炎病毒传播的恢复。免疫荧光分析表明，HB-ind1与NS5A、FKBP8和双链RNA共定位于丙型肝炎病毒复制子细胞中。经Hsp90抑制剂处理后，丙型肝炎病毒复制子细胞表现出比亲代细胞和治愈细胞更强的未折叠蛋白反应(UPR)。这些结果表明，包含HB-ind1的Hsp90依赖的伴侣途径参与了膜网络中的蛋白质折叠，以绕过UPR，并促进了丙型肝炎病毒的复制。
Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a component of the replication complex consisting of several host and viral proteins. We have previously reported that human butyrate-induced transcript 1 (hB-ind1) recruits heat shock protein 90 (Hsp90) and FK506-binding protein 8 (FKBP8) to the replication complex through interaction with NS5A. To gain more insights into the biological functions of hB-ind1 in HCV replication, we assessed the potential cochaperone-like activity of hB-ind1, because it has significant homology with cochaperone p23, which regulates Hsp90 chaperone activity. The chimeric p23 in which the cochaperone domain was replaced with the p23-like domain of hB-ind1 exhibited cochaperone activity comparable to that of the authentic p23, inhibiting the glucocorticoid receptor signaling in an Hsp90-dependent manner. Conversely, the chimeric hB-ind1 in which the p23-like domain was replaced with the cochaperone domain of p23 resulted in the same level of recovery of HCV propagation as seen in the authentic hB-ind1 in cells with knockdown of the endogenous hB-ind1. Immunofluorescence analyses revealed that hB-ind1 was colocalized with NS5A, FKBP8, and double-stranded RNA in the HCV replicon cells. HCV replicon cells exhibited a more potent unfolded-protein response (UPR) than the parental and the cured cells upon treatment with an inhibitor for Hsp90. These results suggest that an Hsp90-dependent chaperone pathway incorporating hB-ind1 is involved in protein folding in the membranous web for the circumvention of the UPR and that it facilitates HCV replication.