Involvement of FKBP6 in hepatitis C virus replication.
Involvement of FKBP6 in hepatitis C virus replication.
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DOI：
10.1038/srep16699
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发表时间：
2015-11-16
影响因子：
4.6
通讯作者：
Moriishi K
中科院分区：
文献类型：
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作者：
Kasai H;Kawakami K;Yokoe H;Yoshimura K;Matsuda M;Yasumoto J;Maekawa S;Yamashita A;Tanaka T;Ikeda M;Kato N;Okamoto T;Matsuura Y;Sakamoto N;Enomoto N;Takeda S;Fujii H;Tsubuki M;Kusunoki M;Moriishi K
已知伴侣系统被病毒利用来进行复制。在本研究中，我们确定辅助伴侣 FKBP6 是丙型肝炎病毒 (HCV) 复制所需的宿主因子。 FKBP6 是一种肽基脯氨酰顺反异构酶，具有四三肽重复 (TPR) 的三个结构域，但缺乏 FK-506 结合能力。 FKBP6 与 HCV 非结构蛋白 5A (NS5A) 相互作用，还与 FKBP6 本身或 FKBP8 形成复合物，已知该复合物对于 HCV 复制至关重要。 NS5A 的 Val121 和 FKBP6 的 TPR 结构域负责 NS5A 和 FKBP6 之间的相互作用。在 HCV 感染的细胞中，FKBP6 与 NS5A、FKBP8 和双链 RNA 共定位。在 FKBP6 敲除的肝癌细胞系中，HCV 复制被完全抑制，而 FKBP6 的表达在 FKBP6 敲除的细胞中恢复了 HCV 复制。 FKBP8抑制剂N-(N',N'-二甲基甲酰胺甲基)放线菌酮治疗损害了由FKBP6和/或FKBP8组成的同源或异源复合物的形成，并抑制了HCV复制。 HCV感染促进培养细胞和人肝组织中FKBP6的表达，但不促进FKBP8的表达。这些结果表明FKBP6是HCV诱导的宿主因子，与NS5A协同支持病毒复制。
The chaperone system is known to be exploited by viruses for their replication. In the present study, we identified the cochaperone FKBP6 as a host factor required for hepatitis C virus (HCV) replication. FKBP6 is a peptidyl prolyl cis-trans isomerase with three domains of the tetratricopeptide repeat (TPR), but lacks FK-506 binding ability. FKBP6 interacted with HCV nonstructural protein 5A (NS5A) and also formed a complex with FKBP6 itself or FKBP8, which is known to be critical for HCV replication. The Val121 of NS5A and TPR domains of FKBP6 were responsible for the interaction between NS5A and FKBP6. FKBP6 was colocalized with NS5A, FKBP8, and double-stranded RNA in HCV-infected cells. HCV replication was completely suppressed in FKBP6-knockout hepatoma cell lines, while the expression of FKBP6 restored HCV replication in FKBP6-knockout cells. A treatment with the FKBP8 inhibitor N-(N′, N′-dimethylcarboxamidomethyl)cycloheximide impaired the formation of a homo- or hetero-complex consisting of FKBP6 and/or FKBP8, and suppressed HCV replication. HCV infection promoted the expression of FKBP6, but not that of FKBP8, in cultured cells and human liver tissue. These results indicate that FKBP6 is an HCV-induced host factor that supports viral replication in cooperation with NS5A.