Hepatitis C Virus NS5A Hijacks ARFGAP1 To Maintain a Phosphatidylinositol 4-Phosphate-Enriched Microenvironment
Hepatitis C Virus NS5A Hijacks ARFGAP1 To Maintain a Phosphatidylinositol 4-Phosphate-Enriched Microenvironment
复制标题
丙型肝炎病毒 NS5A 劫持 ARFGAP1 以维持富含磷脂酰肌醇 4-磷酸盐的微环境
DOI：
10.1128/jvi.03738-13
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发表时间：
2014-06-01
影响因子：
5.4
通讯作者：
Zhang, Leiliang
中科院分区：
文献类型：
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作者：
Li, Hongyan;Yang, Xiaojie;Zhang, Leiliang
摘要众所周知，磷脂酰肌醇4-磷酸（PI 4 P）在丙型肝炎病毒（HCV）复制过程中上调。PI 4激酶在HCV中的作用已被广泛研究。HCV是否改变了PI 4P磷酸酶Sac 1仍不清楚。在这里，我们确定ARFGAP 1是一种新的宿主因子HCV复制。我们进一步表明Sac 1与ARFGAP 1相互作用并抑制HCV复制。当外壳体蛋白I（COPI）途径被抑制时，HCV NS 5A诱导的PI 4P升高被废除。我们还发现NS 5A和ARFGAP 1之间存在相互作用。此外，我们确定了一个保守的带正电荷的氨基酸在NS 5A和ARFGAP 1之间的相互作用，诱导PI 4P，HCV复制的关键NS 5A簇。我们的数据表明，ARFGAP 1是HCV RNA复制的宿主因子。ARFGAP 1被HCV NS 5A劫持，从HCV复制位点移除COPI货物Sac 1，以维持高水平的PI 4P。我们的研究结果提供了一种额外的机制，通过这种机制，HCV增强了富含PI 4P的环境的形成。重要性PI 4P在HCV的复制区富集;然而，PI 4P磷酸酶Sac 1是否被HCV破坏尚未确定。COPI如何促进病毒复制的详细机制仍然未知，尽管COPI组分被HCV劫持。我们证明了ARFGAP 1被HCV NS 5A劫持，从HCV复制区移除COPI货物Sac 1，以维持NS 5A产生的高水平PI 4P。此外，我们确定了一个保守的带正电荷的氨基酸在NS 5A，这是至关重要的NS 5A和ARFGAP 1之间的相互作用，诱导PI 4P和HCV复制。这项研究将揭示其他RNA病毒如何劫持COPI和Sac 1的机制。
ABSTRACT Phosphatidylinositol 4-phosphate (PI4P) is well known to be upregulated during hepatitis C virus (HCV) replication. The role of PI4 kinases in HCV has been extensively investigated. Whether the PI4P phosphatase Sac1 is altered by HCV remains unclear. Here, we identified ARFGAP1 to be a novel host factor for HCV replication. We further show that Sac1 interacts with ARFGAP1 and inhibits HCV replication. The elevation of PI4P induced by HCV NS5A is abrogated when the coatomer protein I (COPI) pathway is inhibited. We also found an interaction between NS5A and ARFGAP1. Furthermore, we identified a conserved cluster of positively charged amino acids in NS5A critical for interaction between NS5A and ARFGAP1, induction of PI4P, and HCV replication. Our data demonstrate that ARFGAP1 is a host factor for HCV RNA replication. ARFGAP1 is hijacked by HCV NS5A to remove COPI cargo Sac1 from the site of HCV replication to maintain high levels of PI4P. Our findings provide an additional mechanism by which HCV enhances formation of a PI4P-rich environment. IMPORTANCE PI4P is enriched in the replication area of HCV; however, whether PI4P phosphatase Sac1 is subverted by HCV is not established. The detailed mechanism of how COPI contributes to viral replication remains unknown, though COPI components were hijacked by HCV. We demonstrate that ARFGAP1 is hijacked by HCV NS5A to remove COPI cargo Sac1 from the HCV replication area to maintain high-level PI4P generated by NS5A. Furthermore, we identify a conserved cluster of positively charged amino acids in NS5A, which are critical for interaction between NS5A and ARFGAP1, induction of PI4P, and HCV replication. This study will shed mechanistic insight on how other RNA viruses hijack COPI and Sac1.