Interaction between hepatic membrane type 1 matrix metalloproteinase and acireductone dioxygenase 1 regulates hepatitis C virus infection
Interaction between hepatic membrane type 1 matrix metalloproteinase and acireductone dioxygenase 1 regulates hepatitis C virus infection
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DOI：
10.1111/jvh.12486
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发表时间：
2016-04-01
影响因子：
2.5
通讯作者：
Yeh, C. -T.
中科院分区：
文献类型：
--
作者：
Chang, M. -L.;Huang, Y. -H.;Yeh, C. -T.
膜1型基质金属蛋白酶（MT 1-MMP）结合到富含四跨膜蛋白的微结构域并调节其功能。它还与密蛋白-1和酸还原酮双加氧酶1（ADI 1）发生物理相互作用，两者都与丙型肝炎病毒（HCV）细胞进入相关。在这里，我们研究了MT 1-MMP，ADI 1和claudin-1的肝脏表达以及它们与血清或肝内HCV-RNA水平的物理相互作用。共104例慢性丙型肝炎患者的肝活检和84例手术切除的HCV相关肝细胞癌的非癌部分的肝组织进行了分析。肝活检组织中胞浆ADI 1阳性与较高的血清HCV-RNA水平相关（P=0.009）。通过免疫共沉淀评估的阳性MT 1-MMP和ADI 1相互作用与较低的组织HCV-RNA水平相关（P=0.009）。在MT 1-MMP和ADI 1免疫共沉淀物中，肝脏HCV-RNA水平与ADI 1水平呈正相关（P=0.030）。MT 1-MMP在Huh7.5细胞中的过表达抑制HCV假颗粒的细胞进入以及HCV-infection。ADI 1的共表达可逆转这种抑制作用，且呈剂量依赖性。总之，临床和基于细胞的实验表明，MT 1-MMP和ADI 1之间的物理相互作用导致HCV感染的抑制。这种抑制作用可以通过ADI 1过表达来逆转。
Membrane type 1 matrix metalloproteinase (MT1-MMP) binds to and regulates the function of tetraspanin-enriched microdomains. It also physically interacts with claudin-1 and acireductone dioxygenase 1 (ADI1), both associated with hepatitis C virus (HCV) cell entry. Here, we examined hepatic expression of MT1-MMP, ADI1 and claudin-1 as well as their physical interaction in relation to serum or intrahepatic HCV-RNA levels. A total of 104 liver biopsies obtained from chronic hepatitis C patients and 84 liver tissues obtained from noncancerous parts of surgically removed HCV-related hepatocellular carcinoma were analysed. Positive cytoplasmic ADI1 in liver biopsies was associated with higher serum HCV-RNA levels (P=0.009). Positive MT1-MMP and ADI1 interaction assessed by co-immunoprecipitation was associated with lower tissue HCV-RNA levels (P=0.009). Hepatic HCV-RNA levels were positively associated with ADI1 levels in the MT1-MMP and ADI1 co-immunoprecipitates (P=0.030). Overexpression of MT1-MMP in Huh7.5 cells suppressed cell entry of HCV pseudoparticles as well as HCVcc infection. The suppression effect could be reversed by co-expression of ADI1 in a dose-dependent manner. In summary, clinical and cell-based experiments suggested that physical interaction between MT1-MMP and ADI1 led to suppression of HCV infection. This inhibitory effect could be reversed by ADI1 overexpression.