Granzyme H of Cytotoxic Lymphocytes Is Required for Clearance of the Hepatitis B Virus through Cleavage of the Hepatitis B Virus X Protein
Granzyme H of Cytotoxic Lymphocytes Is Required for Clearance of the Hepatitis B Virus through Cleavage of the Hepatitis B Virus X Protein
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细胞毒性淋巴细胞的颗粒酶 H 是通过裂解乙型肝炎病毒 X 蛋白清除乙型肝炎病毒所必需的
DOI：
10.4049/jimmunol.1102205
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Fan, Zusen
中科院分区：
文献类型：
--
作者：
Tang, Haidong;Li, Chong;Wang, Li;Zhang, Honglian;Fan, Zusen
细胞毒性淋巴细胞的颗粒胞吐途径在清除细胞内病毒中起着关键作用。然而，如何清除B型肝炎病毒（HBV）尚未确定。为了阐明抑制HBV复制的免疫机制，研究了颗粒酶H（GzmH）与HBV清除的关系。在这项研究中，我们发现颗粒胞吐途径可以抑制HBV复制，而不诱导感染细胞的细胞溶解。GzmH对于HBV根除至关重要。HBV复制所需的HBx蛋白（HBx）在Met 79处被GzmH切割。GzmH抑制剂可阻断GzmH和淋巴因子激活的杀伤细胞介导的HBx降解和HBV清除。HBx缺陷型HBV对GzmH和淋巴因子激活的杀伤细胞介导的病毒清除具有抗性。将GzmH过表达的NK细胞连续转移到HBV携带者小鼠中有助于体内HBV根除。重要的是，GzmH在细胞毒性淋巴细胞中的低表达对HBV感染和肝细胞癌易感。这些结果表明，GzmH检测可能作为一个潜在的参数，用于诊断HBV感染和肝细胞癌。
The granule exocytosis pathway of cytotoxic lymphocytes plays critical roles in eradication of intracellular viruses. However, how hepatitis B virus (HBV) is cleared has not been defined. To clarify immune mechanisms underlying inhibition of the HBV replication, the relationship between granzyme H (GzmH) and HBV clearance was investigated. In this study, we found that the granule exocytosis pathway can inhibit HBV replication without induction of cytolysis of the infected cells. GzmH is essential for HBV eradication. The HBx protein (HBx), required for the replication of HBV, is cleaved at Met79 by GzmH. GzmH inhibitor can abolish GzmH- and lymphokine-activated killer cell-mediated HBx degradation and HBV clearance. An HBx-deficient HBV is resistant to GzmH- and lymphokine-activated killer cell-mediated viral clearance. Adoptive transfer of GzmH-overexpressing NK cells into HBV carrier mice facilitates in vivo HBV eradication. Importantly, low GzmH expression in cytotoxic lymphocytes of individuals is susceptible to HBV infection and hepatocellular carcinoma. These results indicate that GzmH might be detected as a potential parameter for diagnosis of HBV infection and hepatocellular carcinoma.
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DOI：
10.1073/pnas.0913498107
发表时间：
2010-01-12
影响因子：
11.1
作者：
Yang, Priscilla L.;Althage, Alana;Chisari, Francis V.
通讯作者：
Chisari, Francis V.
影响因子：
12.4
作者：
T. Zhao;Honglian Zhang;Yuting Guo;Qianjing Zhang;G. Hua;Hongxia Lu;Q. Hou;H. Liu;Z. Fan
通讯作者：
T. Zhao;Honglian Zhang;Yuting Guo;Qianjing Zhang;G. Hua;Hongxia Lu;Q. Hou;H. Liu;Z. Fan
影响因子：
5.4
作者：
Leupin, O;Bontron, S;Strubin, M
通讯作者：
Strubin, M
影响因子：
3.8
作者：
Henkler, F;Hoare, J;King, IA
通讯作者：
King, IA
影响因子：
14.8
作者：
Cooper, Maggie S.;Sabbah, Emmanuelle;Mather, Stephen J.
通讯作者：
Mather, Stephen J.