State Key Laboratory of Virology, College of Life Sciences, and Chinese-French Liver Disease Research Institute at Zhongnan Hospital, Wuhan University, Wuhan, China.
J Virol. 2012 Dec;86(23):12531-43. doi: 10.1128/JVI.01136-12. Epub 2012 Sep 5.
Hepatitis C virus (HCV) infection is associated with numerous liver diseases and causes serious global health problems, but the mechanisms underlying the pathogenesis of HCV infections remain largely unknown. In this study, we demonstrate that signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-2 (MMP-2), and B-cell lymphoma 2 (Bcl-2) are significantly stimulated in HCV-infected patients. We further show that HCV activates STAT3, MMP-2, Bcl-2, extracellular regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK) in infected Huh7.5.1 cells. Functional screening of HCV proteins revealed that nonstructural protein 4B (NS4B) is responsible for the activation of MMP-2 and Bcl-2 by stimulating STAT3 through repression of the suppressor of cytokine signaling 3 (SOCS3). Our results also demonstrate that multiple signaling cascades, including several members of the protein kinase C (PKC) family, JNK, ERK, and STAT3, play critical roles in the activation of MMP-2 and Bcl-2 mediated by NS4B. Further studies revealed that the C-terminal domain (CTD) of NS4B is sufficient for the activation of STAT3, JNK, ERK, MMP-2, and Bcl-2. We also show that amino acids 227 to 250 of NS4B are essential for regulation of STAT3, JNK, ERK, MMP-2, and Bcl-2, and among them, three residues (237L, 239S, and 245L) are crucial for this regulation. Thus, we reveal a novel mechanism underlying HCV pathogenesis in which multiple intracellular signaling cascades are cooperatively involved in the activation of two important cellular factors, MMP-2 and Bcl-2, in response to HCV infection.
丙型肝炎病毒 (HCV) 感染与多种肝脏疾病有关，并导致严重的全球健康问题，但 HCV 感染发病机制的机制在很大程度上仍然未知。在这项研究中，我们证明了 HCV 感染患者中的信号转导和转录激活因子 3（STAT3）、基质金属蛋白酶-2（MMP-2）和 B 细胞淋巴瘤 2（Bcl-2）显着受到刺激。我们进一步表明，HCV 在感染的 Huh7.5.1 细胞中激活 STAT3、MMP-2、Bcl-2、细胞外调节蛋白激酶（ERK）和 c-Jun N-末端激酶（JNK）。HCV 蛋白的功能筛选表明，非结构蛋白 4B（NS4B）通过抑制细胞因子信号转导抑制剂 3（SOCS3）刺激 STAT3 激活 MMP-2 和 Bcl-2。我们的结果还表明，包括蛋白激酶 C（PKC）家族的多个成员、JNK、ERK 和 STAT3 在内的多种信号级联在 NS4B 介导的 MMP-2 和 Bcl-2 的激活中起关键作用。进一步的研究表明，NS4B 的 C 末端结构域（CTD）足以激活 STAT3、JNK、ERK、MMP-2 和 Bcl-2。我们还表明，NS4B 的 227 至 250 个氨基酸残基对于调节 STAT3、JNK、ERK、MMP-2 和 Bcl-2 是必需的，其中三个残基（237L、239S 和 245L）对于这种调节至关重要。因此，我们揭示了 HCV 发病机制的一种新机制，其中多种细胞内信号级联反应协同参与 HCV 感染后两种重要细胞因子 MMP-2 和 Bcl-2 的激活。
