Reactive Oxygen Species-Mediated c-Jun NH2-Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction
Reactive Oxygen Species-Mediated c-Jun NH2-Terminal Kinase Activation Contributes to Hepatitis B Virus X Protein-Induced Autophagy via Regulation of the Beclin-1/Bcl-2 Interaction
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DOI：
10.1128/jvi.00001-17
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发表时间：
2017-05
影响因子：
5.4
通讯作者：
Linmao Zhong;Wangqin Shu;W. Dai;Bo Gao;S. Xiong
中科院分区：
文献类型：
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作者：
Linmao Zhong;Wangqin Shu;W. Dai;Bo Gao;S. Xiong
摘要 自噬与乙型肝炎病毒（HBV）复制的调节密切相关。 HBV X 蛋白 (HBx) 是 HBV 相关生物过程中的多功能调节因子，已被证明对于 HBV 诱导自噬至关重要。然而，HBx诱导自噬的分子机制，特别是所涉及的信号通路，仍然难以捉摸。在本研究中，我们证明 HBx 独立于 I 类磷脂酰肌醇 3 激酶 (PI3K)/AKT/mTOR 信号通路诱导自噬体形成。相比之下，III 类 PI3K(VPS34)/beclin-1 途径被证明对于 HBx 诱导的自噬体形成至关重要。进一步研究表明，HBx 不影响 VPS34 和 beclin-1 表达水平，但抑制 beclin-1/Bcl-2 关联，并且发现 c-Jun NH2 末端激酶 (JNK) 信号传导在此过程中非常重要。此外，发现 HBx 处理会导致活性氧 (ROS) 的产生，而抑制 ROS 活性会消除 JNK 激活和自噬体形成。重要的是，ROS-JNK 信号传导也被发现在 HBV 诱导的自噬体形成和随后的 HBV 复制中发挥重要作用。这些数据可以更深入地了解 HBx 诱导自噬的机制，并有助于设计针对 HBV 感染的新治疗策略。重要性 HBx 在多种 HBV 相关生物过程中发挥着关键作用，包括自噬诱导。然而，HBx诱导自噬的分子机制，特别是所涉及的信号通路，仍然难以捉摸。在本研究中，我们发现 HBx 独立于 I 类 PI3K/AKT/mTOR 信号通路诱导自噬，而 III 类 PI3K(VPS34)/beclin-1 通路对此过程至关重要。进一步的数据表明，HBx 激活 ROS-JNK 导致 beclin-1 从与 Bcl-2 的结合中释放出来，与 VPS34 形成复合物，从而增强自噬体的形成。重要的是，ROS-JNK 信号传导也被证明通过调节自噬诱导对 HBV 复制至关重要。这些数据有助于阐明 HBx/HBV 诱导自噬的分子机制，并可能有助于设计针对 HBV 感染的新治疗方法。
ABSTRACT Autophagy is closely associated with the regulation of hepatitis B virus (HBV) replication. HBV X protein (HBx), a multifunctional regulator in HBV-associated biological processes, has been demonstrated to be crucial for autophagy induction by HBV. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we demonstrated that HBx induced autophagosome formation independently of the class I phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway. In contrast, the class III PI3K(VPS34)/beclin-1 pathway was revealed to be critical for HBx-induced autophagosome formation. Further study showed that HBx did not affect the level of VPS34 and beclin-1 expression but inhibited beclin-1/Bcl-2 association, and c-Jun NH2-terminal kinase (JNK) signaling was found to be important for this process. Moreover, it was found that HBx treatment led to the generation of reactive oxygen species (ROS), and inhibition of ROS activity abrogated both JNK activation and autophagosome formation. Of importance, ROS-JNK signaling was also revealed to play an important role in HBV-induced autophagosome formation and subsequent HBV replication. These data may provide deeper insight into the mechanisms of autophagy induction by HBx and help in the design of new therapeutic strategies against HBV infection. IMPORTANCE HBx plays a key role in diverse HBV-associated biological processes, including autophagy induction. However, the molecular mechanisms of autophagy induction by HBx, especially the signaling pathways involved, remain elusive. In the present investigation, we found that HBx induced autophagy independently of the class I PI3K/AKT/mTOR signaling pathway, while the class III PI3K(VPS34)/beclin-1 pathway was revealed to be crucial for this process. Further data showed that ROS-JNK activation by HBx resulted in the release of beclin-1 from its association with Bcl-2 to form a complex with VPS34, thus enhancing autophagosome formation. Of importance, ROS-JNK signaling was also demonstrated to be critical for HBV replication via regulation of autophagy induction. These data help to elucidate the molecular mechanisms of autophagy induction by HBx/HBV and might be useful for designing novel therapeutic approaches to HBV infection.