乙型肝炎病毒打乱线粒体动态：诱导裂变和线粒体自噬减弱

StephenW

Research Article
Hepatitis B Virus Disrupts Mitochondrial Dynamics: Induces Fission and Mitophagy to Attenuate Apoptosis

    Seong-Jun Kim,

    Mohsin Khan,

    Jun Quan,

    Andreas Till,

    Suresh Subramani,

    Aleem Siddiqui

    Published: December 05, 2013
    DOI: 10.1371/journal.ppat.1003722


Abstract

Human hepatitis B virus (HBV) causes chronic hepatitis and is associated with the development of hepatocellular carcinoma. HBV infection alters mitochondrial metabolism. The selective removal of damaged mitochondria is essential for the maintenance of mitochondrial and cellular homeostasis. Here, we report that HBV shifts the balance of mitochondrial dynamics toward fission and mitophagy to attenuate the virus-induced apoptosis. HBV induced perinuclear clustering of mitochondria and triggered mitochondrial translocation of the dynamin-related protein (Drp1) by stimulating its phosphorylation at Ser616, leading to mitochondrial fission. HBV also stimulated the gene expression of Parkin, PINK1, and LC3B and induced Parkin recruitment to the mitochondria. Upon translocation to mitochondria, Parkin, an E3 ubiquitin ligase, underwent self-ubiquitination and facilitated the ubiquitination and degradation of its substrate Mitofusin 2 (Mfn2), a mediator of mitochondrial fusion. In addition to conventional immunofluorescence, a sensitive dual fluorescence reporter expressing mito-mRFP-EGFP fused in-frame to a mitochondrial targeting sequence was employed to observe the completion of the mitophagic process by delivery of the engulfed mitochondria to lysosomes for degradation. Furthermore, we demonstrate that viral HBx protein plays a central role in promoting aberrant mitochondrial dynamics either when expressed alone or in the context of viral genome. Perturbing mitophagy by silencing Parkin led to enhanced apoptotic signaling, suggesting that HBV-induced mitochondrial fission and mitophagy promote cell survival and possibly viral persistence. Altered mitochondrial dynamics associated with HBV infection may contribute to mitochondrial injury and liver disease pathogenesis.

StephenW

研究论文
乙型肝炎病毒打乱线粒体动态：诱导裂变和线粒体自噬减弱细胞凋亡

    诚俊金，

    穆赫辛·汗，

    俊泉，

    安德烈亚斯截止，

    苏雷什SUBRAMANI ，

    西迪基ALEEM

    发布时间： 2013年12月5日
    DOI ： 10.1371/journal.ppat.1003722


摘要

人类乙型肝炎病毒（HBV）引起的慢性肝炎，并与肝细胞癌的发展相关联。 HBV感染改变线粒体代谢。选择性地除去受损的线粒体是线粒体和细胞内环境稳定的维持所必需的。在这里，我们报告说，乙肝病毒移向裂变和线粒体自噬减弱病毒诱导的细胞凋亡的线粒体动力学的平衡。乙肝病毒引起的线粒体核周聚集，并引发了与dynamin相关蛋白（ DRP1 ）的线粒体易位通过刺激其磷酸化Ser616 ，导致线粒体分裂。乙肝病毒也刺激帕金， PINK1和LC3B和基因表达诱导帕金招聘到线粒体。一旦易位到线粒体​​，帕金，一个E3泛素连接酶，进行自我泛素化和促进其底物线粒体融合蛋白2 （ Mfn2的） ，线粒体融合的调解员的泛素化和降解。除了常规免疫，表达线粒体MRFP -EGFP一个敏感的双荧光报告框融合到线粒体定位序列是受雇于交付吞噬线粒体的观察完成的mitophagic过程中溶酶体降解。此外，我们证明，病毒HBx蛋白对促进单独或病毒基因组的上下文中表达时异常线粒体动力学的核心作用。通过沉默帕金扰动线粒体自噬导致增强的凋亡信号，表明乙肝病毒诱导的线粒体裂变和线粒体自噬促进细胞存活，并可能病毒持续感染。与乙肝病毒感染相关的改变线粒体的动态可能有助于线粒体损伤和肝脏疾病的发病机制。