Hepatitis B virus disrupts mitochondrial dynamics: induces fission and mitophagy to attenuate apoptosis.
Hepatitis B virus disrupts mitochondrial dynamics: induces fission and mitophagy to attenuate apoptosis.
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DOI：
10.1371/journal.ppat.1003722
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Siddiqui A
中科院分区：
文献类型：
--
作者：
Kim SJ;Khan M;Quan J;Till A;Subramani S;Siddiqui A
人肝炎B病毒（HBV）引起慢性肝炎并与肝细胞癌的发展相关。HBV感染改变线粒体代谢。选择性去除受损的线粒体对于维持线粒体和细胞的稳态是必不可少的。在这里，我们报告说，HBV的平衡线粒体动力学向分裂和线粒体自噬减弱病毒诱导的细胞凋亡。HBV诱导线粒体核周聚集，并通过刺激其Ser 616磷酸化来触发动力蛋白相关蛋白（Drp 1）的线粒体移位，导致线粒体分裂。HBV还刺激Parkin、PINK 1和LC 3B的基因表达，并诱导Parkin募集到线粒体。在转运到线粒体后，E3泛素连接酶Parkin经历自身泛素化，并促进其底物线粒体融合蛋白2（Mfn 2）的泛素化和降解，线粒体融合的介体。除了常规的免疫荧光之外，采用表达与线粒体靶向序列框内融合的mito-mRFP-EGFP的敏感的双重荧光报告基因，通过将吞噬的线粒体递送至溶酶体进行降解来观察线粒体吞噬过程的完成。此外，我们证明，病毒HBx蛋白在促进异常线粒体动力学中起着核心作用，无论是单独表达还是在病毒基因组的背景下。通过沉默帕金干扰线粒体自噬导致细胞凋亡信号增强，表明HBV诱导的线粒体分裂和线粒体自噬促进细胞存活和可能的病毒持久性。与HBV感染相关的线粒体动力学改变可能有助于线粒体损伤和肝病发病机制。B型肝炎病毒（HBV）慢性感染是肝细胞癌发生的常见原因。线粒体肝损伤一直被认为是慢性肝炎期间HBV感染的后果之一。线粒体是动态细胞器，其经历分裂、融合和选择性自噬去除（线粒体自噬），以维持线粒体稳态并满足细胞能量需求。清除受损的线粒体对于维持线粒体和细胞的稳态是必不可少的。我们观察到，HBV及其编码的HBx蛋白促进线粒体断裂（分裂）和线粒体自噬。HBV/HBx诱导动力蛋白相关蛋白1（Drp 1）的表达和Ser 616磷酸化及其随后的易位到线粒体，导致增强的线粒体片段化。HBV还促进了细胞质E3泛素连接酶Parkin的线粒体易位和随后的线粒体自噬。HBV感染细胞中线粒体自噬的扰动导致线粒体凋亡信号的增强。线粒体动力学向增强的分裂和线粒体自噬的这种转变对于清除受损的线粒体是必不可少的，并且用于防止HBV感染细胞的凋亡细胞死亡以促进持续感染。
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. Hepatitis B virus (HBV) chronic infections represent the common cause for the development of hepatocellular carcinoma. Mitochondrial liver injury has been long recognized as one of the consequences of HBV infection during chronic hepatitis. Mitochondria are dynamic organelles that undergo fission, fusion, and selective-autophagic removal (mitophagy), in their pursuit to maintain mitochondrial homeostasis and meet cellular energy requirements. The clearance of damaged mitochondria is essential for the maintenance of mitochondrial and cellular homeostasis. We observed that HBV and its encoded HBx protein promoted mitochondrial fragmentation (fission) and mitophagy. HBV/HBx induced the expression and Ser616 phosphorylation of dynamin-related protein 1 (Drp1) and its subsequent translocation to the mitochondria, resulting in enhanced mitochondrial fragmentation. HBV also promoted the mitochondrial translocation of Parkin, a cytosolic E3 ubiquitin ligase, and subsequent mitophagy. Perturbation of mitophagy in HBV-infected cells resulted in enhanced mitochondrial apoptotic signaling. This shift of the mitochondrial dynamics towards enhanced fission and mitophagy is essential for the clearance of damaged mitochondria and serves to prevent apoptotic cell death of HBV-infected cells to facilitate persistent infection.
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影响因子：
4.9
作者：
Ladner, SK;Otto, MJ;King, RW
通讯作者：
King, RW
影响因子：
3.8
作者：
Henkler, F;Hoare, J;King, IA
通讯作者：
King, IA
影响因子：
5.4
作者：
Kim, Sujeong;Kim, Hye-Young;Cho, Hyeseong
通讯作者：
Cho, Hyeseong
DOI：
10.1083/jcb.200211046
发表时间：
2003-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen H;Detmer SA;Ewald AJ;Griffin EE;Fraser SE;Chan DC
通讯作者：
Chan DC
影响因子：
9.7
作者：
Bouchard, Michael J.;Navas-Martin, Sonia
通讯作者：
Navas-Martin, Sonia