Hepatitis B Virus-Induced Parkin-Dependent Recruitment of Linear Ubiquitin Assembly Complex (LUBAC) to Mitochondria and Attenuation of Innate Immunity.
Hepatitis B Virus-Induced Parkin-Dependent Recruitment of Linear Ubiquitin Assembly Complex (LUBAC) to Mitochondria and Attenuation of Innate Immunity.
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DOI：
10.1371/journal.ppat.1005693
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发表时间：
2016-06
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：
Khan M;Syed GH;Kim SJ;Siddiqui A
乙肝病毒(乙肝病毒)抑制先天免疫信号以建立持续性感染。尽管乙肝病毒是一种脱氧核糖核酸病毒，但它的前基因组核糖核酸可以被RIG-I感知，并激活MAV介导干扰素λ的合成。尽管pgRNA激活了RIG-I-MAVS轴，但解释乙肝病毒感染未能诱导干扰素-αβ合成的潜在机制仍不清楚。我们证明，乙肝病毒诱导的Parkin能够将线性泛素组装复合体招募到线粒体，并阻止干扰素β的合成。Parkin与MAV相互作用，通过LUBAC在MAV上积累非锚定的线性泛素链，干扰MAV信号小体并减弱IRF3的激活。这项研究强调了parkin在抗病毒信号中的新作用，这涉及到LUBAC被招募到线粒体。这些结果为研究线粒体动力学在先天免疫中的作用提供了途径。乙肝病毒慢性感染是导致肝细胞癌的主要原因之一。乙肝病毒感染与线粒体功能障碍有关。我们之前的研究表明，持续的乙肝病毒感染需要通过有丝分裂来快速清除受损的线粒体，有丝分裂是一种细胞质量控制过程，可以确保受乙肝病毒感染的细胞的存活。在这个过程中，一种RBR E3连接酶Parkin被招募到线粒体以诱导有丝分裂。在这项研究中，我们证明了Parkin，在调节先天免疫信号中起着关键作用。利用表达乙肝病毒的细胞，我们发现Parkin将线性泛素组装复合体(LUBAC)招募到线粒体，随后抑制线粒体抗病毒信号蛋白(MAVS)的下游信号。然后，线粒体LUBAC催化MAVs上的线性泛素链，从而取消其下游事件，如MAVS-TRAF相互作用，并取消IRF3的磷酸化。这项研究的结果突出了解释乙肝病毒如何抑制干扰素合成的分子细节，暗示了Parkin不依赖于有丝分裂的作用。乙肝病毒诱导的线粒体损伤是Parkin和LUBAC招募的平台，这两个基因共同通过泛素化修饰MAV，并削弱其下游信号转导。
Hepatitis B virus (HBV) suppresses innate immune signaling to establish persistent infection. Although HBV is a DNA virus, its pre-genomic RNA (pgRNA) can be sensed by RIG-I and activates MAVS to mediate interferon (IFN) λ synthesis. Despite of the activation of RIG-I-MAVS axis by pgRNA, the underlying mechanism explaining how HBV infection fails to induce interferon-αβ (IFN) synthesis remained uncharacterized. We demonstrate that HBV induced parkin is able to recruit the linear ubiquitin assembly complex (LUBAC) to mitochondria and abrogates IFN β synthesis. Parkin interacts with MAVS, accumulates unanchored linear polyubiquitin chains on MAVS via LUBAC, to disrupt MAVS signalosome and attenuate IRF3 activation. This study highlights the novel role of parkin in antiviral signaling which involves LUBAC being recruited to the mitochondria. These results provide avenues of investigations on the role of mitochondrial dynamics in innate immunity. Hepatitis B virus (HBV) chronic infection is one of the major causes of hepatocellular carcinoma. HBV infection is associated with mitochondrial dysfunction. We previously showed that persistent infection of HBV requires rapid clearance of impaired mitochondria by mitophagy, a cellular quality control process that insures survival of HBV infected cells. During the process, Parkin, an RBR E3 ligase, is recruited to mitochondria to induce mitophagy. In this study, we show that the Parkin, plays a critical role in the modulation of innate immune signaling. Using HBV expressing cells, we show that the Parkin recruits linear ubiquitin assembly complex (LUBAC) to the mitochondria and subsequently inhibits downstream signaling of mitochondrial antiviral signaling protein (MAVS). Mitochondrial LUBAC then catalyzes linear ubiquitin chains on MAVS, which abrogates its downstream events such as MAVS-TRAFs interaction and abolishes IRF3 phosphorylation. The results of this study highlight the molecular details explaining how HBV can suppress interferon synthesis implicating a mitophagy-independent role of Parkin. HBV-induced mitochondrial damage serves as the platform for recruitment of Parkin and LUBAC, which together modify MAVS by ubiquitination and cripples its downstream signaling.