ITCH E3 Ubiquitin Ligase Interacts with Ebola Virus VP40 To Regulate Budding
ITCH E3 Ubiquitin Ligase Interacts with Ebola Virus VP40 To Regulate Budding
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DOI：
10.1128/jvi.01078-16
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发表时间：
2016-10-01
影响因子：
5.4
通讯作者：
Harty, Ronald N.
中科院分区：
文献类型：
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作者：
Han, Ziying;Sagum, Cari A.;Harty, Ronald N.
埃博拉病毒(EBOV)和马尔堡病毒(MARV)属于丝状病毒科，可引起严重出血热暴发，人类死亡率高。EBOV VP40(EVP40)和Marv VP40(MVP40)基质蛋白在病毒粒子组装和输出中起着核心作用，因此VP40的独立表达导致病毒样颗粒(VLP)的产生和输出，从而准确地模拟感染性病毒的萌发。EVP40后期(L)萌芽结构域招募宿主蛋白(例如，Tsg101、Nedd4和Alix)，这些宿主蛋白对于有效的病毒出口和传播是重要的。例如，eVP40和mVP40的PPxY型L结构域通过其WW域招募宿主Nedd4 E3泛素连接酶以促进发芽。在这里，我们试图确定额外的WW域宿主相互作用因子，并证明eVP40的PPxY L结构域与宿主E3泛素连接酶瘙痒的WW域特异相互作用。ITCH和Nedd4一样，是E3泛素连接酶Hect类的成员，与eVP40产生的物理和功能相互作用促进了VLP和病毒的萌发。这种新的eVP40相互作用因子的发现突显了细胞E3连接酶、泛素化和VP40介导的出口调节之间的功能相互作用。重要的是，最近在西非爆发的2014-2015年EBOV疫情的规模和范围前所未有，并在美国和其他国家出现，这突显了更好地了解这种新出现的病原体的生物学和发病机制的迫切需要。我们已经确定了一个新的和功能强大的EBOV VP40相互作用元件，ITCH，它调节VP40介导的出口。这种病毒与宿主的相互作用可能代表了我们之前发现的病毒出口小分子抑制剂的新靶点。
Ebola virus (EBOV) and Marburg virus (MARV) belong to the Filoviridae family and can cause outbreaks of severe hemorrhagic fever, with high mortality rates in humans. The EBOV VP40 (eVP40) and MARV VP40 (mVP40) matrix proteins play a central role in virion assembly and egress, such that independent expression of VP40 leads to the production and egress of virus-like particles (VLPs) that accurately mimic the budding of infectious virus. Late (L) budding domains of eVP40 recruit host proteins (e. g., Tsg101, Nedd4, and Alix) that are important for efficient virus egress and spread. For example, the PPxY-type L domain of eVP40 and mVP40 recruits the host Nedd4 E3 ubiquitin ligase via itsWWdomains to facilitate budding. Here we sought to identify additionalWWdomain host interactors and demonstrate that the PPxY L domain motif of eVP40 interacts specifically with theWWdomain of the host E3 ubiquitin ligase ITCH. ITCH, like Nedd4, is a member of the HECT class of E3 ubiquitin ligases, and the resultant physical and functional interaction with eVP40 facilitates VLP and virus budding. Identification of this novel eVP40 interactor highlights the functional interplay between cellular E3 ligases, ubiquitination, and regulation of VP40-mediated egress.IMPORTANCEThe unprecedented magnitude and scope of the recent 2014-2015 EBOV outbreak in West Africa and its emergence here in the United States and other countries underscore the critical need for a better understanding of the biology and pathogenesis of this emerging pathogen. We have identified a novel and functional EBOV VP40 interactor, ITCH, that regulates VP40-mediated egress. This virus-host interaction may represent a new target for our previously identified small-molecule inhibitors of virus egress.