The nuclear egress complex of Epstein-Barr virus buds membranes through an oligomerization-driven mechanism.
The nuclear egress complex of Epstein-Barr virus buds membranes through an oligomerization-driven mechanism.
复制标题
EB病毒的核出口复合物通过寡聚化驱动机制芽膜。
DOI：
10.1371/journal.ppat.1010623
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发表时间：
2022-07
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
在复制过程中，疱疹病毒衣壳通过一种称为核出口的不寻常机制从细胞核移位到细胞质中，该机制涉及衣壳在内核膜处的出芽。这个过程是由病毒核出口复合物（NEC）介导的，它使衣壳周围的膜变形。尽管NEC对于疱疹病毒科的所有三个亚科的衣壳核出口是必不可少的，但迄今为止的大多数研究都集中在来自α和β的NEC同源物上，而不是γ疱疹病毒。在这里，我们报告的晶体结构的NEC从爱泼斯坦-巴尔病毒（EBV），一个典型的γ疱疹病毒。该结构类似于NEC同系物的已知结构，但构象动态。我们还表明，纯化，重组EBV NEC芽合成膜在体外，并形成未知几何形状的膜结合涂层。然而，与其他NEC同系物不同，EBV NEC在晶体中形成二聚体而不是六聚体。在EBV NEC晶体中观察到的二聚体界面类似于在其他NEC同系物中观察到的六聚体界面。此外，经工程改造以破坏二聚体界面的突变减少出芽。把这些数据放在一起，我们提出，EBV NEC介导的出芽是由寡聚化成膜结合的外套。疱疹病毒，感染世界上大多数人口的生活，易位其衣壳从细胞核，在那里他们形成，进入细胞质，在那里他们成熟成感染性病毒粒子，通过一个不寻常的机制，称为核出口。在核出芽期间，这一过程的早期步骤，被称为核出口复合物（NEC）的两种病毒蛋白质的复合物使衣壳周围的内核膜变形。NEC在疱疹病毒的所有三个亚科中是保守的，并且对于核出口是必需的。然而，迄今为止，大多数研究都集中在α和β疱疹病毒的NEC同源物上，而对γ疱疹病毒的NEC知之甚少。在这里，我们确定了晶体结构的NEC从爱泼斯坦-巴尔病毒（EBV），一种典型的γ疱疹病毒，并研究其膜出芽特性在体外。我们的数据表明，通过形成膜结合的外套和结构的囊泡膜的能力是保守的NEC同系物从所有三个亚科。然而，由于其结构的灵活性和形成不同几何形状的涂层的能力，EBV NEC可能采用不同的膜出芽机制。
During replication, herpesviral capsids are translocated from the nucleus into the cytoplasm by an unusual mechanism, termed nuclear egress, that involves capsid budding at the inner nuclear membrane. This process is mediated by the viral nuclear egress complex (NEC) that deforms the membrane around the capsid. Although the NEC is essential for capsid nuclear egress across all three subfamilies of the Herpesviridae, most studies to date have focused on the NEC homologs from alpha- and beta- but not gammaherpesviruses. Here, we report the crystal structure of the NEC from Epstein-Barr virus (EBV), a prototypical gammaherpesvirus. The structure resembles known structures of NEC homologs yet is conformationally dynamic. We also show that purified, recombinant EBV NEC buds synthetic membranes in vitro and forms membrane-bound coats of unknown geometry. However, unlike other NEC homologs, EBV NEC forms dimers in the crystals instead of hexamers. The dimeric interfaces observed in the EBV NEC crystals are similar to the hexameric interfaces observed in other NEC homologs. Moreover, mutations engineered to disrupt the dimeric interface reduce budding. Putting together these data, we propose that EBV NEC-mediated budding is driven by oligomerization into membrane-bound coats. Herpesviruses, which infect most of the world’s population for life, translocate their capsids from the nucleus, where they are formed, into the cytoplasm, where they mature into infectious virions, by an unusual mechanism, termed nuclear egress. During nuclear budding, an early step in this process, the inner nuclear membrane is deformed around the capsid by the complex of two viral proteins termed the nuclear egress complex (NEC). The NEC is conserved across all three subfamilies of Herpesviruses and essential for nuclear egress. However, most studies to date have focused on the NEC homologs from alpha- and betaherpesviruses while less is known about the NEC from gammaherpesviruses. Here, we determined the crystal structure of the NEC from Epstein-Barr virus (EBV), a prototypical gammaherpesvirus, and investigated its membrane budding properties in vitro. Our data show that the ability to vesiculate membranes by forming membrane-bound coats and the structure are conserved across the NEC homologs from all three subfamilies. However, the EBV NEC may employ a distinct membrane-budding mechanism due to its structural flexibility and the ability to form coats of different geometry.
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