Norovirus MLKL-like protein initiates cell death to induce viral egress.
Norovirus MLKL-like protein initiates cell death to induce viral egress.
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DOI：
10.1038/s41586-023-05851-w
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发表时间：
2023-04
期刊：
影响因子：
64.8
通讯作者：
Reese, Tiffany A.
中科院分区：
文献类型：
--
作者：
Wang, Guoxun;Zhang, Di;Orchard, Robert C.;Hancks, Dustin C.;Reese, Tiffany A.
无包膜病毒需要细胞裂解以从感染的细胞释放新的病毒体，这表明这些病毒需要诱导细胞死亡的机制。诺如病毒就是这样一组病毒，但是没有已知的机制导致诺如病毒感染触发的细胞死亡和裂解。在这里，我们确定了诺如病毒诱导细胞死亡的分子机制。我们发现，诺如病毒编码的NS 3含有一个N-末端四螺旋束结构域同源的假激酶混合谱系激酶结构域样（MLKL）的膜破坏域。NS 3具有线粒体定位信号，因此通过靶向线粒体诱导细胞死亡。全长NS 3和蛋白质的N-末端片段结合线粒体膜脂质心磷脂，使线粒体膜透化并诱导线粒体功能障碍。NS 3的N-末端区域和线粒体定位基序对于小鼠中的细胞死亡、病毒从细胞中流出和病毒复制都是必不可少的。这些发现表明，诺如病毒已经获得了宿主MLKL样孔形成结构域，以通过诱导线粒体功能障碍促进病毒排出。
Non-enveloped viruses require cell lysis to release new virions from infected cells, suggesting that these viruses require mechanisms to induce cell death. Noroviruses are one such group of viruses, but there is no known mechanism that causes norovirus infection-triggered cell death and lysis. Here we identify a molecular mechanism of norovirus-induced cell death. We found that the norovirus-encoded NS3 contains an N-terminal four-helix bundle domain homologous to the membrane-disruption domain of the pseudokinase mixed lineage kinase domain-like (MLKL). NS3 has a mitochondrial localization signal and thus induces cell death by targeting mitochondria. Full-length NS3 and an N-terminal fragment of the protein bound the mitochondrial membrane lipid cardiolipin, permeabilized the mitochondrial membrane and induced mitochondrial dysfunction. Both the N-terminal region and the mitochondrial localization motif of NS3 were essential for cell death, viral egress from cells and viral replication in mice. These findings suggest that noroviruses have acquired a host MLKL-like pore-forming domain to facilitate viral egress by inducing mitochondrial dysfunction.
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通讯作者：
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作者：
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通讯作者：
Uyttendaele, Mieke