近日，美国德克萨斯大学西南医学中心Tiffany A. Reese等研究人员合作发现，诺如病毒MLKL样蛋白启动细胞死亡来诱导病毒排出。该研究于2023年3月29日在线发表于国际一流学术期刊《自然》。

研究人员确定了诺如病毒诱导细胞死亡的分子机制。研究人员发现诺如病毒编码的NTP酶NS3含有一个N端四螺旋束结构域，与假激酶混合系激酶域（MLKL）的膜断裂结构域同源。NS3有一个线粒体定位信号，因此通过靶向线粒体诱导细胞死亡。全长的NS3和该蛋白的N端片段与线粒体膜脂质心磷脂结合，使线粒体膜透化并诱发线粒体功能障碍。NS3的N端区域和线粒体定位图案对小鼠的细胞死亡、病毒从细胞中排出和病毒复制都至关重要。这些发现表明，诺如病毒已经获得了一个类似于宿主MLKL的成孔结构域，通过诱导线粒体功能障碍来促进病毒排出。

据了解，无包膜病毒需要细胞裂解才能从被感染的细胞中释放出新的病毒，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，但目前还没有已知的导致诺如病毒感染触发的细胞死亡和裂解的机制。

附：英文原文

Title: Norovirus MLKL-like protein initiates cell death to induce viral egress

Author: Wang, Guoxun, Zhang, Di, Orchard, Robert C., Hancks, Dustin C., Reese, Tiffany A.

Issue&Volume: 2023-03-29

Abstract: 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 lysis1,2,3. Here we identify a molecular mechanism of norovirus-induced cell death. We found that the norovirus-encoded NTPase 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.

DOI: 10.1038/s41586-023-05851-w

Source: https://www.nature.com/articles/s41586-023-05851-w