The Amino Acid at Position 8 of the Proteolytic Cleavage Site of the Mumps Virus Fusion Protein Affects Viral Proteolysis and Fusogenicity
The Amino Acid at Position 8 of the Proteolytic Cleavage Site of the Mumps Virus Fusion Protein Affects Viral Proteolysis and Fusogenicity
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DOI：
10.1128/jvi.01732-20
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发表时间：
2020-09
影响因子：
5.4
通讯作者：
Sarah Hüttl;M. Hoffmann;T. Steinmetzer;C. Sauder;Nadine Krüger
中科院分区：
文献类型：
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作者：
Sarah Hüttl;M. Hoffmann;T. Steinmetzer;C. Sauder;Nadine Krüger
腮腺炎病毒（MuV）是高度传染性疾病腮腺炎的病原体。流行性腮腺炎主要与轻微症状有关，但也可能发生严重的并发症，如脑炎，脑膜炎或睾丸炎。有证据表明，不同MuV毒株和变体的毒力可能与融合蛋白（F）介导细胞间融合的能力相关。然而，毒力和融合性之间的关系或不同的MuV毒株的不同融合性的机制还不完全清楚。在这里，我们集中在MuV F的蛋白水解切割位点的位置8（P8）处的氨基酸残基，因为该氨基酸残基根据MuV的基因型显示出显著的变异性。P8残基对MuV F的蛋白水解加工和融合性具有显著影响，从而可能决定感染组织内病毒传播的途径。摘要腮腺炎病毒（MuV）融合蛋白（F）通过介导病毒与细胞膜之间以及感染细胞与邻近细胞之间的融合，在感染的进入过程和传播中起着至关重要的作用。MuV的融合性因菌株而异，可能与毒力相关;然而，目前还不清楚哪些机制有助于分化的融合性。MuV F的切割基序在所有菌株中高度保守，除了位置8（P8）的氨基酸残基显示出一定的变异性，总共有四种氨基酸变体（亮氨酸[L]、脯氨酸[P]、丝氨酸[S]和苏氨酸[T]）。我们证明P8影响MuV F的蛋白水解加工和融合性。在P8的L或S的存在下，MuV F的蛋白水解速度较慢，弗林蛋白酶和介导细胞-细胞融合的能力降低。然而，病毒-细胞融合是更有效的F蛋白窝藏L或S在P8，这表明P8有助于病毒传播的机制：P和T能够通过细胞间融合的感染快速传播，而病毒窝藏L或S在P8传播优先通过释放感染性病毒颗粒。我们的研究为MuV的融合性及其对感染组织内病毒传播机制的影响提供了新的见解。假设MuV的融合性和毒力之间的相关性，在P8的氨基酸残基的序列信息可能有助于估计流行和新出现的菌株的毒力。重要性腮腺炎病毒（MuV）是高度传染性疾病腮腺炎的病原体。流行性腮腺炎主要与轻微症状有关，但也可能发生严重的并发症，如脑炎，脑膜炎或睾丸炎。有证据表明，不同MuV毒株和变体的毒力可能与融合蛋白（F）介导细胞间融合的能力相关。然而，毒力和融合性之间的关系或不同的MuV毒株的不同融合性的机制还不完全清楚。在这里，我们集中在MuV F的蛋白水解切割位点的位置8（P8）处的氨基酸残基，因为该氨基酸残基根据MuV的基因型显示出显著的变异性。P8残基对MuV F的蛋白水解加工和融合性具有显著影响，从而可能决定感染组织内病毒传播的途径。
Mumps virus (MuV) is the causative agent of the highly infectious disease mumps. Mumps is mainly associated with mild symptoms, but severe complications such as encephalitis, meningitis, or orchitis can also occur. There is evidence that the virulence of different MuV strains and variants might correlate with the ability of the fusion protein (F) to mediate cell-to-cell fusion. However, the relation between virulence and fusogenicity or the mechanisms responsible for the varied fusogenicity of different MuV strains are incompletely understood. Here, we focused on the amino acid residue at position 8 (P8) of the proteolytic cleavage site of MuV F, because this amino acid residue shows a striking variability depending on the genotype of MuV. The P8 residue has a significant effect on the proteolytic processing and fusogenicity of MuV F and might thereby determine the route of viral spread within infected tissues. ABSTRACT The mumps virus (MuV) fusion protein (F) plays a crucial role for the entry process and spread of infection by mediating fusion between viral and cellular membranes as well as between infected and neighboring cells, respectively. The fusogenicity of MuV differs depending on the strain and might correlate with the virulence; however, it is unclear which mechanisms contribute to the differentiated fusogenicity. The cleavage motif of MuV F is highly conserved among all strains, except the amino acid residue at position 8 (P8) that shows a certain variability with a total of four amino acid variants (leucine [L], proline [P], serine [S], and threonine [T]). We demonstrate that P8 affects the proteolytic processing and the fusogenicity of MuV F. The presence of L or S at P8 resulted in a slower proteolysis of MuV F by furin and a reduced ability to mediate cell-cell fusion. However, virus-cell fusion was more efficient for F proteins harboring L or S at P8, suggesting that P8 contributes to the mechanism of viral spread: P and T enable a rapid spread of infection by cell-to-cell fusion, whereas viruses harboring L or S at P8 spread preferentially by the release of infectious viral particles. Our study provides novel insights into the fusogenicity of MuV and its influence on the mechanisms of virus spread within infected tissues. Assuming a correlation between MuV fusogenicity and virulence, sequence information on the amino acid residue at P8 might be helpful to estimate the virulence of circulating and emerging strains. IMPORTANCE Mumps virus (MuV) is the causative agent of the highly infectious disease mumps. Mumps is mainly associated with mild symptoms, but severe complications such as encephalitis, meningitis, or orchitis can also occur. There is evidence that the virulence of different MuV strains and variants might correlate with the ability of the fusion protein (F) to mediate cell-to-cell fusion. However, the relation between virulence and fusogenicity or the mechanisms responsible for the varied fusogenicity of different MuV strains are incompletely understood. Here, we focused on the amino acid residue at position 8 (P8) of the proteolytic cleavage site of MuV F, because this amino acid residue shows a striking variability depending on the genotype of MuV. The P8 residue has a significant effect on the proteolytic processing and fusogenicity of MuV F and might thereby determine the route of viral spread within infected tissues.