Strategy of paramyxovirusto attenuate cytopathicity

副粘病毒包括猴病毒5（SV 5）通过病毒包膜糖蛋白HN和F之间的相互作用介导膜融合，其中HN蛋白促进F蛋白的融合诱导功能。我在这里报告的SV 5 HN蛋白的茎区参与与F蛋白的相互作用，与其他副粘病毒一样。此外，我报告的第一次，四个离散域的F蛋白参与与FIN蛋白的相互作用。另一方面，如先前公开的，与原型WR株相比，SV 5的T1株显示出诱导细胞-细胞融合的能力降低，因此对病毒感染的细胞带来最小的细胞病变。为探讨T1病毒致细胞病变弱的分子机制，采用噬斑克隆法从T1病毒中获得了高度融合的变异株。该变体在FIN蛋白中具有三个突变L182 R、K45 IT和V536 M，在F蛋白中没有突变。值得注意的是，L182 R突变被证明提高了HN蛋白的融合促进功能，并且位置182处的亮氨酸突变为除Ala之外的其它氨基酸也促进了HN蛋白的融合促进功能。然而，其HN和/或F蛋白已被替换为Ti对应物的重组WR病毒中的任一个都是融合的，这表明其他T1病毒蛋白如M蛋白可能有助于T1 FIN蛋白的融合抑制功能。由于T1病毒可以进行多步复制，因此包膜和细胞膜之间的融合似乎正常发生。因此，我们假设T1 FIN蛋白可能通过将信号转导至细胞内分子如肌动蛋白或黏着斑蛋白来抑制细胞-细胞融合，L182 R突变或与WRM蛋白的组合可能以某种方式取消这种信号转导的抑制。

Paramyxoviruses including simian virus 5(SV5)mediate membrane fusion through an interaction between viral envelope glycoproteins HN and F, in which the HN protein promotes fusion-inducing function of the F protein. I report here that the stalk region of SV5 HN protein is involved in the interaction with the F protein the same as those of other paramyxoviruses. Furthermore, I report for the first time that four discrete domains of the F proteins participate in the interaction with the FIN protein. As published previously, on the other hand, the T1 strain of SV5 displays reduced ability to induce cell-cell fusion and thus brings minimal cytopathicity to the virus-infected cells as compared to the prototype WR strain. To investigate the molecular mechanism of the attenuated cytopathicity of T1 virus, highly fusogenic variant was obtained from T1 virus by plaque cloning. This variant possessed three mutations L182R, K45 IT, and V536M in the FIN protein, with no mutation in the F protein. Notably, L182R mutation proved to raise the fusion-promoting function of the HN protein and that mutation of leucine at position 182 to other amino acids other than Ala also facilitates the fusion-promoting function of the HN protein. However, either of the recombinant WR viruses whose HN and/or F proteins had been replaced with the Ti counterparts were fusogenic, indicating that other T1 virus proteins such as M protein might contribute to the fusion-inhibiting function of the T1 FIN protein. Since T1 virus could perform multiple-step replication, the fusion between envelope and cell membrane seems to take place normally. We thus hypothesize that T1 FIN protein may suppresses cell-cell fusion by transducing a signal to the intracellular molecules such as actin or vinculin that the L182R mutation or combination with WR M protein may somehow cancel this suppression of signal transduction.