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首页> 外文期刊>Journal of Molecular Biology >Modulation of an ectodomain motif in the influenza A virus neuraminidase alters tetherin sensitivity and results in virus attenuation in vivo
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Modulation of an ectodomain motif in the influenza A virus neuraminidase alters tetherin sensitivity and results in virus attenuation in vivo

机译：甲型流感病毒神经氨酸酶中​​胞外域基序的调节改变了系链素的敏感性，并导致病毒在体内减弱

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We previously demonstrated that ectodomain residue Asp286 in N2 neuraminidase (NA; Asp268 in N1 NA) present in budding-capable NA proteins contributes to productive NA plasma membrane transport partly by mediating escape from tetherin restriction [Yondola MA, Fernandes F, Belicha-Villanueva A, Uccelini M, Gao Q, Carter C, et al. (2011). Budding capability of the influenza virus neuraminidase can be modulated by tetherin. J Virol, 85, 2480-2491]. Budding-incapable NA proteins contain a G at this position and either co-expression of human immunodeficiency virus type 1 vpu or siRNA-mediated depletion of tetherin rescued budding capabilities in these proteins [Yondola MA, Fernandes F, Belicha-Villanueva A, Uccelini M, Gao Q, Carter C, et al. (2011). Budding capability of the influenza virus neuraminidase can be modulated by tetherin. J Virol, 85, 2480-2491]. Furthermore, replacement of D286 with G in budding-capable NA proteins caused loss of function, preventing release of NA virus-like particles (VLPs). Here, we show that mutation of this residue specifically modulates the ability of NA to escape tetherin restriction at the plasma membrane and results in virus attenuation in vivo. Based on immunogold electron microscopy and co-immunoprecipitation assays, both NA D286-containing and NAD286G-containing proteins associated with tetherin in the endoplasmic reticulum (ER). However, the NA D286G loss-of-function mutant also associated with the host factor outside the ER and in plasma-membrane-localized VLPs as visualized using immunogold electron microscopy. We conclude that the presence of aspartate at residue 286 liberates NA from tetherin-dependent restriction upon exit from the ER compartment thus preventing restriction at the plasma membrane. Underscoring the importance of these observations, knockdown of tetherin resulted in a 1-1.5 log increase in influenza virus growth. Additionally, the loss-of-function mutation conferred attenuation in a mouse model of influenza infection as evidenced by a 5-fold increase in LD50 and increases in either percent survival or time to death dependent on the administered dose in vivo.
机译：我们以前证明存在芽能力的NA蛋白中存在的N2神经氨酸酶（NA; N1 NA中的Asp268）的胞外域残基Asp286部分地通过介导从系链素限制中逃逸而有助于生产性NA质膜运输[Yondola MA，Fernandes F，Belicha-Villanueva A ，Uccelini M，Gao Q，Carter C等。 （2011）。流感病毒神经氨酸酶的萌发能力可以通过系链素调节。 J Virol，85，2480-2491]。无法萌芽的NA蛋白在此位置含有G，并且可以共同表达1型人类免疫缺陷病毒vpu或siRNA介导的tetherin耗竭，从而挽救了这些蛋白的出芽能力[Yondola MA，Fernandes F，Belicha-Villanueva A，Uccelini M ，Gao Q，Carter C等。 （2011）。流感病毒神经氨酸酶的萌发能力可以通过系链素调节。 J Virol，85，2480-2491]。此外，在具有萌芽能力的NA蛋白中用G替代D286导致功能丧失，从而阻止了NA病毒样颗粒（VLP）的释放。在这里，我们显示该残基的突变特异性调节NA逃脱质膜上的束缚素限制，并导致病毒在体内的衰减。基于免疫金电子显微镜和免疫共沉淀分析，内质网（ER）中含有NAD286和NAD286G的蛋白质都与系链素相关。但是，NA D286G功能丧失突变体也与ER外部和血浆膜定位VLPs中的宿主因子相关，如使用免疫金电子显微镜观察到的。我们得出的结论是，残基286上存在天冬氨酸后，从ER隔室退出后，NA不受系链素依赖性限制的释放，从而阻止了质膜的限制。强调这些发现的重要性，敲除系链素导致流感病毒的生长增加了1-1.5 log。另外，功能丧失突变在流感病毒感染的小鼠模型中具有减弱作用，这取决于LD50的5倍增加以及存活百分比或死亡时间的增加，具体取决于体内给药剂量。

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