The Immune-Evasive Proline 283 Substitution in Influenza Nucleoprotein Increases Aggregation Propensity Without Altering the Native Structure.
The Immune-Evasive Proline 283 Substitution in Influenza Nucleoprotein Increases Aggregation Propensity Without Altering the Native Structure.
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流感核蛋白中的免疫逃避脯氨酸 283 取代增加了聚集倾向而不改变天然结构。
DOI：
10.1101/2023.09.08.556894
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Shoulders,MatthewD
中科院分区：
文献类型：
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作者：
Yoon,Jimin;Zhang,YuMeng;Her,Cheenou;Grant,RobertA;Ponomarenko,AnnaM;Ackermann,BryceE;Debelouchina,GaliaT;Shoulders,MatthewD
核蛋白(NP)是流感病毒核糖核蛋白复合体的关键结构蛋白，是病毒RNA包装和运输的中心。NP还决定了流感对粘病毒耐药蛋白1(MXA)的敏感性，MXA是一种限制流感复制的先天免疫因子。在NP中已经发现了一些关键的MXA抗性突变，包括高度保守的Proline-283替换。这种必需的脯氨酸-283替代会损害流感的生长，这是一种健康缺陷，在发烧的温度(39摄氏度)下，当宿主伴侣耗尽时，这种缺陷变得特别明显。在这里，我们对Proline-283 NP和Serine-283 NP进行生物物理表征，以测试适应性缺陷是否是由于Pro-283取代引入折叠缺陷引起的。我们发现，Pro-283取代改变了NP的折叠途径，使NP在折叠过程中更容易聚集，但不会改变蛋白质的天然结构。这些发现表明，流感已经进化成劫持宿主伴侣，以促进原本生物物理上不能发挥作用的病毒蛋白的折叠，从而使先天性免疫系统得以逃脱。
Nucleoprotein (NP) is a key structural protein of influenza ribonucleoprotein complexes and is central to viral RNA packing and trafficking. NP also determines the sensitivity of influenza to myxovirus resistance protein 1 (MxA), an innate immunity factor that restricts influenza replication. A few critical MxA-resistant mutations have been identified in NP, including the highly conserved proline-283 substitution. This essential proline-283 substitution impairs influenza growth, a fitness defect that becomes particularly prominent at febrile temperature (39°C) when host chaperones are depleted. Here, we biophysically characterize proline-283 NP and serine-283 NP to test whether the fitness defect is caused by the proline-283 substitution introducing folding defects. We show that the proline-283 substitution changes the folding pathway of NP, making NP more aggregation prone during folding, but does not alter the native structure of the protein. These findings suggest that influenza has evolved to hijack host chaperones to promote the folding of otherwise biophysically incompetent viral proteins that enable innate immune system escape.