From the Institute of Virology, Medical Center-University of Freiburg, Hermann-Herder-Strasse 11, 79104 Freiburg, Germany.
the Spemann Graduate School of Biology and Medicine, University of Freiburg, Albertstrasse 19a, 79104 Freiburg, Germany.
J Biol Chem. 2018 Mar 2;293(9):3056-3072. doi: 10.1074/jbc.M117.812784. Epub 2018 Jan 12.
Only a minority of patients infected with seasonal influenza A viruses exhibit a severe or fatal outcome of infection, but the reasons for this inter-individual variability in influenza susceptibility are unclear. To gain further insights into the molecular mechanisms underlying this variability, we investigated naturally occurring allelic variations of the myxovirus resistance 1 () gene coding for the influenza restriction factor MxA. The interferon-induced dynamin-like GTPase consists of an N-terminal GTPase domain, a bundle signaling element, and a C-terminal stalk responsible for oligomerization and viral target recognition. We used online databases to search for variations in the gene. Deploying approaches, we found that non-synonymous variations in the GTPase domain cause the loss of antiviral and enzymatic activities. Furthermore, we showed that these amino acid substitutions disrupt the interface for GTPase domain dimerization required for the stimulation of GTP hydrolysis. Variations in the stalk were neutral or slightly enhanced or abolished MxA antiviral function. Remarkably, two other stalk variants altered MxA's antiviral specificity. Variations causing the loss of antiviral activity were found only in heterozygous carriers. Interestingly, the inactive stalk variants blocked the antiviral activity of WT MxA in a dominant-negative way, suggesting that heterozygotes are phenotypically MxA-negative. In contrast, the GTPase-deficient variants showed no dominant-negative effect, indicating that heterozygous carriers should remain unaffected. Our results demonstrate that naturally occurring mutations in the human gene can influence MxA function, which may explain individual variations in influenza virus susceptibility in the human population.
只有少数感染季节性甲型流感病毒的患者表现出严重或致命的感染后果，但导致这种流感易感性个体间差异的原因尚不清楚。为了更深入地了解导致这种变异性的分子机制，我们研究了编码流感限制因子 MxA 的天然存在的异源等位基因变异。干扰素诱导的类似于动力蛋白的 GTPase 由一个 N 端 GTP 酶结构域、一个束状信号元件和一个负责寡聚化和病毒靶标识别的 C 端茎组成。我们使用在线数据库搜索 基因中的变异。通过部署功能获得和功能丧失方法，我们发现 GTP 酶结构域中的非同义变异导致抗病毒和酶活性丧失。此外，我们表明这些氨基酸取代破坏了 GTP 水解刺激所需的 GTP 酶结构域二聚化界面。茎的变异是中性的或略微增强或消除了 MxA 的抗病毒功能。值得注意的是，另外两个茎变体改变了 MxA 的抗病毒特异性。仅在杂合子携带者中发现导致抗病毒活性丧失的变异。有趣的是，无活性的茎变体以显性负性方式阻断 WT MxA 的抗病毒活性，表明杂合子在表型上是 MxA 阴性。相比之下，缺乏 GTP 酶的变体没有表现出显性负性效应，表明杂合子携带者应该不受影响。我们的研究结果表明，人类 基因中的天然突变可以影响 MxA 的功能，这可能解释了人群中流感病毒易感性的个体差异。
