Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Proc Natl Acad Sci U S A. 2021 Mar 16;118(11). doi: 10.1073/pnas.2019251118.
The mosquito protein AEG12 is up-regulated in response to blood meals and flavivirus infection though its function remained elusive. Here, we determine the three-dimensional structure of AEG12 and describe the binding specificity of acyl-chain ligands within its large central hydrophobic cavity. We show that AEG12 displays hemolytic and cytolytic activity by selectively delivering unsaturated fatty acid cargoes into phosphatidylcholine-rich lipid bilayers. This property of AEG12 also enables it to inhibit replication of enveloped viruses such as Dengue and Zika viruses at low micromolar concentrations. Weaker inhibition was observed against more distantly related coronaviruses and lentivirus, while no inhibition was observed against the nonenveloped virus adeno-associated virus. Together, our results uncover the mechanistic understanding of AEG12 function and provide the necessary implications for its use as a broad-spectrum therapeutic against cellular and viral targets.
蚊子蛋白 AEG12 可响应血餐和黄病毒感染而上调，但其功能仍不清楚。在这里，我们确定了 AEG12 的三维结构，并描述了其大的中心疏水性腔内酰基链配体的结合特异性。我们表明，AEG12 通过将不饱和脂肪酸货物选择性递送至富含磷脂酰胆碱的脂质双层中，显示出溶血和细胞毒性活性。AEG12 的这种特性还使其能够以低微摩尔浓度抑制包膜病毒（如登革热和寨卡病毒）的复制。对亲缘关系较远的冠状病毒和慢病毒的抑制作用较弱，而对非包膜病毒腺相关病毒则没有抑制作用。总之，我们的研究结果揭示了 AEG12 功能的机制理解，并为其作为针对细胞和病毒靶标的广谱治疗药物的应用提供了必要的启示。
