Interferon-Induced Transmembrane Protein 3 Blocks Fusion of Diverse Enveloped Viruses by Altering Mechanical Properties of Cell Membranes.
Interferon-Induced Transmembrane Protein 3 Blocks Fusion of Diverse Enveloped Viruses by Altering Mechanical Properties of Cell Membranes.
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DOI：
10.1021/acsnano.0c10567
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发表时间：
2021-05-25
期刊：
影响因子：
17.1
通讯作者：
Melikyan GB
中科院分区：
文献类型：
--
作者：
Guo X;Steinkühler J;Marin M;Li X;Lu W;Dimova R;Melikyan GB
干扰素诱导的跨膜蛋白3（IFITM 3）通过在半融合阶段捕获病毒融合体，有效地抑制多种包膜病毒的进入，但其潜在机制尚不清楚。在这里，我们表明重组IFITM 3重组成脂质囊泡诱导负膜曲率，这种效果映射到其小的两亲性螺旋（AH）。我们证明AH：（i）分区进入脂质无序结构域，其中发生IAV融合，（ii）诱导负膜曲率，和（iii）增加脂质有序性和膜刚度。这些对膜性质的影响与融合抑制活性相关，因为将异位表达的AH肽靶向细胞质膜的胞质小叶减少了IAV-1，因此，我们的研究结果表明，IFITM 3通过施加不利的膜曲率和增加细胞质小叶的有序性和刚度来抑制从半融合到完全融合的转变。内体膜我们的发现揭示了一种普遍的机制，细胞通过这种机制阻止不同包膜病毒的进入。
Interferon-induced transmembrane protein 3 (IFITM3) potently inhibits entry of diverse enveloped viruses by trapping the viral fusion at a hemifusion stage, but the underlying mechanism remains unclear. Here, we show that recombinant IFITM3 reconstituted into lipid vesicles induces negative membrane curvature and that this effect maps to its small amphipathic helix (AH). We demonstrate that AH: (i) partitions into lipid-disordered domains where IAV fusion occurs, (ii) induces negative membrane curvature, and (iii) increases lipid order and membrane stiffness. These effects on membrane properties correlate with the fusion-inhibitory activity, as targeting the ectopically expressed AH peptide to the cytoplasmic leaflet of the cell plasma membrane diminishes IAV-cell surface fusion induced by exposure to acidic pH. Our results thus imply that IFITM3 inhibits the transition from hemifusion to full fusion by imposing an unfavorable membrane curvature and increasing the order and stiffness of the cytoplasmic leaflet of endosomal membranes. Our findings reveal a universal mechanism by which cells block entry of diverse enveloped viruses.
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