Interferon-inducible transmembrane proteins (IFITM1/2/3) have been reported to suppress the entry of a wide range of viruses. However, their antiviral functional residues and specific mechanisms are still unclear. Here, we firstly resolved the topology of IFITM1 on the plasma membrane where N-terminus points into the cytoplasm and C-terminus resides extracellularly. Further, KRRK basic residues of IFITM1 locating at 62-67 of the conserved intracellular loop (CIL) were found to play a key role in the restriction on the Zika virus (ZIKV) and dengue virus (DENV). Similarly, KRRK basic residues of IFITM2/3 also contributed to suppressing ZIKV replication. Finally, IFITM1 was revealed to be capable of restricting the release of ZIKV particles from endosome to cytosol so as to impede the entry of ZIKV into host cells, which was tightly related with the inhibition of IFITM1 on the acidification of organelles. Overall, our study provided topology, antiviral functional residues and the mechanism of interferon-inducible transmembrane proteins.

中文翻译：

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IFITM1的拓扑，抗病毒功能残基和机理。

据报道，干扰素诱导的跨膜蛋白（IFITM1 / 2/3）可以抑制多种病毒的进入。但是，它们的抗病毒功能残基和具体机制仍不清楚。在这里，我们首先解析了IFITM1在质膜上的拓扑结构，其中N端指向细胞质，C端位于细胞外。此外，发现位于保守的细胞内环（CIL）62-67处的IFIRM1的KRRK基本残基在限制寨卡病毒（ZIKV）和登革热病毒（DENV）中起关键作用。同样，IFIRM2 / 3的KRRK基本残基也有助于抑制ZIKV复制。最后，IFITM1能够限制ZIKV颗粒从内体释放到细胞质，从而阻止ZIKV进入宿主细胞，这与IFITM1对细胞器酸化的抑制作用密切相关。总的来说，我们的研究提供了拓扑结构，抗病毒功能残基和干扰素诱导的跨膜蛋白的机制。