Cyclosporines Antagonize the Antiviral Activity of IFITMProteins by Redistributing Them toward the Golgi Apparatus.
Cyclosporines Antagonize the Antiviral Activity of IFITMProteins by Redistributing Them toward the Golgi Apparatus.
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DOI：
10.3390/biom13060937
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发表时间：
2023-06-03
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
干扰素诱导的跨膜蛋白（IFITM）可能通过增加细胞膜的刚性来阻断不同包膜病毒的融合。先前的研究报告称，IFITM家族成员IFITM 3的抗病毒活性可通过使用雷帕霉素衍生物以及促进IFITM 3降解的环孢菌素A和H（CsA和CsH）进行细胞预处理来拮抗。在这里，我们表明，CsA和CsH有效地增强病毒融合IFITM1和IFITM3表达细胞诱导其快速重新定位从质膜和内体，分别向高尔基体。这种重新定位与IFITM的显著降解无关。虽然长期暴露于CsA诱导表达低内源性水平的该蛋白的细胞中IFITM3降解，但其水平在干扰素处理的细胞或异位表达IFITM3的细胞中基本保持不变。重要的是，CsA介导的IFITM重新分布到高尔基体的时间尺度比降解短得多，因此可能代表了增强病毒进入的主要机制。我们进一步表明，雷帕霉素也诱导IFITM重新定位向高尔基体，虽然效率低于环孢素。我们的研究结果强调了IFITM运输的调节对于其抗病毒活性的重要性，并揭示了环孢菌素介导的细胞对包膜病毒感染易感性的调节的新机制。
Interferon-induced transmembrane proteins (IFITMs) block the fusion of diverse enveloped viruses, likely through increasing the cell membrane’s rigidity. Previous studies have reported that the antiviral activity of the IFITM family member, IFITM3, is antagonized by cell pretreatment with rapamycin derivatives and cyclosporines A and H (CsA and CsH) that promote the degradation of IFITM3. Here, we show that CsA and CsH potently enhance virus fusion with IFITM1- and IFITM3-expressing cells by inducing their rapid relocalization from the plasma membrane and endosomes, respectively, towards the Golgi. This relocalization is not associated with a significant degradation of IFITMs. Although prolonged exposure to CsA induces IFITM3 degradation in cells expressing low endogenous levels of this protein, its levels remain largely unchanged in interferon-treated cells or cells ectopically expressing IFITM3. Importantly, the CsA-mediated redistribution of IFITMs to the Golgi occurs on a much shorter time scale than degradation and thus likely represents the primary mechanism of enhancement of virus entry. We further show that rapamycin also induces IFITM relocalization toward the Golgi, albeit less efficiently than cyclosporines. Our findings highlight the importance of regulation of IFITM trafficking for its antiviral activity and reveal a novel mechanism of the cyclosporine-mediated modulation of cell susceptibility to enveloped virus infection.
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