mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3.
mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3.
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DOI：
10.1073/pnas.1811892115
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发表时间：
2018-10-23
影响因子：
11.1
通讯作者：
Compton AA
中科院分区：
文献类型：
--
作者：
Shi G;Ozog S;Torbett BE;Compton AA
病毒样颗粒的基因传递对于纠正遗传性疾病和预防传染病具有巨大的治疗潜力。然而，细胞表达的抗病毒因子可以防止病毒感染，从而限制了基因治疗的成功。在这里，我们揭示了雷帕霉素药物改善慢病毒介导的基因传递的机制。雷帕霉素处理导致 IFITM3 降解，IFITM3 是一种广泛而有效的抗病毒蛋白，可抑制病毒进入细胞。 IFITM3 被选择性地从核内体（病毒和细胞膜融合的位点）中清除，并被分类以在溶酶体中处置。在揭示具有临床益处的免疫抑制功能的同时，我们警告说，雷帕霉素在人体中的使用可能会促进甲型流感病毒等致病病毒的感染。雷帕霉素及其衍生物是哺乳动物雷帕霉素靶点 (mTOR) 激酶的特异性抑制剂，因此是成熟的免疫抑制剂和抗肿瘤药物。此外，此类药物通过促进慢病毒载体进入细胞来促进基因传递，揭示了其改善基因治疗效果的潜力。然而，确切的机制尚不清楚。在这里，我们报告 mTOR 抑制剂治疗导致 IFN 诱导的跨膜 (IFITM) 蛋白下调。 IFITM 蛋白，尤其是 IFITM3，是病毒-细胞融合的有效抑制剂，并且对一系列致病病毒具有广泛的活性。我们发现，在原代细胞和转化细胞中，IFITM 沉默或敲除后，雷帕霉素处理对慢病毒转导的影响减弱，转导增强的程度取决于 IFITM 蛋白的基础表达，其中 IFITM3 的主要贡献。雷帕霉素治疗对 IFITM3 的影响体现在蛋白质水平，而不是 mRNA 水平，并且是选择性的，因为许多其他内体相关跨膜蛋白不受影响。雷帕霉素介导的 IFITM3 降解需要内体运输、泛素化、运输 (ESCRT) 机制所需的内体分选复合物和溶酶体酸化。由于 IFITM 蛋白表现出广泛的抗病毒活性，我们发现 mTOR 抑制也会促进另一种 IFITM 敏感病毒（甲型流感病毒）的感染，但不会促进对 IFITM 具有抗性的仙台病毒的感染。我们的结果确定了 mTOR 抑制剂增强病毒进入细胞的分子基础，并揭示了这些临床重要药物以前未被认识的免疫抑制特征。此外，这项研究揭示了 mTOR 通路和内溶酶体膜上的 IFITM 蛋白之间的功能趋同。
Gene delivery by virus-like particles holds enormous therapeutic potential to correct inherited genetic disorders and to prevent infectious disease. However, cells express antiviral factors that prevent virus infection and, consequently, limit the success of gene therapy. Here, we reveal the mechanism by which the drug rapamycin improves lentivirus-mediated gene delivery. Rapamycin treatment led to degradation of IFITM3, a broad and potent antiviral protein which inhibits virus entry into cells. IFITM3 is selectively cleared from endosomes, the sites where viral and cellular membranes fuse, and is sorted for disposal in lysosomes. While revealing an immunosuppressive function with clinical benefits, we caution that rapamycin use in humans may facilitate infection by pathogenic viruses like Influenza A virus. Rapamycin and its derivatives are specific inhibitors of mammalian target of rapamycin (mTOR) kinase and, as a result, are well-established immunosuppressants and antitumorigenic agents. Additionally, this class of drug promotes gene delivery by facilitating lentiviral vector entry into cells, revealing its potential to improve gene therapy efforts. However, the precise mechanism was unknown. Here, we report that mTOR inhibitor treatment results in down-regulation of the IFN-induced transmembrane (IFITM) proteins. IFITM proteins, especially IFITM3, are potent inhibitors of virus–cell fusion and are broadly active against a range of pathogenic viruses. We found that the effect of rapamycin treatment on lentiviral transduction is diminished upon IFITM silencing or knockout in primary and transformed cells, and the extent of transduction enhancement depends on basal expression of IFITM proteins, with a major contribution from IFITM3. The effect of rapamycin treatment on IFITM3 manifests at the level of protein, but not mRNA, and is selective, as many other endosome-associated transmembrane proteins are unaffected. Rapamycin-mediated degradation of IFITM3 requires endosomal trafficking, ubiquitination, endosomal sorting complex required for transport (ESCRT) machinery, and lysosomal acidification. Since IFITM proteins exhibit broad antiviral activity, we show that mTOR inhibition also promotes infection by another IFITM-sensitive virus, Influenza A virus, but not infection by Sendai virus, which is IFITM-resistant. Our results identify the molecular basis by which mTOR inhibitors enhance virus entry into cells and reveal a previously unrecognized immunosuppressive feature of these clinically important drugs. In addition, this study uncovers a functional convergence between the mTOR pathway and IFITM proteins at endolysosomal membranes.
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影响因子：
4.3
作者：
Englund, Janet;Feuchtinger, Tobias;Ljungman, Per
通讯作者：
Ljungman, Per
影响因子：
5.4
作者：
Gorman, Matthew J.;Poddar, Subhajit;Diamond, Michael S.
通讯作者：
Diamond, Michael S.
DOI：
10.4161/cc.8.7.8044
发表时间：
2009-04-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Foster DA;Toschi A
通讯作者：
Toschi A
影响因子：
30.3
作者：
Compton AA;Bruel T;Porrot F;Mallet A;Sachse M;Euvrard M;Liang C;Casartelli N;Schwartz O
通讯作者：
Schwartz O
影响因子：
64.8
作者：
Everitt, Aaron R.;Clare, Simon;Pertel, Thomas;John, Sinu P.;Wash, Rachael S.;Smith, Sarah E.;Chin, Christopher R.;Feeley, Eric M.;Sims, Jennifer S.;Adams, David J.;Wise, Helen M.;Kane, Leanne;Goulding, David;Digard, Paul;Anttila, Verneri;Baillie, J. Kenneth;Walsh, Tim S.;Hume, David A.;Palotie, Aarno;Xue, Yali;Colonna, Vincenza;Tyler-Smith, Chris;Dunning, Jake;Gordon, Stephen B.;Smyth, Rosalind L.;Openshaw, Peter J.;Dougan, Gordon;Brass, Abraham L.;Kellam, Paul
通讯作者：
Kellam, Paul