Interferons (IFNs) control viral infections by inducing expression of IFN-stimulated genes (ISGs) that restrict distinct steps of viral replication. We report herein that gamma-interferon-inducible lysosomal thiol reductase (GILT), a lysosome-associated ISG, restricts the infectious entry of selected enveloped RNA viruses. Specifically, we demonstrated that GILT was constitutively expressed in lung epithelial cells and fibroblasts and its expression could be further induced by type II interferon. While overexpression of GILT inhibited the entry mediated by envelope glycoproteins of SARS coronavirus (SARS-CoV), Ebola virus (EBOV) and Lassa fever virus (LASV), depletion of GILT enhanced the entry mediated by these viral envelope glycoproteins. Furthermore, mutations that impaired the thiol reductase activity or disrupted the N-linked glycosylation, a posttranslational modification essential for its lysosomal localization, largely compromised GILT restriction of viral entry. We also found that the induction of GILT expression reduced the level and activity of cathepsin L, which is required for the entry of these RNA viruses in lysosomes. Our data indicate that GILT is a novel antiviral ISG that specifically inhibits the entry of selected enveloped RNA viruses in lysosomes via disruption of cathepsin L metabolism and function and may play a role in immune control and pathogenesis of these viruses.

中文翻译：

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GILT限制了由SARS-CoV，埃博拉病毒和拉沙热病毒的包膜糖蛋白介导的细胞进入。

干扰素（IFN）通过诱导限制病毒复制的不同步骤的IFN刺激基因（ISG）的表达来控制病毒感染。我们在这里报告，γ-干扰素诱导的溶酶体硫醇还原酶（GILT），一种溶酶体相关的ISG，限制了选定的包膜RNA病毒的感染性进入。具体而言，我们证明了GILT在肺上皮细胞和成纤维细胞中组成性表达，II型干扰素可进一步诱导其表达。尽管GILT的过表达抑制了SARS冠状病毒（SARS-CoV），埃博拉病毒（EBOV）和拉沙热病毒（LASV）的包膜糖蛋白介导的进入，但GILT的耗竭却增强了这些病毒包膜糖蛋白介导的进入。此外，损害硫醇还原酶活性或破坏N-联糖基化的突变，翻译后修饰对其溶酶体定位必不可少，大大损害了GILT对病毒进入的限制。我们还发现诱导GILT表达降低了组织蛋白酶L的水平和活性，这是这些RNA病毒进入溶酶体所必需的。我们的数据表明，GILT是一种新型抗病毒ISG，可通过破坏组织蛋白酶L的代谢和功能来特异性抑制所选包膜RNA病毒进入溶酶体，并可能在这些病毒的免疫控制和发病机理中发挥作用。