Human IFIT proteins inhibit lytic replication of KSHV: A new feed-forward loop in the innate immune system
Human IFIT proteins inhibit lytic replication of KSHV: A new feed-forward loop in the innate immune system
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DOI：
10.1371/journal.ppat.1007609
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发表时间：
2019-02-01
期刊：
影响因子：
6.7
通讯作者：
Swaminathan, Sankar
中科院分区：
文献类型：
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作者：
Li, Dajiang;Swaminathan, Sankar
Kaposi肉瘤相关疱疹病毒(KSHV)与Kaposi肉瘤、原发性渗出性淋巴瘤(PEL)和多中心Castleman病有关。IFIT家族蛋白可以抑制某些病毒的复制，但它们对KSHV裂解复制的影响尚不清楚。在这里，我们发现KSHV裂解复制诱导上皮细胞表达IFIT。去除IFIT1、IFIT2和IFIT3(IFITs)可使感染性KSHV病毒粒子的产量比对照细胞增加25-32倍。KSHV裂解基因的表达被广泛上调，与裂解病毒复制相关的几个基因优先激活。细胞内KSHV基因组数量也因IFIT基因敲除而增加，这与IFIT抑制KSHV DNA复制一致。RNA序列显示，IFIT缺失还导致干扰素和几个干扰素刺激基因(ISGs)的下调，特别是OAS蛋白。OAS下调导致核糖核酸酶L活性下降，总核糖核酸产量略有增加。IFIT免疫沉淀实验还表明，IFIT 1可与病毒mRNAs和细胞内有帽的mRNAs结合，但不能与去帽的RNA或三甲基化的RNA结合，提示IFIT 1也可能通过直接结合抑制病毒的mRNAs表达。综上所述，IFIT通过正向调节干扰素和OAS核糖核酸酶L途径降解核糖核酸来抑制KSHV的裂解复制，此外还可能直接靶向病毒的mRNA。入侵病原体的识别是由各种传感器或模式识别受体(PRRs)进行的，它们检测病原体的保守特征，包括脂质、核酸和蛋白质。PRR的激活触发了最终导致病原体破坏的途径，包括干扰素反应。干扰素反过来诱导许多干扰素刺激的基因，这些基因抑制或摧毁包括病毒在内的各种病原体。IFITs是一种干扰素诱导的蛋白质家族，被认为可以识别RNA，主要对RNA病毒具有抗病毒作用。Kaposi肉瘤相关疱疹病毒(KSHV)是一种DNA病毒，与Kaposi肉瘤和淋巴样恶性肿瘤有关。在这项研究中，我们证明了IFITs不仅通过抑制KSHV mRNA的丰度，而且通过增强干扰素反应的其他效应来限制KSHV的复制。这项研究表明，先天性免疫反应不仅可以控制入侵的病毒，而且可以控制从潜伏期重新激活的病毒，IFITs可以抑制疱疹病毒的复制，并且IFITs可能通过前馈机制放大先天性免疫反应。
Kaposi's sarcoma-associated herpesvirus (KSHV) is causally associated with Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease. The IFIT family of proteins inhibits replication of some viruses, but their effects on KSHV lytic replication was unknown. Here we show that KSHV lytic replication induces IFIT expression in epithelial cells. Depletion of IFIT1, IFIT2 and IFIT3 (IFITs) increased infectious KSHV virion production 25-32-fold compared to that in control cells. KSHV lytic gene expression was upregulated broadly with preferential activation of several genes involved in lytic viral replication. Intracellular KSHV genome numbers were also increased by IFIT knockdown, consistent with inhibition of KSHV DNA replication by IFITs. RNA seq demonstrated that IFIT depletion also led to downregulation of IFN and several interferon-stimulated genes (ISGs), especially OAS proteins. OAS down-regulation led to decreased RNase L activity and slightly increased total RNA yield. IFIT immunoprecipitation also showed that IFIT1 bound to viral mRNAs and cellular capped mRNAs but not to uncapped RNA or trimethylated RNAs, suggesting that IFIT1 may also inhibit viral mRNA expression through direct binding. In summary, IFIT inhibits KSHV lytic replication through positively regulating the IFN and OAS RNase L pathway to degrade RNA in addition to possibly directly targeting viral mRNAs.Author summary The innate immune response to infections is triggered by recognition of pathogens as foreign or non-self. Recognition of invading pathogens is carried out by various sensors or pattern recognition receptors (PRRs) that detect conserved features of pathogens including lipids, nucleic acids and proteins. PRR activation triggers pathways that ultimately lead to pathogen destruction, including the interferon response. Interferons, in turn induce many interferon-stimulated genes, which inhibit or destroy a wide variety of pathogens, including viruses. IFITs are a family of interferon induced proteins that are thought to recognize RNAs and have antiviral effects primarily on RNA viruses. Kaposi's sarcoma-associated herpesvirus (KSHV), a DNA virus, is associated with Kaposi's sarcoma and lymphoid malignancies. In this study we show that IFITs restrict replication of KSHV and does so not only by inhibiting KSHV mRNA abundance but also by enhancing other effectors of the interferon response. This study reveals that the innate immune response can control not only invading viruses but ones that reactivate from latency, that IFITs can inhibit herpesvirus replication and that IFITs may amplify the innate immune response by a feed-forward mechanism.