GBP5 Is an Interferon-Induced Inhibitor of Respiratory Syncytial Virus
GBP5 Is an Interferon-Induced Inhibitor of Respiratory Syncytial Virus
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GBP5 是干扰素诱导的呼吸道合胞病毒抑制剂
DOI：
10.1128/jvi.01407-20
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发表时间：
2020-11-01
影响因子：
5.4
通讯作者：
Zhang, Wenyan
中科院分区：
文献类型：
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作者：
Li, Zhaolong;Qu, Xinglong;Zhang, Wenyan
鸟苷酸结合蛋白5（Guanylate binding protein 5，GBP 5）属于GT3亚家族，其主要由干扰素γ（IFN-γ）诱导并参与许多重要的细胞过程，包括炎性小体激活和针对多种微生物病原体的先天免疫。然而，GBP 5是否抑制呼吸道合胞病毒（RSV）感染尚不清楚。在这项研究中，我们确定GBP 5作为IFN-γ抗RSV活性的效应子，并发现在儿童中，较弱的免疫应答，特别是较弱的IFN-γ应答和GBP 5表达降低，导致RSV易感性。此外，我们发现GBP 5降低了RSV小疏水（SH）蛋白的细胞相关水平，该蛋白被鉴定为病毒孔蛋白。相反，在GBP 5存在下，SH蛋白的过表达拯救了RSV复制。GBP 5诱导的细胞内SH蛋白水平的降低是因为GBP 5促进SH蛋白释放到细胞培养物中。此外，在C末端具有变化的GBP 5 C583 A突变体或缺乏C末端区域的GBP 5 Δ C突变体（其损害GBP 5在高尔基体中的定位）不能抑制RSV感染，而GTP酶缺陷型GBP 5维持RSV抑制，这表明RSV抑制需要GBP 5的高尔基体定位而不是GTP酶活性。有趣的是，我们发现RSV感染或RSV G蛋白通过上调DZIP 3（一种E3连接酶）下调GBP 5表达，DZIP 3通过K48泛素化和蛋白酶体途径诱导GBP 5降解。因此，这项研究揭示了宿主限制性因子GBP 5和RSV感染之间复杂的相互作用，并为了解RSV的发病机制提供了重要信息。重要RSV是一种高度传染性病毒，在婴儿出生后的第一年内引起多次感染。它也容易引起老年人或免疫功能低下的个体感染，表明免疫力的个体差异在RSV感染中起重要作用。因此，深入研究RSV的致病机制，筛选出抑制RSV感染的关键基因，对开发有效的RSV感染控制策略具有重要意义。在这里，我们报告说，干扰素诱导基因GBP 5有效地抑制RSV复制，通过减少RSV小疏水（SH）蛋白，这是一种病毒孔蛋白的细胞相关水平。相反，RSV G蛋白显示上调DZIP 3蛋白的表达，DZIP 3蛋白是一种通过蛋白酶体途径降解GBP 5的E3连接酶。本研究为深入了解RSV的致病机制、宿主免疫机制以及病毒与宿主之间复杂的相互作用提供了重要信息。
Guanylate binding protein 5 (GBP5) belongs to the GTPase subfamily, which is mainly induced by interferon gamma (IFN-gamma) and is involved in many important cellular processes, including inflammasome activation and innate immunity against a wide variety of microbial pathogens. However, it is unknown whether GBP5 inhibits respiratory syncytial virus (RSV) infection. In this study, we identified GBP5 as an effector of the anti-RSV activity of IFN-gamma and found that in children, the weaker immune response, especially the weaker IFN-gamma response and the decreased GBP5 expression, leads to RSV susceptibility. Furthermore, we revealed that GBP5 reduced the cell-associated levels of the RSV small hydrophobic (SH) protein, which was identified as a viroporin. In contrast, overexpression of the SH protein rescued RSV replication in the presence of GBP5. The GBP5-induced decrease in intracellular SH protein levels is because GBP5 promotes the release of the SH protein into the cell culture. Moreover, the GBP5 C583A mutants with changes at the C terminus or the GBP5 Delta C mutant lacking the C-terminal region, which impairs GBP5 localization in the Golgi, could not inhibit RSV infection, whereas the GTPase-defective GBP5 maintained RSV inhibition, suggesting that Golgi localization but not the GTPase activity of GBP5 is required for RSV inhibition. Interestingly, we found that RSV infection or RSV G protein downregulates GBP5 expression by upregulating DZIP3, an E3 ligase, which induces GBP5 degradation through the K48 ubiquitination and proteasomal pathways. Thus, this study reveals a complicated interplay between host restrictive factor GBP5 and RSV infection and provides important information for understanding the pathogenesis of RSV.IMPORTANCE RSV is a highly contagious virus that causes multiple infections in infants within their first year of life. It can also easily cause infection in elderly or immunocompromised individuals, suggesting that individual differences in immunity play an important role in RSV infection. Therefore, exploring the pathogenic mechanisms of RSV and identifying essential genes which inhibit RSV infection are necessary to develop an effective strategy to control RSV infection. Here, we report that the IFN-inducible gene GBP5 potently inhibits RSV replication by reducing the cell-associated levels of the RSV small hydrophobic (SH) protein, which is a viroporin. In contrast, the RSV G protein was shown to upregulate the expression of the DZIP3 protein, an E3 ligase that degrades GBP5 through the proteasomal pathway. Our study provides important information for the understanding of the pathogenic mechanisms of RSV and host immunity as well as the complicated interplay between the virus and host.