ZMPSTE24 defends against influenza and other pathogenic viruses.
ZMPSTE24 defends against influenza and other pathogenic viruses.
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DOI：
10.1084/jem.20161270
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发表时间：
2017-04-03
期刊：
影响因子：
--
通讯作者：
Dorf ME
中科院分区：
文献类型：
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作者：
Fu B;Wang L;Li S;Dorf ME
Fu等人表明ZMPSTE24是一种广谱抗病毒蛋白，其通过在IFITM途径中作为效应子发挥作用来抑制所选融合病毒的进入。ZMPSTE24蛋白酶活性对于病毒限制是不确定的。在小鼠中，ZMPSTE24缺陷增加了对流感感染的易感性。锌金属肽酶STE24（ZMPSTE24）是一种跨膜金属蛋白酶，其催化活性对于处理核内膜上的核纤层蛋白A和清除内质网上堵塞的translocons至关重要。我们现在报告ZMPSTE24是一种病毒特异性效应子，可限制包膜RNA和DNA病毒，包括甲型流感病毒、寨卡病毒、埃博拉病毒、辛德比斯病毒、水疱性口炎病毒、牛痘病毒和牛痘病毒，但不限制鼠白血病病毒或腺病毒。ZMPSTE24介导的抗病毒作用不依赖于蛋白酶活性。免疫共沉淀研究表明ZMPSTE24可以与干扰素诱导的跨膜蛋白（IFITM）家族的蛋白质复合。IFITM蛋白阻止病毒进入，ZMPSTE24表达是IFITM抗病毒活性所必需的。体内研究表明，ZMPSTE24缺陷型小鼠在流感感染后表现出更高的病毒负荷、增强的细胞因子产生和增加的死亡率。总的来说，这些发现将ZMPSTE24确定为一种内在的广谱抗病毒蛋白，并为抗病毒防御机制提供了见解。
Fu et al. show that ZMPSTE24 is a broad-spectrum antiviral protein that inhibits entry of selected fusogenic viruses by functioning as an effector in the IFITM pathway. ZMPSTE24 protease activity is dispensable for viral restriction. In mice, ZMPSTE24 deficiency increases susceptibility to influenza infection. Zinc metallopeptidase STE24 (ZMPSTE24) is a transmembrane metalloprotease whose catalytic activity is critical for processing lamin A on the inner nuclear membrane and clearing clogged translocons on the endoplasmic reticulum. We now report ZMPSTE24 is a virus-specific effector that restricts enveloped RNA and DNA viruses, including influenza A, Zika, Ebola, Sindbis, vesicular stomatitis, cowpox, and vaccinia, but not murine leukemia or adenovirus. ZMPSTE24-mediated antiviral action is independent of protease activity. Coimmunoprecipitation studies indicate ZMPSTE24 can complex with proteins of the interferon-induced transmembrane protein (IFITM) family. IFITM proteins impede viral entry, and ZMPSTE24 expression is necessary for IFITM antiviral activity. In vivo studies demonstrate ZMPSTE24-deficient mice display higher viral burdens, enhanced cytokine production, and increased mortality after influenza infection. Collectively, these findings identify ZMPSTE24 as an intrinsic broad-spectrum antiviral protein and provide insights into antiviral defense mechanisms.