Human Hemoglobin Subunit Beta Functions as a Pleiotropic Regulator of RIG-I/MDA5-Mediated Antiviral Innate Immune Responses
Human Hemoglobin Subunit Beta Functions as a Pleiotropic Regulator of RIG-I/MDA5-Mediated Antiviral Innate Immune Responses
复制标题
人血红蛋白亚基 Beta 作为 RIG-I/MDA5 介导的抗病毒先天免疫反应的多效调节剂
DOI：
10.1128/jvi.00718-19
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发表时间：
2019-08-01
影响因子：
5.4
通讯作者：
Qiu, Hua-Ji
中科院分区：
文献类型：
--
作者：
Yang, Qian;Bai, Si-Yu;Qiu, Hua-Ji
血红蛋白是最重要的携氧蛋白，参与先天免疫反应的调节。我们以前曾报道，猪血红蛋白β亚基（HB）通过调节I型干扰素的产生发挥抗病毒活性。然而，抗病毒活性和潜在的机制来源于其他动物的乙肝病毒一直知之甚少。在这里，我们确定了人HB（hHB）作为一个多效性调节RNA病毒的复制通过调节RIG-I/MDA 5介导的信号通路。hHB通过依赖于hHB诱导的活性氧（ROS）促进RIG-I泛素化来增强RIG-I介导的抗病毒应答，而它通过抑制MDA 5-dsRNA相互作用来阻断MDA 5介导的抗病毒信号传导。我们的研究结果有助于理解hHB在RIG-I/MDA 5介导的信号通路调节中的关键作用。我们还提供了新的见解的细胞间氧化还原状态与抗病毒天然免疫的调节的相关性。摘要血红蛋白是一种重要的携氧蛋白，在建立宿主对病原体的抵抗力和调节天然免疫反应中起着至关重要的作用。血红蛋白β亚基（HB）是血红蛋白的重要组成部分，我们以前已经证明，猪HB（pHB）的抗病毒作用是通过促进I型干扰素途径介导的。因此，考虑到人HB（hHB）和pHB之间的高度同源性，我们假设hHB在抗病毒天然免疫中也起着重要作用。在这项研究中，我们的特点是hHB作为一个调节因子的RNA病毒复制的差异调节RIG-I和MDA 5介导的抗病毒信号通路。此外，我们发现hHB通过减少MDA 5-双链RNA（dsRNA）相互作用直接抑制MDA 5介导的信号传导。此外，hHB需要hHB诱导的活性氧（ROS）通过增强K63连接的RIG-I泛素化来促进RIG-I介导的信号传导。综上所述，我们的研究结果表明，hHB是RIG-I/MDA 5介导的抗病毒反应的多效性调节剂，并进一步强调了细胞间微环境（包括氧化还原状态）在调节抗病毒先天免疫反应中的重要性。重要性血红蛋白是最重要的携氧蛋白，参与先天免疫反应的调节。我们以前曾报道，猪血红蛋白β亚基（HB）通过调节I型干扰素的产生发挥抗病毒活性。然而，抗病毒活性和潜在的机制来源于其他动物的乙肝病毒一直知之甚少。在这里，我们确定了人HB（hHB）作为一个多效性调节RNA病毒的复制通过调节RIG-I/MDA 5介导的信号通路。hHB通过依赖于hHB诱导的活性氧（ROS）促进RIG-I泛素化来增强RIG-I介导的抗病毒应答，而它通过抑制MDA 5-dsRNA相互作用来阻断MDA 5介导的抗病毒信号传导。我们的研究结果有助于理解hHB在RIG-I/MDA 5介导的信号通路调节中的关键作用。我们还提供了新的见解的细胞间氧化还原状态与抗病毒天然免疫的调节的相关性。
Hemoglobin, the most important oxygen-carrying protein, is involved in the regulation of innate immune responses. We have previously reported that the porcine hemoglobin subunit beta (HB) exerts antiviral activity through regulation of type I interferon production. However, the antiviral activities and the underlying mechanisms of HBs originating from other animals have been poorly understood. Here, we identified human HB (hHB) as a pleiotropic regulator of the replication of RNA viruses through regulation of RIG-I/MDA5-mediated signaling pathways. hHB enhances RIG-I-mediated antiviral responses by promoting RIG-I ubiquitination depending on the hHB-induced reactive oxygen species (ROS), while it blocks MDA5-mediated antiviral signaling by suppressing the MDA5-dsRNA interaction. Our results contribute to an understanding of the crucial roles of hHB in the regulation of the RIG-I/MDA5-mediated signaling pathways. We also provide novel insight into the correlation of the intercellular redox state with the regulation of antiviral innate immunity. ABSTRACT Hemoglobin is an important oxygen-carrying protein and plays crucial roles in establishing host resistance against pathogens and in regulating innate immune responses. The hemoglobin subunit beta (HB) is an essential component of hemoglobin, and we have previously demonstrated that the antiviral role of the porcine HB (pHB) is mediated by promoting type I interferon pathways. Thus, considering the high homology between human HB (hHB) and pHB, we hypothesized that hHB also plays an important role in the antiviral innate immunity. In this study, we characterized hHB as a regulatory factor for the replication of RNA viruses by differentially regulating the RIG-I- and MDA5-mediated antiviral signaling pathways. Furthermore, we showed that hHB directly inhibited MDA5-mediated signaling by reducing the MDA5–double-stranded RNA (dsRNA) interaction. Additionally, hHB required hHB-induced reactive oxygen species (ROS) to promote RIG-I-mediated signaling through enhancement of K63-linked RIG-I ubiquitination. Taken together, our findings suggest that hHB is a pleiotropic regulator of RIG-I/MDA5-mediated antiviral responses and further highlight the importance of the intercellular microenvironment, including the redox state, in regulating antiviral innate immune responses. IMPORTANCE Hemoglobin, the most important oxygen-carrying protein, is involved in the regulation of innate immune responses. We have previously reported that the porcine hemoglobin subunit beta (HB) exerts antiviral activity through regulation of type I interferon production. However, the antiviral activities and the underlying mechanisms of HBs originating from other animals have been poorly understood. Here, we identified human HB (hHB) as a pleiotropic regulator of the replication of RNA viruses through regulation of RIG-I/MDA5-mediated signaling pathways. hHB enhances RIG-I-mediated antiviral responses by promoting RIG-I ubiquitination depending on the hHB-induced reactive oxygen species (ROS), while it blocks MDA5-mediated antiviral signaling by suppressing the MDA5-dsRNA interaction. Our results contribute to an understanding of the crucial roles of hHB in the regulation of the RIG-I/MDA5-mediated signaling pathways. We also provide novel insight into the correlation of the intercellular redox state with the regulation of antiviral innate immunity.