Jiang Xuefeng, Tang Tian, Guo Jinfeng, Wang Yuhang, Li Peipei, Chen Xiangjun, Wang Lily, Wen Yiqun, Jia Junli, Emanuela Garbarino, Hu Benshun, Chen Shuhua, Yao Kun, Li Linyun, Tang Huaming
Department of Immunology, Nanjing Medical University, Nanjing, People's Republic of China.
Department of Women's Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, People's Republic of China.
mBio. 2021 Feb 16;12(1):e03505-20. doi: 10.1128/mBio.03505-20.
U26 is one of the roseolovirus unique genes with unknown function. Human herpesvirus 6B (HHV-6B) pU26 is predicted to be an 8-transmembrane protein containing a mitochondrion location signal. Here, we analyzed U26 function during HHV-6B infection and find that (i) HHV-6B U26 is expressed at a very early stage during HHV-6B infection, and knockdown of it results in a significant decrease of HHV-6B progeny virus production; (ii) U26 inhibits the activation of the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)/mitochondrial antiviral signaling protein (MAVS) signaling pathway, an important anti-HHV-6B infection innate immune response, by targeting MAVS protein for degradation; and (iii) a portion of U26 locates to the mitochondria, which could affect the mitochondrial membrane potential and finally leads to MAVS degradation. These findings indicate that HHV-6B U26 is a novel antagonistic viral factor against host innate antiviral immunity. HHV-6B (human herpesvirus 6B) is well known to evade host antiviral responses and establish a lifelong latent infection. How HHV-6B evades RNA recognition is still poorly understood. Our results indicate that HHV-6 U26 plays a vital role in RLR/MAVS signaling pathway activity. Knockout of endogenous MAVS could facilitate HHV-6B replication. The findings in this study could provide new insights into host-virus interactions and help develop a new therapy against HHV-6B infection.
U26是玫瑰疹病毒中功能未知的独特基因之一。人疱疹病毒6B（HHV-6B）的pU26被预测为一种含有线粒体定位信号的8次跨膜蛋白。在此，我们分析了HHV-6B感染期间U26的功能，发现：（i）HHV-6B U26在HHV-6B感染的极早期表达，敲低它会导致HHV-6B子代病毒产生显著减少；（ii）U26通过靶向MAVS蛋白进行降解，抑制视黄酸诱导基因I（RIG-I）样受体（RLR）/线粒体抗病毒信号蛋白（MAVS）信号通路的激活，这是一种重要的抗HHV-6B感染的先天免疫反应；（iii）一部分U26定位于线粒体，这可能影响线粒体膜电位并最终导致MAVS降解。这些发现表明，HHV-6B U26是一种针对宿主先天抗病毒免疫的新型拮抗病毒因子。众所周知，HHV-6B（人疱疹病毒6B）可逃避宿主抗病毒反应并建立终身潜伏感染。HHV-6B如何逃避RNA识别仍知之甚少。我们的结果表明，HHV-6 U26在RLR/MAVS信号通路活性中起重要作用。敲除内源性MAVS可促进HHV-6B复制。本研究中的发现可为宿主-病毒相互作用提供新见解，并有助于开发针对HHV-6B感染的新疗法。
