Histone H2A Nuclear/Cytoplasmic Trafficking Is Essential for Negative Regulation of Antiviral Immune Response and Lysosomal Degradation of TBK1 and IRF3.
Histone H2A Nuclear/Cytoplasmic Trafficking Is Essential for Negative Regulation of Antiviral Immune Response and Lysosomal Degradation of TBK1 and IRF3.
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组蛋白 H2A 核/细胞质运输对于抗病毒免疫反应的负调节以及 TBK1 和 IRF3 的溶酶体降解至关重要
DOI：
10.3389/fimmu.2021.771277
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发表时间：
2021
影响因子：
7.3
通讯作者：
Chang MX
中科院分区：
文献类型：
--
作者：
Wu XM;Fang H;Zhang J;Bi YH;Chang MX
组蛋白H2 A是以核小体形式紧密结合的核分子。我们以前的研究已经证明了鱼H2 A变体对革兰氏阴性细菌杀鱼爱德华氏菌和革兰氏阳性细菌无乳链球菌的抗菌特性。本研究旨在探讨鱼H2 A蛋白在RLR信号通路和宿主天然免疫应答中的负调控作用及其机制。SVCV感染在感染早期显着抑制组蛋白H2 A的表达，但在感染晚期（例如48和72 hpi）诱导组蛋白H2 A的表达。在正常生理条件下，组蛋白H2 A是核定位的。然而，SVCV感染促进组蛋白H2 A从细胞核迁移到细胞质。体内研究表明，组蛋白H2 A过表达导致SVCV基因表达增加，存活率降低。组蛋白H2 A的过表达也显著降低了参与RLR抗病毒信号通路的基因的表达水平。此外，组蛋白H2 A靶向TBK 1和IRF 3，以促进其通过溶酶体途径的蛋白质降解，并损害TBK 1-IRF 3功能复合物的形成。重要的是，组蛋白H2 A完全消除了TBK 1介导的抗病毒活性，并极大地损害了IRF 3的蛋白表达，特别是核IRF 3。进一步的分析表明，抑制组蛋白H2 A的核质转运可以减轻TBK 1和IRF 3的蛋白降解，阻断组蛋白H2 A对SVCV感染的负调控作用。总的来说，我们的研究结果表明，组蛋白H2 A核/胞质运输是必不可少的负调控的RLR信号通路和抗病毒免疫反应，在SVCV感染。
Histone H2A is a nuclear molecule tightly associated in the form of the nucleosome. Our previous studies have demonstrated the antibacterial property of piscine H2A variants against gram-negative bacteria Edwardsiella piscicida and Gram-positive bacteria Streptococcus agalactiae. In this study, we show the function and mechanism of piscine H2A in the negative regulation of RLR signaling pathway and host innate immune response against spring viremia of carp virus (SVCV) infection. SVCV infection significantly inhibits the expression of histone H2A during an early stage of infection, but induces the expression of histone H2A during the late stage of infection such as at 48 and 72 hpi. Under normal physiological conditions, histone H2A is nuclear-localized. However, SVCV infection promotes the migration of histone H2A from the nucleus to the cytoplasm. The in vivo studies revealed that histone H2A overexpression led to the increased expression of SVCV gene and decreased survival rate. The overexpression of histone H2A also significantly impaired the expression levels of those genes involved in RLR antiviral signaling pathway. Furthermore, histone H2A targeted TBK1 and IRF3 to promote their protein degradation via the lysosomal pathway and impair the formation of TBK1-IRF3 functional complex. Importantly, histone H2A completely abolished TBK1-mediated antiviral activity and enormously impaired the protein expression of IRF3, especially nuclear IRF3. Further analysis demonstrated that the inhibition of histone H2A nuclear/cytoplasmic trafficking could relieve the protein degradation of TBK1 and IRF3, and blocked the negative regulation of histone H2A on the SVCV infection. Collectively, our results suggest that histone H2A nuclear/cytoplasmic trafficking is essential for negative regulation of RLR signaling pathway and antiviral immune response in response to SVCV infection.
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影响因子：
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DOI：
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发表时间：
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