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Abstract：
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.
摘要：
组蛋白H2A是以核小体形式紧密结合的核分子。我们先前的研究已经证明了猪H2A变体对革兰氏阴性菌毕西氏菌和革兰氏阳性菌无乳链球菌的抗菌性能。在这项研究中,我们展示了猪H2A在负向调节RLR信号通路和宿主针对鲤鱼春季病毒血症（SVCV）感染的先天免疫应答中的功能和机制。SVCV感染在感染早期显著抑制组蛋白H2A的表达,但在感染后期如48和72hpi诱导组蛋白H2A的表达。在正常生理条件下,组蛋白H2A是核定位的。然而,SVCV感染促进组蛋白H2A从细胞核迁移到细胞质。体内研究表明，组蛋白H2A过表达导致SVCV基因表达增加，存活率降低。组蛋白H2A的过表达也显著损害了RLR抗病毒信号通路中涉及的那些基因的表达水平。此外，组蛋白H2A靶向TBK1和IRF3，通过溶酶体途径促进其蛋白质降解，并损害TBK1-IRF3功能复合物的形成。重要的是,组蛋白H2A完全消除了TBK1介导的抗病毒活性，并极大地损害了IRF3，尤其是核IRF3的蛋白表达。进一步分析表明，抑制组蛋白H2A核/细胞质运输可以减轻TBK1和IRF3的蛋白质降解，并阻断组蛋白H2A对SVCV感染的负调控。总的来说，我们的结果表明,组蛋白H2A核/细胞质运输对于响应SVCV感染的RLR信号通路和抗病毒免疫应答的负调控至关重要.
