BRLF1 suppresses RNA Pol III-mediated RIG-I inflammasome activation in the early EBV lytic lifecycle.
BRLF1 suppresses RNA Pol III-mediated RIG-I inflammasome activation in the early EBV lytic lifecycle.
复制标题
BRLF1 在 EBV 裂解生命周期早期抑制 RNA Pol III 介导的 RIG-I 炎性体激活。
DOI：
10.15252/embr.202050714
复制
发表时间：
2021-01-07
期刊：
影响因子：
7.7
通讯作者：
Kuang, Ersheng
中科院分区：
文献类型：
--
作者：
Long, Xubing;Yang, Jing;Kuang, Ersheng
疱疹病毒的潜伏感染组成性激活炎性小体，而裂解性复制通过不同的机制抑制其激活。然而，EB病毒（EBV）裂解性复制如何抑制炎性小体的激活仍然是未知的。在这里，我们揭示了EBV立即早期蛋白BRLF 1抑制炎性小体激活，BRLF 1缺乏显着增加炎性小体的激活和细胞裂解生命周期早期的pyroptosis。BRLF 1与RNA聚合酶III亚基相互作用以抑制免疫刺激性小RNA转录、RIG-I炎性小体激活和抗病毒反应。因此，BRLF 1缺陷型EBV初次感染通过IL-1 β和IL-18诱导强大的T细胞和NK细胞活化和杀伤。抑制炎性小体活化的BRLF 1衍生肽足以抑制淋巴细胞中BRLF 1缺陷型EBV原发感染期间的T细胞和NK细胞应答。这些结果揭示了一种新的机制，参与逃避炎性小体激活和抗病毒反应在EBV早期裂解感染，并提供了一个有前途的方法，针对致癌疱疹病毒感染的炎性小体的操作。
Latent infection with herpesviruses constitutively activates inflammasomes, while lytic replication suppresses their activation through distinct mechanisms. However, how Epstein-Barr virus (EBV) lytic replication inhibits the activation of inflammasomes remains unknown. Here, we reveal that the EBV immediate-early protein BRLF1 inhibits inflammasome activation, and BRLF1 deficiency significantly increases the activation of inflammasomes and pyroptosis during early lytic lifecycle. BRLF1 interacts with RNA polymerase III subunits to suppress immunostimulatory small RNA transcription, RIG-I inflammasome activation, and antiviral responses. Consequently, BRLF1-deficient EBV primary infection induces robust T-cell and NK cell activation and killing through IL-1beta and IL-18. A BRLF1-derived peptide that inhibits inflammasome activation is sufficient to suppress T-cell and NK cell responses during BRLF1-deficient EBV primary infection in lymphocytes. These results reveal a novel mechanism involved in the evasion of inflammasome activation and antiviral responses during EBV early lytic infection and provide a promising approach for the manipulation of inflammasomes against infection of oncogenic herpesviruses.