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KAP1-Mediated Epigenetic Suppression in Anti-RNA Viral Responses by Direct Targeting RIG-I and MDA5
The Journal of Immunology ( IF 3.6 ) Pub Date : 2021-10-01 , DOI: 10.4049/jimmunol.2100342
Qi Li 1 , Ying Qin 1 , Wenwen Wang 1 , Mutian Jia 1 , Wei Zhao 2 , Chunyuan Zhao 3
Affiliation  

Retinoic acid–inducible gene-I (RIG-I)–like receptors (RLRs), including RIG-I (encoded by Ddx58) and melanoma differentiation–associated gene 5 (MDA5) (encoded by Ifih1), are crucial for initiating antiviral responses. Endogenous retroviral elements (ERVs) are transposable elements derived from exogenous retroviruses that are integrated into the genome. KRAB-associated protein 1 (KAP1) is a key epigenetic suppressor of ERVs that protects cells from detrimental genome instability. Increased ERV transcripts are sensed by RLRs and trigger innate immune signaling. However, whether KAP1 directly controls RLRs activity remains unclear. In this study, we show that KAP1 attenuates RNA viral infection–induced type I IFNs and facilitates viral replication by inhibiting RIG-I/MDA5 expression in primary peritoneal macrophages (PMs) of C57BL/6J mice. Kap1 deficiency increases IFN-β expression and inhibits vesicular stomatitis virus replication in C57BL/6J mice in vivo. Mechanistically, KAP1 binds to the promoter regions of Ddx58 and Ifih1 and promotes the establishment of repressive histone marks in primary PMs of C57BL/6J mice. Concordantly, KAP1 suppresses the expression of RIG-I and MDA5 at the transcriptional level in primary PMs of C57BL/6J mice. Our results establish that KAP1 epigenetically suppresses host antiviral responses by directly targeting RIG-1 and MDA5, thus facilitating the immune escape of RNA viruses.



中文翻译:

通过直接靶向 RIG-I 和 MDA5,KAP1 介导的抗 RNA 病毒反应的表观遗传抑制

视黄酸诱导基因-I (RIG-I) 样受体 (RLR),包括 RIG-I(由Ddx58编码)和黑色素瘤分化相关基因 5(MDA5)(由Ifih1编码)),对于启动抗病毒反应至关重要。内源性逆转录病毒元件 (ERV) 是源自整合到基因组中的外源性逆转录病毒的转座元件。KRAB 相关蛋白 1 (KAP1) 是 ERV 的关键表观遗传抑制因子,可保护细胞免受有害基因组不稳定性的影响。增加的 ERV 转录物被 RLR 感知并触发先天免疫信号。然而,KAP1 是否直接控制 RLRs 活动仍不清楚。在这项研究中,我们表明 KAP1 通过抑制 C57BL/6J 小鼠原代腹膜巨噬细胞 (PMs) 中的 RIG-I/MDA5 表达来减弱 RNA 病毒感染诱导的 I 型干扰素并促进病毒复制。卡普1缺乏会增加 IFN-β 表达并抑制 C57BL/6J 小鼠体内水泡性口炎病毒的复制。从机制上讲,KAP1 与Ddx58Ifih1的启动子区域结合,并促进 C57BL/6J 小鼠初级 PM 中抑制性组蛋白标记的建立。一致地,KAP1 在 C57BL/6J 小鼠的初级 PM 中在转录水平上抑制 RIG-I 和 MDA5 的表达。我们的结果表明,KAP1 通过直接靶向 RIG-1 和 MDA5 在表观遗传上抑制宿主抗病毒反应,从而促进 RNA 病毒的免疫逃逸。

更新日期:2021-09-21
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