College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China.
College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China.
Cell Rep. 2024 Sep 24;43(9):114687. doi: 10.1016/j.celrep.2024.114687. Epub 2024 Aug 30.
Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with mitochondrial antiviral signaling proteins (MAVSs) to activate IRF3 and nuclear factor κB (NF-κB) signaling, initiating innate immune responses. Thus, RLR activation plays a vital role in the removal of invasive RNA viruses while maintaining immune homeostasis. However, inadequate or excessive activation of immunity can cause harm and can even lead to lethal consequences. In this study, we identify an E3 ligase, ankyrin repeat and IBR domain containing 1 (ANKIB1), which suppresses RLR signaling via MAVS. ANKIB1 binds to MAVS to enhance K48-linked polyubiquitination with K311R, causing proteasomal degradation of MAVS. Deficiency of ANKIB1 significantly increases the RLR-mediated production of type I interferon (IFN) along with pro-inflammatory factors. Consequently, ANKIB1 deficiency remarkably increases antiviral immunity and decreases viral replication in vivo. Therefore, we reveal that ANKIB1 restricts RLR-induced innate immune activation, indicating its potential role as a therapeutic target for viral infections.
在感知细胞质病毒 RNA 后，视黄酸诱导基因-I 样受体 (RLR) 与线粒体抗病毒信号蛋白 (MAVS) 相互作用，激活 IRF3 和核因子 κB (NF-κB) 信号通路，启动固有免疫反应。因此，RLR 的激活在清除入侵性 RNA 病毒的同时，对维持免疫稳态起着至关重要的作用。然而，免疫的不足或过度激活会造成伤害，甚至可能导致致命后果。在这项研究中，我们发现了一种 E3 连接酶，ankyrin 重复和 IBR 结构域包含 1 型 (ANKIB1)，它通过 MAVS 抑制 RLR 信号。ANKIB1 与 MAVS 结合，增强 K48 连接的多泛素化，导致 MAVS 的蛋白酶体降解。ANKIB1 的缺乏显著增加了 RLR 介导的 I 型干扰素 (IFN) 和促炎因子的产生。因此，ANKIB1 缺乏显著增加了抗病毒免疫，并减少了体内的病毒复制。因此，我们揭示了 ANKIB1 限制了 RLR 诱导的固有免疫激活，表明其作为病毒感染治疗靶点的潜力。
