The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I
The E3 Ubiquitin Ligase TRIM40 Attenuates Antiviral Immune Responses by Targeting MDA5 and RIG-I
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E3 泛素连接酶 TRIM40 通过靶向 MDA5 和 RIG-I 减弱抗病毒免疫反应。
DOI：
10.1016/j.celrep.2017.10.020
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发表时间：
2017-11-07
期刊：
影响因子：
8.8
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Zhao, Chunyuan;Jia, Mutian;Cao, Xuetao
视黄酸诱导基因-I (RIG-I) 样受体 (RLR)，包括黑色素瘤分化相关基因 5 (MDA5) 和 RIG-I，对于宿主识别非自身 RNA，尤其是病毒 RNA 至关重要。因此，RLRs的表达和激活在消除入侵的RNA病毒和维持免疫稳态方面发挥着重要作用。然而，RLR 表达如何受到严格调控仍有待进一步研究。在这项研究中，我们鉴定了一个主要组织相容性复合体 (MHC) 编码基因，三重相互作用基序 40 (TRIM40)，通过直接靶向 MDA5 和 RIG-I 作为 RLR 信号传导的抑制剂。 TRIM40 与 MDA5 和 RIG-I 结合，并通过其 E3 连接酶活性促进其 K27 和 K48 连接的多聚泛素化，从而导致其蛋白酶体降解。 TRIM40 缺陷会增强 RLR 触发的信号传导。因此，TRIM40 缺陷极大地增强了抗病毒免疫反应并减少了体内病毒复制。因此，我们证明 TRIM40 限制 RLR 触发的先天激活，表明 TRIM40 作为控制病毒感染的潜在治疗靶点。
Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including melanoma differentiation-associated gene 5 (MDA5) and RIG-I, are crucial for host recognition of non-self RNAs, especially viral RNA. Thus, the expression and activation of RLRs play fundamental roles in eliminating the invading RNA viruses and maintaining immune homeostasis. However, how RLR expression is tightly regulated remains to be further investigated. In this study, we identified a major histocompatibility complex (MHC)-encoded gene, tripartite interaction motif 40 (TRIM40), as a suppressor of RLR signaling by directly targeting MDA5 and RIG-I. TRIM40 binds to MDA5 and RIG-I and promotes their K27- and K48-linked polyubiquitination via its E3 ligase activity, leading to their proteasomal degradation. TRIM40 deficiency enhances RLR-triggered signaling. Consequently, TRIM40 deficiency greatly enhances antiviral immune responses and decreases viral replication in vivo. Thus, we demonstrate that TRIM40 limits RLR-triggered innate activation, suggesting TRIM40 as a potential therapeutic target for the control of viral infection.