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RNA Helicase LGP2 Negatively Regulates RIG-I Signaling by Preventing TRIM25-Mediated Caspase Activation and Recruitment Domain Ubiquitination.
Journal of Interferon & Cytokine Research ( IF 1.9 ) Pub Date : 2019-06-25 , DOI: 10.1089/jir.2019.0059
Kendra M Quicke 1, 2 , Kristin Y Kim 1, 2 , Curt M Horvath 3 , Mehul S Suthar 1, 2
Affiliation  

The retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are a family of cytosolic pattern recognition receptors that play a critical role in binding viral RNA and triggering antiviral immune responses. The RLR LGP2 (or DHX58) is a known regulator of the RIG-I signaling pathway; however, the underlying mechanism by which LGP2 regulates RIG-I signaling is poorly understood. To better understand the effects of LGP2 on RIG-I-specific signaling and myeloid cell responses, we probed RIG-I signaling using a highly specific RIG-I agonist to compare transcriptional profiles between WT and Dhx58-/- C57BL\6 bone marrow-derived dendritic cells. Dhx58-/- cells exhibited a marked increase in the magnitude and kinetics of type I interferon (IFN) induction and a broader antiviral response as early as 1 h post-treatment. We determined that LGP2 inhibited RIG-I-mediated IFN-β, IRF-3, and NF-κB promoter activities, indicating a function upstream of the RLR adaptor protein mitochondrial antiviral signaling. Mutational analysis of LGP2 revealed that RNA binding, ATP hydrolysis, and the C-terminal domain fragment were dispensable for inhibiting RIG-I signaling. Using mass spectrometry, we discovered that LGP2 interacted with the E3 ubiquitin ligase TRIM25. Finally, we determined that LGP2 inhibited the TRIM25-mediated K63-specific ubiquitination of the RIG-I N-terminus required for signaling activation.

中文翻译:

RNA 解旋酶 LGP2 通过阻止 TRIM25 介导的半胱天冬酶激活和募集域泛素化来负向调节 RIG-I 信号。

视黄酸诱导基因 I (RIG-I) 样受体 (RLR) 是细胞溶质模式识别受体家族,在结合病毒 RNA 和触发抗病毒免疫反应中起关键作用。RLR LGP2(或 DHX58)是 RIG-I 信号通路的已知调节因子;然而,人们对 LGP2 调节 RIG-I 信号的潜在机制知之甚少。为了更好地了解 LGP2 对 RIG-I 特异性信号和骨髓细胞反应的影响,我们使用高度特异性的 RIG-I 激动剂探测 RIG-I 信号,以比较 WT 和 Dhx58-/- C57BL\6 骨髓之间的转录谱-衍生的树突状细胞。早在治疗后 1 小时,Dhx58-/- 细胞就表现出 I 型干扰素 (IFN) 诱导的强度和动力学显着增加以及更广泛的抗病毒反应。我们确定 LGP2 抑制 RIG-I 介导的 IFN-β、IRF-3 和 NF-κB 启动子活性,表明 RLR 衔接蛋白线粒体抗病毒信号上游的功能。LGP2 的突变分析表明,RNA 结合、ATP 水解和 C 末端结构域片段对于抑制 RIG-I 信号传导是可有可无的。使用质谱法,我们发现 LGP2 与 E3 泛素连接酶 TRIM25 相互作用。最后,我们确定 LGP2 抑制了信号激活所需的 RIG-I N 末端的 TRIM25 介导的 K63 特异性泛素化。和 C 端结构域片段对于抑制 RIG-I 信号是可有可无的。使用质谱法,我们发现 LGP2 与 E3 泛素连接酶 TRIM25 相互作用。最后,我们确定 LGP2 抑制了信号激活所需的 RIG-I N 末端的 TRIM25 介导的 K63 特异性泛素化。和 C 端结构域片段对于抑制 RIG-I 信号是可有可无的。使用质谱法,我们发现 LGP2 与 E3 泛素连接酶 TRIM25 相互作用。最后,我们确定 LGP2 抑制了信号激活所需的 RIG-I N 末端的 TRIM25 介导的 K63 特异性泛素化。
更新日期:2019-11-01
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