LRRC59 modulates type I interferon signaling by restraining the SQSTM1/p62-mediated autophagic degradation of pattern recognition receptor DDX58/RIG-I
LRRC59 modulates type I interferon signaling by restraining the SQSTM1/p62-mediated autophagic degradation of pattern recognition receptor DDX58/RIG-I
复制标题
LRRC59 通过抑制 SQSTM1/p62 介导的模式识别受体 DDX58/RIG-I 的自噬降解来调节 I 型干扰素信号传导。
DOI：
10.1080/15548627.2019.1615303
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发表时间：
2019-05-24
期刊：
影响因子：
13.3
通讯作者：
Cui, Jun
中科院分区：
文献类型：
--
作者：
Xian, Huifang;Yang, Shuai;Cui, Jun
DDX 58/RIG-Ⅰ是病毒RNA的重要模式识别受体，在抗病毒免疫中起重要作用。其翻译后修饰和稳定性受到严格调控，以介导I型IFN的适度产生，从而维持免疫稳态。最近，我们报道了巨自噬/自噬通过LRRC 25选择性降解ISG 15相关的DDX 58来平衡I型IFN信号传导。然而，关于DDX 58自噬降解的调节机制在很大程度上仍不清楚。在这里，我们确定LRRC 59作为DDX 58介导的I型IFN信号传导的重要正调节因子。在病毒感染后，LRRC 59特异性地与ISG 15相关的DDX 58相互作用，并阻断其与LRRC 25的结合，LRRC 25是将DDX 58递送到自噬体进行SQSTM 1/p62依赖性降解的第二受体，导致更强的抗病毒免疫应答。因此，我们的研究揭示了选择性自噬在LRRC家族成员交叉调节介导的先天性抗病毒反应中的新的调节作用。这些数据进一步提供了对自噬和先天免疫反应之间串扰的见解。缩写ATG：自噬相关; Baf A1：巴弗洛霉素A1; DDX58/RIG-I：DEAD [Asp-Glu-Ala-Asp] box多肽58; EV：空载体; IC poly[I：C]：细胞内多聚核糖肌苷多聚核糖胞苷酸; IFIH 1/MDA 5：用解旋酶C结构域1诱导的干扰素; IFN：干扰素; ISG 15：ISG 15泛素样修饰剂; IKBKE：核因子κ B激酶亚基α抑制剂; IRF 3：干扰素调节因子3; KO：敲除; LRRC：含富含亮氨酸重复序列; MAVS：线粒体抗病毒信号蛋白; CGAS/MB 21 D1：环GMP-AMP合酶; SeV：仙台病毒; siRNA：小干扰RNA; SQSTM 1/p62：Sequestosome 1; TBK 1：TANK结合激酶1; TLR：Toll样受体; TMEM 173/STING：跨膜蛋白173; VSV：水疱性口炎病毒; WT：野生型
ABSTRACT DDX58/RIG-I, is a critical pattern recognition receptor for viral RNA, which plays an essential role in antiviral immunity. Its posttranslational modifications and stability are tightly regulated to mediate the moderate production of type I IFN to maintain the immune homeostasis. Recently, we reported that macroautophagy/autophagy balances type I IFN signaling through selective degradation of ISG15-associated DDX58 via LRRC25. However, the regulatory mechanism about the autophagic degradation of DDX58 remains largely undefined. Here, we identified LRRC59 as a vital positive regulator of DDX58-mediated type I IFN signaling. Upon virus infection, LRRC59 specifically interacted with ISG15-associated DDX58 and blocked its association with LRRC25, the secondary receptor to deliver DDX58 to autophagosomes for SQSTM1/p62-dependent degradation, leading to the stronger antiviral immune responses. Thus, our study reveals a novel regulatory role of selective autophagy in innate antiviral responses mediated by the cross-regulation of LRRC family members. These data further provide insights into the crosstalk between autophagy and innate immune responses. Abbreviations ATG: Autophagy-related; Baf A1: Bafilomycin A1; DDX58/RIG-I: DEAD [Asp-Glu-Ala-Asp] box polypeptide 58; EV: Empty vector; IC poly[I:C]: Intracellular polyriboinosinic polyribocytidylic acid; IFIH1/MDA5: Interferon induced with helicase C domain 1; IFN: Interferon; ISG15: ISG15 ubiquitin like modifier; IKBKE: Inhibitor of nuclear factor kappa B kinase subunit epsilon; IRF3: Interferon regulatory factor 3; KO: Knockout; LRRC: Leucine rich repeat containing; MAVS: Mitochondrial antiviral signaling protein; CGAS/MB21D1: Cyclic GMP-AMP synthase; SeV: Sendai virus; siRNA: small interfering RNA; SQSTM1/p62: Sequestosome 1; TBK1: TANK binding kinase 1; TLR: Toll like receptor; TMEM173/STING: Transmembrane protein 173; VSV: Vesicular stomatitis virus; WT: Wild type