Department of Internal Medicine, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, and MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, GD, China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, GD, China.
Autophagy. 2020 Mar;16(3):408-418. doi: 10.1080/15548627.2019.1615303. Epub 2019 May 22.
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.: ATG: Autophagy-related; Baf A: Bafilomycin A; 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.
DDX58/RIG-I 是一种关键的病毒 RNA 模式识别受体，在抗病毒免疫中发挥着重要作用。其翻译后修饰和稳定性受到严格调控，以介导适度产生 I 型干扰素，维持免疫平衡。最近，我们报道了巨自噬/自噬通过选择性降解 ISG15 相关的 DDX58 来平衡 I 型 IFN 信号，LRRC25 是其关键受体。然而，DDX58 自噬降解的调节机制在很大程度上仍未确定。在这里，我们鉴定了 LRRC59 是 DDX58 介导的 I 型 IFN 信号的重要正向调节剂。在病毒感染时，LRRC59 特异性地与 ISG15 相关的 DDX58 相互作用，并阻止其与 LRRC25 结合，LRRC25 是将 DDX58 递送至自噬体进行 SQSTM1/p62 依赖性降解的二级受体，导致更强的抗病毒免疫反应。因此，我们的研究揭示了选择性自噬在由 LRRC 家族成员的交叉调节介导的先天抗病毒反应中的新的调节作用。这些数据进一步深入了解了自噬和先天免疫反应之间的串扰。
缩写：ATG: 自噬相关; Baf A: 巴弗霉素 A; DDX58/RIG-I: DEAD [Asp-Glu-Ala-Asp] box polypeptide 58; EV: 空载体; IC poly[I:C]: 细胞内多聚肌苷酸多聚胞苷酸; IFIH1/MDA5: 干扰素诱导的含有螺旋酶 C 结构域 1; IFN: 干扰素; ISG15: ISG15 泛素样修饰物; IKBKE: 核因子 kappa B 激酶亚单位 epsilon 抑制剂; IRF3: 干扰素调节因子 3; KO: 敲除; LRRC: 富含亮氨酸重复序列; MAVS: 线粒体抗病毒信号蛋白; CGAS/MB21D1: 环鸟苷酸-AMP 合酶; SeV: 仙台病毒; siRNA: 小干扰 RNA; SQSTM1/p62: 自噬体相关蛋白 1; TBK1: TANK 结合激酶 1; TLR: Toll 样受体; TMEM173/STING: 跨膜蛋白 173; VSV: 水疱性口炎病毒; WT: 野生型。
