Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Department of Rheumatology and immunology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
Commun Biol. 2024 Oct 30;7(1):1418. doi: 10.1038/s42003-024-07116-2.
Stimulator of interferon genes (STING) is vital in the cytosolic DNA-sensing process and critical for initiating the innate immune response, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases. Zinc finger CCCH-type antiviral protein 1 (ZC3HAV1) specifically binds the CpG dinucleotides in the viral RNAs of multiple viruses and promotes their degradation. ZAPS (ZC3HAV1 short isoform) is a potent stimulator of retinoid acid-inducible gene I (RIG-I) signaling during the antiviral response. However, how ZC3HAV1 controls STING signaling is unclear. Here, we show that ZC3HAV1 specifically potentiates STING activation by associating with STING to promote its oligomerization and translocation from the endoplasmic reticulum (ER) to the Golgi, which facilitates activation of IRF3 and NF-κB pathway. Accordingly, Zc3hav1 deficiency protects mice against herpes simplex virus-1 (HSV-1) infection- or 5,6-dimethylxanthenone-4-acetic acid (DMXAA)-induced inflammation in a STING-dependent manner. These results indicate that ZC3HAV1 is a key regulator of STING signaling, which suggests its possible use as a therapeutic target for STING-dependent inflammation.
干扰素基因刺激物 (STING) 在细胞质 DNA 感应过程中至关重要，对于启动先天免疫反应至关重要，先天免疫反应在宿主防御中具有重要功能，并有助于炎症性疾病的发病机制。锌指 CCCH 型抗病毒蛋白 1 (ZC3HAV1) 特异性结合多种病毒的 RNA 中的 CpG 二核苷酸，并促进其降解。ZAPS（ZC3HAV1 短型）是抗病毒反应中视黄酸诱导基因 I (RIG-I) 信号的有效刺激物。然而，ZC3HAV1 如何控制 STING 信号尚不清楚。在这里，我们表明 ZC3HAV1 通过与 STING 结合来特异性增强 STING 的激活，从而促进其寡聚化和从内质网 (ER) 向高尔基体的易位，从而促进 IRF3 和 NF-κB 途径的激活。因此，Zc3hav1 缺陷以 STING 依赖性方式保护小鼠免受单纯疱疹病毒 1 (HSV-1) 感染或 5,6-二甲基黄嘌呤-4-乙酸 (DMXAA) 诱导的炎症。这些结果表明 ZC3HAV1 是 STING 信号的关键调节剂，这表明它可能被用作 STING 依赖性炎症的治疗靶点。
