Neonatal/Pediatric Intensive Care Unit, Children's Medical Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
J Med Virol. 2022 Sep;94(9):4490-4501. doi: 10.1002/jmv.27860. Epub 2022 May 25.
Stimulator of interferon genes (STING) is a pivotal innate immune adaptor, and its functions during DNA virus infections have been extensively documented. However, its homeostatic regulation is not well understood. Our study demonstrates that Unc-93 homolog B1 (UNC93B1) is a crucial checker for STING to prevent hyperactivation. Ectopic expression of UNC93B1 attenuates IFN-β promoter activity and the transcriptions of IFN-β, ISG54, and ISG56 genes. Moreover, UNC93B1 also blocks the IRF3 nuclear translocation induced by ectopic expression of both cyclic GMP-AMP synthase (cGAS) and STING and reduces the stability of STING by facilitating its autophagy-lysosome degradation, which can be reversed by lysosome inhibitors. Mechanistically, UNC93B1 interacts with STING and suppresses STING-activated downstream signaling by delivering STING to the lysosomes for degradation, depending on its trafficking capability. UNC93B1 knockout in human embryonic kidney 293T cells facilitates IFN-β promoter activity, IFN-β, ISG54, and ISG56 transcriptions, and IRF3 nuclear translocation induced by ectopic expression of cGAS and STING. Infected with herpes simplex virus-1 (HSV-1), UNC93B1 knockdown BJ cells or primary peritoneal macrophages from Unc93b1-deficient (Unc93b1 ) mice show enhanced IFN-β, ISG54, and ISG56 transcriptions, TBK1 phosphorylation, and reduced STING degradation and viral replication. In addition, Unc93b1 mice exhibit higher IFN-β, ISG54, and ISG56 transcriptions and lower mortality upon HSV-1 infection in vivo. Collectively, these findings demonstrate that UNC93B1 attenuates the cGAS-STING signaling pathway by targeting STING for autophagy-lysosome degradation and provide novel insights into the function of UNC93B1 in antiviral innate immunity.
干扰素基因刺激物（STING）是一种关键的先天免疫衔接蛋白，其在 DNA 病毒感染过程中的功能已得到广泛证实。然而，其自身的稳态调节机制尚不清楚。本研究表明，UNC93B1 是 STING 的重要检查点，可防止其过度激活。UNC93B1 的异位表达可减弱 IFN-β 启动子活性以及 IFN-β、ISG54 和 ISG56 基因的转录。此外，UNC93B1 还可阻断由 cGAS 和 STING 异位表达诱导的 IRF3 核易位，并通过促进 STING 自噬溶酶体降解来降低 STING 的稳定性，溶酶体抑制剂可逆转这一过程。机制上，UNC93B1 与 STING 相互作用，并通过将 STING 递送至溶酶体进行降解，从而抑制 STING 激活的下游信号转导，这依赖于其转运能力。UNC93B1 在人胚肾 293T 细胞中的敲除促进了由 cGAS 和 STING 异位表达诱导的 IFN-β 启动子活性、IFN-β、ISG54 和 ISG56 的转录以及 IRF3 的核易位。感染单纯疱疹病毒-1（HSV-1）后，UNC93B1 敲低的 BJ 细胞或 UNC93b1 缺陷（Unc93b1 ）小鼠的原代腹腔巨噬细胞中 IFN-β、ISG54 和 ISG56 的转录、TBK1 磷酸化以及 STING 降解和病毒复制减少。此外，在体内 HSV-1 感染过程中，Unc93b1 小鼠表现出更高的 IFN-β、ISG54 和 ISG56 的转录以及更低的死亡率。综上所述，这些发现表明 UNC93B1 通过靶向 STING 进行自噬溶酶体降解来减弱 cGAS-STING 信号通路，并为 UNC93B1 在抗病毒先天免疫中的功能提供了新的见解。
