State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, 430072 Wuhan, China.
Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, 266071 Qingdao, China.
J Immunol. 2019 Jan 15;202(2):559-566. doi: 10.4049/jimmunol.1801325. Epub 2018 Dec 7.
IFN production is crucial for hosts to defend against viral infection, yet it must be tightly controlled to maintain immune homeostasis. TANK-binding kinase 1 (TBK1) is a pivotal kinase in the IFN induction signaling pathway, but it is negatively regulated by multiple molecules to avoid the excessive expression of IFN in mammals. However, the identified TBK1 suppressors and the mechanisms are rare in fish. In this study, we show that zebrafish major vault protein (MVP) recruits and degrades TBK1 in a lysosome-dependent manner to inhibit IFN production. Through viral infection, polyinosinic:polycytidylic acid and RIG-I-like receptor factor stimulation upregulated IFN expression, but overexpression of MVP significantly subverted these inductions. On the protein level, MVP interacted with TBK1, and interestingly, MVP recruited TBK1 from a uniformly distributed state in the cytoplasm to an aggregated state. Finally, MVP mediated the lysosome-dependent degradation of TBK1 and decreased the IFN response and IFN-stimulated genes expression. Our findings reveal that zebrafish MVP is a negative regulator of IFN production by restricting the activation of TBK1, supplying evidence of the balanced mechanisms of IFN expression in lower vertebrates.
IFN 的产生对于宿主抵抗病毒感染至关重要，但必须严格控制以维持免疫稳态。TANK 结合激酶 1（TBK1）是 IFN 诱导信号通路中的关键激酶，但在哺乳动物中，它受到多种分子的负调控以避免 IFN 的过度表达。然而，在鱼类中，鉴定到的 TBK1 抑制剂及其机制很少。在本研究中，我们表明斑马鱼主要穹窿蛋白（MVP）以溶酶体依赖的方式招募和降解 TBK1 以抑制 IFN 的产生。通过病毒感染、多聚肌苷酸：多聚胞苷酸和 RIG-I 样受体因子的刺激上调了 IFN 的表达，但 MVP 的过表达显著颠覆了这些诱导。在蛋白质水平上，MVP 与 TBK1 相互作用，有趣的是，MVP 将 TBK1 从细胞质中均匀分布的状态募集到聚集状态。最后，MVP 介导了 TBK1 的溶酶体依赖性降解，并降低了 IFN 反应和 IFN 刺激基因的表达。我们的研究结果表明，斑马鱼 MVP 通过限制 TBK1 的激活来抑制 IFN 的产生，为较低等脊椎动物中 IFN 表达的平衡机制提供了证据。
