Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Department of Microbiology and Immunology, Stanford University, CA, USA.
US Army Medical Research Institute of Infectious Diseases, Viral Immunology Branch, Fort Detrick, Maryland, USA.
Antiviral Res. 2020 Dec;184:104966. doi: 10.1016/j.antiviral.2020.104966. Epub 2020 Nov 1.
Global health is threatened by emerging viruses, many of which lack approved therapies and effective vaccines, including dengue, Ebola, and Venezuelan equine encephalitis. We previously reported that AAK1 and GAK, two of the four members of the understudied Numb-associated kinases (NAK) family, control intracellular trafficking of RNA viruses. Nevertheless, the role of BIKE and STK16 in viral infection remained unknown. Here, we reveal a requirement for BIKE, but not STK-16, in dengue virus (DENV) infection. BIKE mediates both early (postinternalization) and late (assembly/egress) stages in the DENV life cycle, and this effect is mediated in part by phosphorylation of a threonine 156 (T156) residue in the μ subunit of the adaptor protein (AP) 2 complex. Pharmacological compounds with potent anti-BIKE activity, including the investigational anticancer drug 5Z-7-oxozeaenol and more selective inhibitors, suppress DENV infection both in vitro and ex vivo. BIKE overexpression reverses the antiviral activity, validating that the mechanism of antiviral action is, at least in part, mediated by BIKE. Lastly, 5Z-7-oxozeaenol exhibits antiviral activity against viruses from three unrelated RNA viral families with a high genetic barrier to resistance. These findings reveal regulation of poorly understood stages of the DENV life cycle via BIKE signaling and establish a proof-of-principle that pharmacological inhibition of BIKE can be potentially used as a broad-spectrum strategy against acute emerging viral infections.
全球健康受到新兴病毒的威胁，其中许多病毒缺乏经过批准的治疗方法和有效的疫苗，包括登革热、埃博拉病毒和委内瑞拉马脑炎。我们之前曾报道过，AAK1 和 GAK 是研究较少的 NUMB 相关激酶 (NAK) 家族的四个成员中的两个，它们控制 RNA 病毒的细胞内运输。然而，BIKE 和 STK16 在病毒感染中的作用仍然未知。在这里，我们揭示了 BIKE（而不是 STK-16）在登革热病毒 (DENV) 感染中的作用。BIKE 介导 DENV 生命周期中的早期（内化后）和晚期（组装/出芽）阶段，这种作用部分是通过衔接蛋白 (AP) 2 复合物 μ 亚基中的丝氨酸 156 (T156) 残基的磷酸化介导的。具有强效抗 BIKE 活性的药理学化合物，包括研究性抗癌药物 5Z-7-氧杂氮杂豆醇和更具选择性的抑制剂，在体外和体内均抑制 DENV 感染。BIKE 的过表达逆转了抗病毒活性，验证了抗病毒作用的机制至少部分是通过 BIKE 介导的。最后，5Z-7-氧杂氮杂豆醇对来自三个具有高遗传抗性的 RNA 病毒家族的病毒具有抗病毒活性。这些发现揭示了 BIKE 信号通路对 DENV 生命周期中未被充分了解的阶段的调节，并确立了一个原理证明，即药理学抑制 BIKE 可潜在用作针对急性新发病毒感染的广谱策略。
