BIKE regulates dengue virus infection and is a cellular target for broad-spectrum antivirals.
BIKE regulates dengue virus infection and is a cellular target for broad-spectrum antivirals.
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DOI：
10.1016/j.antiviral.2020.104966
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发表时间：
2020-12
影响因子：
7.6
通讯作者：
Einav S
中科院分区：
文献类型：
--
作者：
Pu S;Schor S;Karim M;Saul S;Robinson M;Kumar S;Prugar LI;Dorosky DE;Brannan J;Dye JM;Einav S
全球健康受到新出现的病毒的威胁，其中许多病毒缺乏经批准的疗法和有效的疫苗，包括登革热、埃博拉和委内瑞拉马脑炎。我们以前报道，AAK 1和GAK，两个未充分研究的Numb相关激酶（NAK）家族的四个成员，控制RNA病毒的细胞内运输。然而，BIKE和STK 16在病毒感染中的作用仍然未知。在这里，我们揭示了登革热病毒（DENV）感染对BIKE的需求，而不是STK-16。BIKE介导DENV生命周期的早期（内化后）和晚期（组装/外出）阶段，这种作用部分由衔接蛋白（AP）2复合物μ亚基中苏氨酸156（T156）残基的磷酸化介导。具有有效抗BIKE活性的药理学化合物，包括研究性抗癌药物5 Z-7-oxozeaenol和更具选择性的抑制剂，在体外和离体抑制DENV感染。BIKE过表达逆转抗病毒活性，证实抗病毒作用的机制至少部分是由BIKE介导的。最后，5 Z-7-oxozeaenol对来自三个不相关的RNA病毒家族的病毒表现出抗病毒活性，具有高遗传抗性屏障。这些发现揭示了通过BIKE信号传导对DENV生命周期的知之甚少的阶段的调节，并建立了一个原理证明，即BIKE的药理学抑制可以潜在地用作对抗急性新发病毒感染的广谱策略。
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.
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影响因子：
2.7
作者：
Liu, Hsin-Ping;Lin, Ying-Ju;Tsai, Fuu-Jen
通讯作者：
Tsai, Fuu-Jen
影响因子：
3.7
作者：
Tabara H;Naito Y;Ito A;Katsuma A;Sakurai MA;Ohno S;Shimizu H;Yabuta N;Nojima H
通讯作者：
Nojima H
DOI：
10.1083/jcb.200108123
发表时间：
2002-03-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Conner SD;Schmid SL
通讯作者：
Schmid SL
影响因子：
4.8
作者：
Ninomiya-Tsuji, J;Kajino, T;Matsumoto, K
通讯作者：
Matsumoto, K
DOI：
10.1042/bj20140468
发表时间：
2014-10-15
期刊：
The Biochemical journal
影响因子：
--
作者：
In JG;Striz AC;Bernad A;Tuma PL
通讯作者：
Tuma PL