Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection.
Modulation of GSK-3β activity in Venezuelan equine encephalitis virus infection.
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DOI：
10.1371/journal.pone.0034761
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kashanchi F
中科院分区：
文献类型：
--
作者：
Kehn-Hall K;Narayanan A;Lundberg L;Sampey G;Pinkham C;Guendel I;Van Duyne R;Senina S;Schultz KL;Stavale E;Aman MJ;Bailey C;Kashanchi F
甲病毒，包括委内瑞拉马脑炎病毒（VEEV），在马和人类中引起疾病，在很大比例的病例中表现出明显的脑炎。宿主免疫反应和组织特异性反应的特征可能导致致命的结果以及脑炎的发展。先前已经表明，小鼠的VEEV感染诱导促炎细胞因子基因（例如，IFN-γ、IL-6、IL-12、iNOS和TNF-α。GSK-3β是一种已知可调节促炎基因表达的宿主蛋白，并且已成为神经退行性疾病（如阿尔茨海默氏症）的治疗靶点。因此，在脑炎病毒感染的情况下，GSK-3β的抑制在神经保护能力中是有用的。小分子GSK-3β抑制剂和GSK-3β siRNA实验表明GSK-3β对VEEV的复制具有重要作用。测试了38种第二代BIO衍生物，发现BIoder是最有效的抑制剂，IC 50为10.5 μM，CC 50>100 μM。通过未感染和感染细胞的体外激酶试验证明，BIoder是比BIO更有效的GSK-3β抑制剂。尺寸排阻色谱实验表明，GSK-3β在VEEV感染的细胞中以三种不同的复合物存在，而GSK-3β在未感染的细胞中仅以一种复合物存在。用BIoder处理的细胞表现出抗凋亡基因生存素的增加和促凋亡基因BID的减少，这表明促凋亡基因和抗凋亡基因的调节有助于BIoder处理的保护作用。最后，BIoder部分保护小鼠免于VEEV诱导的死亡。我们的研究证明GSK-3β抑制剂可用于调节VEEV感染。
Alphaviruses, including Venezuelan Equine Encephalitis Virus (VEEV), cause disease in both equine and humans that exhibit overt encephalitis in a significant percentage of cases. Features of the host immune response and tissue-specific responses may contribute to fatal outcomes as well as the development of encephalitis. It has previously been shown that VEEV infection of mice induces transcription of pro-inflammatory cytokines genes (e.g., IFN-γ, IL-6, IL-12, iNOS and TNF-α) within 6 h. GSK-3β is a host protein that is known to modulate pro-inflammatory gene expression and has been a therapeutic target in neurodegenerative disorders such as Alzheimer's. Hence inhibition of GSK-3β in the context of encephalitic viral infections has been useful in a neuroprotective capacity. Small molecule GSK-3β inhibitors and GSK-3β siRNA experiments indicated that GSK-3β was important for VEEV replication. Thirty-eight second generation BIO derivatives were tested and BIOder was found to be the most potent inhibitor, with an IC50 of ∼0.5 µM and a CC50 of >100 µM. BIOder was a more potent inhibitor of GSK-3β than BIO, as demonstrated through in vitro kinase assays from uninfected and infected cells. Size exclusion chromatography experiments demonstrated that GSK-3β is found in three distinct complexes in VEEV infected cells, whereas GSK-3β is only present in one complex in uninfected cells. Cells treated with BIOder demonstrated an increase in the anti-apoptotic gene, survivin, and a decrease in the pro-apoptotic gene, BID, suggesting that modulation of pro- and anti-apoptotic genes contributes to the protective effect of BIOder treatment. Finally, BIOder partially protected mice from VEEV induced mortality. Our studies demonstrate the utility of GSK-3β inhibitors for modulating VEEV infection.
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影响因子：
16
作者：
Charvet C;Wissler M;Brauns-Schubert P;Wang SJ;Tang Y;Sigloch FC;Mellert H;Brandenburg M;Lindner SE;Breit B;Green DR;McMahon SB;Borner C;Gu W;Maurer U
通讯作者：
Maurer U
影响因子：
5.3
作者：
Ding, Qingqing;He, Xianghuo;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie
DOI：
10.1073/pnas.86.23.9494
发表时间：
1989-12-01
影响因子：
11.1
作者：
BEYAERT, R;VANHAESEBROECK, B;FIERS, W
通讯作者：
FIERS, W
影响因子：
5.4
作者：
Garmashova, Natalia;Atasheva, Svetlana;Frolov, Ilya
通讯作者：
Frolov, Ilya
影响因子：
--
作者：
Coghlan, MP;Culbert, AA;Holder, JC
通讯作者：
Holder, JC