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Zika virus depletes neural stem cells and evades selective autophagy by suppressing the Fanconi anemia protein FANCC
EMBO Reports ( IF 6.5 ) Pub Date : 2020-10-19 , DOI: 10.15252/embr.201949183
Shashi Kant Tiwari 1 , Jason W Dang 1 , Nianwei Lin 1 , Yue Qin 1, 2 , Shaobo Wang 1 , Tariq M Rana 1
Affiliation  

Zika virus (ZIKV) is an emerging flavivirus, which when passed through vertical transmission from mother to developing fetus can lead to developmental abnormalities, including microcephaly. While there is mounting evidence that suggests a causal relationship between ZIKV infection and microcephaly, the mechanisms by which ZIKV induces these changes remain to be elucidated. Here, we demonstrate that ZIKV infection of neural stems cells, both in vitro and in vivo, induces macroautophagy to enhance viral replication. At the same time, ZIKV downregulates a number of essential selective autophagy genes, including the Fanconi anemia (FA) pathway genes. Bioinformatics analyses indicate that the transcription factor E2F4 promotes FANCC expression and is downregulated upon ZIKV infection. Gain and loss of function assays indicate that FANCC is essential for selective autophagy and acts as a negative regulator of ZIKV replication. Finally, we show that Fancc KO mice have increased ZIKV infection and autophagy protein levels in various brain regions. Taken together, ZIKV downregulates FANCC to modulate the host antiviral response and simultaneously attenuate neuronal growth.

中文翻译:


寨卡病毒通过抑制范可尼贫血蛋白 FANCC 来消耗神经干细胞并逃避选择性自噬



寨卡病毒 (ZIKV) 是一种新兴的黄病毒,当通过母亲垂直传播给发育中的胎儿时,可导致发育异常,包括小头畸形。尽管有越来越多的证据表明 ZIKV 感染与小头畸形之间存在因果关系,但 ZIKV 引起这些变化的机制仍有待阐明。在这里,我们证明,ZIKV在体外体内感染神经干细胞都会诱导巨自噬,从而增强病毒复制。同时,ZIKV 下调许多必需的选择性自噬基因,包括范可尼贫血 (FA) 途径基因。生物信息学分析表明转录因子 E2F4 促进 FANCC 表达,并在 ZIKV 感染后下调。功能获得和丧失检测表明 FANCC 对于选择性自噬至关重要,并且充当 ZIKV 复制的负调节因子。最后,我们发现 Fancc KO 小鼠的不同脑区的 ZIKV 感染和自噬蛋白水平有所增加。综上所述,ZIKV 下调 FANCC 以调节宿主抗病毒反应,同时减弱神经元生长。
更新日期:2020-12-10
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