Zika virus depletes neural stem cells and evades selective autophagy by suppressing the Fanconi anemia protein FANCC.
Zika virus depletes neural stem cells and evades selective autophagy by suppressing the Fanconi anemia protein FANCC.
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DOI：
10.15252/embr.201949183
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发表时间：
2020-12-03
期刊：
影响因子：
7.7
通讯作者：
Rana TM
中科院分区：
文献类型：
--
作者：
Tiwari SK;Dang JW;Lin N;Qin Y;Wang S;Rana TM
寨卡病毒（ZIKV）是一种新兴的黄病毒，当从母亲垂直传播到发育中的胎儿时，可导致发育异常，包括小头畸形。虽然有越来越多的证据表明ZIKV感染和小头畸形之间存在因果关系，但ZIKV诱导这些变化的机制仍有待阐明。在这里，我们证明了ZIKV感染神经干细胞，在体外和体内，诱导巨自噬，以增强病毒复制。与此同时，ZIKV下调了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，并且在ZIKV感染后下调。功能获得和丧失测定表明FANCC对于选择性自噬是必需的，并且充当ZIKV复制的负调节剂。最后，我们表明Fancc KO小鼠各个大脑区域的ZIKV感染和自噬蛋白水平增加。总之，ZIKV下调FANCC以调节宿主抗病毒应答并同时减弱神经元生长。ZIKV劫持宿主机制以诱导大自噬并增强病毒复制。它还下调Fanconi贫血基因FANCC，促进抗病毒选择性自噬和神经发生。
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. ZIKV hijacks the host machinery to induce macroautophagy and enhance viral replication. It also downregulates the Fanconi anemia gene FANCC that promotes antiviral selective autophagy and neurogenesis.