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Zika Virus Infection Prevents Host mRNA Nuclear Export by Disrupting UPF1 Function
bioRxiv - Microbiology Pub Date : 2020-12-07 , DOI: 10.1101/2020.12.03.410837
Kristoffer Leon , Ryan Flynn , Mir M. Khalid , Krystal A. Fontaine , Tom Nguyen , G. Renuka Kumar , Camille R Simoneau , Sakshi Tomar , David Jimenez-Morales , Mariah Dunlap , Julia Kaye , Priya S Shah , Steven Finkbeiner , Nevan J Krogan , Carolyn Bertozzi , Jan E. Carette , Melanie Ott

Zika virus (ZIKV) is a mosquito-borne RNA virus that can infect fetuses in utero causing characteristic neurodevelopmental disorders including microcephaly. We previously showed that ZIKV infection downregulates expression of up-frameshift protein 1 (UPF1), a helicase/ATPase and central regulator of the nonsense-mediated mRNA decay pathway. Here, we identify a novel function of nuclear UPF1 in mRNA export. Using crosslinking immunoprecipitation of UPF1 followed by sequencing of associated transcripts as well as fluorescent in situ hybridization experiments, we find widespread mRNA accumulation in the cell nucleus of human neural progenitor cells (NPCs) upon ZIKV infection or UPF1 knockdown. Knockdown of FREM2, a top UPF1 target transcript encoding an extra-cellular matrix protein critical in fetal development, decreased expression of pluripotency markers and increased neuronal differentiation in NPCs, consistent with the model that trapping FREM2 mRNA in the nucleus perturbs proper NPC function. Collectively, our data uncovers a new posttranscriptional mechanism by which ZIKV "shuts off" host mRNA export via UPF1. As we find UPF1 linked to many neurodevelopment pathways, we propose that the lack of host mRNA export contributes to virally induced neurodevelopmental disorders in ZIKV infection.

中文翻译:

寨卡病毒感染通过破坏UPF1功能阻止宿主mRNA核输出

寨卡病毒(ZIKV)是一种蚊子传播的RNA病毒,可以感染子宫内的胎儿,引起包括小头畸形在内的特征性神经发育障碍。我们以前显示ZIKV感染下调了移码蛋白1(UPF1),解旋酶/ ATPase和无意义介导的mRNA衰变途径的中央调节剂的表达。在这里,我们确定了核UPF1在mRNA出口中的新型功能。使用UPF1的交联免疫沉淀,然后对相关转录本进行测序,以及进行荧光原位杂交实验,我们发现ZIKV感染或UPF1敲除后人类神经祖细胞(NPC)细胞核中普遍存在mRNA积累。击倒FREM2,这是编码胎儿发育至关重要的细胞外基质蛋白的UPF1最高目标转录本,降低多能性标记物的表达并增加NPC的神经元分化,这与在核中捕获FREM2 mRNA扰乱正常NPC功能的模型一致。总的来说,我们的数据揭示了一种新的转录后机制,通过该机制ZIKV通过UPF1“关闭”宿主mRNA输出。当我们发现UPF1与许多神经发育途径相关时,我们提出宿主mRNA缺乏输出有助于ZIKV感染中病毒诱导的神经发育障碍。
更新日期:2020-12-08
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