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| Status |
Public on Aug 04, 2020 |
| Title |
Virus-Host Interactome Reveals the Unique Blockage of Host RNAi Machinery by the Zika Virus Capsid |
| Organism |
Homo sapiens |
| Experiment type |
Non-coding RNA profiling by high throughput sequencing
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| Summary |
The recent outbreaks of Zika virus (ZIKV) and its association with birth defects known as Congenital Zika Syndrome warrant investigation on the molecular processes related to its infection and pathogenesis. Among the flavivirus family, only ZIKV is linked to microcephaly as announced by World Health Organization, suggesting uniqueness of ZIKV infection compared to other members. By analyzing the ZIKV-host interactome, we found that the key microRNA (miRNA) processing enzyme Dicer was a leading target of ZIKV capsid protein in neural stem cells (NSCs), and its deficiency facilitated ZIKV infection. Mechanistically, ZIKV capsid can directly interact with Dicer and block its ribonuclease activity, dampening the production of host miRNAs that are essential for neurogenesis. Interestingly, this capsid-mediated immune evasion is specific to ZIKV because capsid proteins from other close flaviviruses, e.g., dengue, yellow fever and West Nile viruses, cannot bind to Dicer or inhibit its function. By molecular mapping, we defined a ZIKV capsid H41R mutant with loss of interaction to Dicer and no longer affecting its activity. More importantly, ZIKV H41R mutant exerted almost no impact on neurogenesis in vitro when expressed in NSCs compared to wild type capsid, and in utero infection of recombinant ZIKV-H41R mutant virus resulted in less inhibition on corticogenesis than wild-type ZIKV in mouse embryos. Interestingly, the epidemic ZIKV strain reinforces the capsid-Dicer interaction by two amino acid substitution compared to ancient Africa strain. Thus, our study demonstrated that capsid-dependent suppression of Dicer function is a unique determinant of ZIKV immune evasion and pathogenesis, which may unveil a new mechanism for ZIKV-mediated microcephaly.
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| Overall design |
miRNA-seq of neural stem cells (NSCs) infected with ZKIV or ZKIV H41R or without infection
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| Contributor(s) |
Zeng J, Dong S, Luo Z, Fu B, Li P, Xie X, Yang X, Chen Y, Wang X, Liu C, Liu Z, Wu J, Zhang J, Long G, Ding S, Li S, Zhao Z, Liang Q |
| Citation(s) |
32763144 |
| Submission date |
Sep 17, 2019 |
| Last update date |
Nov 16, 2020 |
| Contact name |
Zhifei Luo |
| E-mail(s) |
Zhifeilu@usc.edu
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| Organization name |
University of Southern California
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| Street address |
1450 Biggy Street, NRT 6514
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90089-9601 |
| Country |
USA |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA565978 |
| SRA |
SRP222066 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE137592_raw_read_counts.txt.gz |
509.6 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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