The Zika Virus Capsid Disrupts Corticogenesis by Suppressing Dicer Activity and miRNA Biogenesis

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

  • Jianxiong Zeng
  • Shupeng Dong
  • Zhifei Luo
  • Xiaochun Xie
  • Bishi Fu
  • Ping Li
  • Chengrong Liu
  • Xing Yang
  • Yujie Chen
  • Xin Wang
  • Zhenshan Liu
  • Jing Wu
  • Youzhen Yan
  • Feng Wang
  • Jian Fu Chen
  • Jian Zhang
  • Gang Long
  • Shitao Li
  • Zhen Zhao
  • Qiming Liang

Zika virus (ZIKV) causes microcephaly and disrupts neurogenesis. Dicer-mediated miRNA biogenesis is required for embryonic brain development and has been suggested to be disrupted upon ZIKV infection. Here we mapped the ZIKV-host interactome in neural stem cells (NSCs) and found that Dicer is specifically targeted by the capsid from ZIKV, but not other flaviviruses, to facilitate ZIKV infection. We identified a capsid mutant (H41R) that loses this interaction and does not suppress Dicer activity. Consistently, ZIKV-H41R is less virulent and does not inhibit neurogenesis in vitro or corticogenesis in utero. Epidemic ZIKV strains contain capsid mutations that increase Dicer binding affinity and enhance pathogenicity. ZIKV-infected NSCs show global dampening of miRNA production, including key miRNAs linked to neurogenesis, which is not observed after ZIKV-H41R infection. Together these findings show that capsid-dependent suppression of Dicer is a major determinant of ZIKV immune evasion and pathogenesis and may underlie ZIKV-related microcephaly.

OriginalsprogEngelsk
TidsskriftCell Stem Cell
Vol/bind27
Udgave nummer4
Sider (fra-til)618-632.e9
ISSN1934-5909
DOI
StatusUdgivet - 1 okt. 2020

Bibliografisk note

Funding Information:
This work was supported by grants from National Key Research and Development Project of China ( 2018YFA0900802 ), NSFC ( 31770176 and 31770183 ), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning , Shanghai Science and Technology Commission ( 2017QA1403200 ), Shanghai Municipal Health Commission ( 2018YQ40 and 201940179 ), Innovative Research Team of High-Level Local Universities in Shanghai , the Key Research and Development Program of Zhejiang Province ( 2020C04002 ), and the National Institutes of Health (NIH) ( NS110687 and AI141399 ). We thank Dr. Shou-Wei Ding (University of California, Riverside) for valuable suggestions. The Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, provided the cDNA plasmids for cloning.

Funding Information:
This work was supported by grants from National Key Research and Development Project of China (2018YFA0900802), NSFC (31770176 and 31770183), the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, Shanghai Science and Technology Commission (2017QA1403200), Shanghai Municipal Health Commission (2018YQ40 and 201940179), Innovative Research Team of High-Level Local Universities in Shanghai, the Key Research and Development Program of Zhejiang Province (2020C04002), and the National Institutes of Health (NIH) (NS110687 and AI141399). We thank Dr. Shou-Wei Ding (University of California, Riverside) for valuable suggestions. The Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, provided the cDNA plasmids for cloning. Q.L. and Z.Z. conceived the research, designed the study, and wrote the manuscript. J. Zeng, S.D. X.X. P.L. C.L. X.Y. X.W. Z. Liu, and Y.Y. performed the experiments and analyzed data. S.L. and B.F. analyzed liquid chromatography-mass spectrometry (LC-MS) data. Z. Luo analyzed RNA-seq data. G.L. and Y.C. provided the ZIKV reverse genetic system. J. Zhang and J.W. performed the co-structure modeling of capsid-Dicer. S.A.G. provided the fNSCs. All authors commented on the manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2020 Elsevier Inc.

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