Zika virus depletes neural stem cells and evades selective autophagy by suppressing the Fanconi anemia protein FANCC

EMBO Rep. 2020 Dec 3;21(12):e49183. doi: 10.15252/embr.201949183. Epub 2020 Oct 19.

Abstract

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.

Keywords: Fanconi anemia protein C; ZIKA virus replication; neural stem cells; selective autophagy; transcription factor E2F4.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy
  • Cell Line
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia* / genetics
  • Macroautophagy
  • Mice
  • Neural Stem Cells*
  • Virus Replication
  • Zika Virus Infection* / genetics
  • Zika Virus* / genetics

Substances

  • FANCC protein, human
  • Fancc protein, mouse
  • Fanconi Anemia Complementation Group C Protein