Frontiers in Microbiology (Jun 2018)

Zika Virus Non-structural Protein 4A Blocks the RLR-MAVS Signaling

  • Jinzhu Ma,
  • Jinzhu Ma,
  • Harshada Ketkar,
  • Tingting Geng,
  • Emily Lo,
  • Leilei Wang,
  • Leilei Wang,
  • Juemin Xi,
  • Qiangming Sun,
  • Zhanbo Zhu,
  • Yudong Cui,
  • Long Yang,
  • Penghua Wang

DOI
https://doi.org/10.3389/fmicb.2018.01350
Journal volume & issue
Vol. 9

Abstract

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Flaviviruses have evolved complex mechanisms to evade the mammalian host immune systems including the RIG-I (retinoic acid-inducible gene I) like receptor (RLR) signaling. Zika virus (ZIKV) is a re-emerging flavivirus that is associated with severe neonatal microcephaly and adult Guillain-Barre syndrome. However, the molecular mechanisms underlying ZIKV pathogenesis remain poorly defined. Here we report that ZIKV non-structural protein 4A (NS4A) impairs the RLR-mitochondrial antiviral-signaling protein (MAVS) interaction and subsequent induction of antiviral immune responses. In human trophoblasts, both RIG-I and melanoma differentiation-associated protein 5 (MDA5) contribute to type I interferon (IFN) induction and control ZIKV replication. Type I IFN induction by ZIKV is almost completely abolished in MAVS-/- cells. NS4A represses RLR-, but not Toll-like receptor-mediated immune responses. NS4A specifically binds the N-terminal caspase activation and recruitment domain (CARD) of MAVS and thus blocks its accessibility by RLRs. Our study provides in-depth understanding of the molecular mechanisms of immune evasion by ZIKV and its pathogenesis.

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