Zika Virus Non-structural Protein 4A Blocks the RLR-MAVS Signaling
Microbiology and Immunology
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.
Ma, J., Ketkar, H., Geng, T., Lo, E., Wang, L., Xi, J., Sun, Q., Zhu, Z., Cui, Y., Yang, L., Wang, P., & Geng, T. (2018). Zika Virus Non-structural Protein 4A Blocks the RLR-MAVS Signaling. Frontiers in Microbiology, 9, 1350. https://doi.org/10.3389/fmicb.2018.01350