Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA

Abstract

Recently, Zika virus (ZIKV) has generated extraordinary concern because of its severe neurotoxicity. Disturbingly, there is no vaccine or specific drug to prevent or treat the diseases caused by ZIKV infection. Thus, it is extremely urgent to characterize the pathogenesis of ZIKV. It has been documented that ZIKV can evade antiviral responses of host cells. Here, we demonstrate that ZIKV strain SZ‐WIV01 down‐regulates the production of type I IFN and IFN‐stimulated genes along with the expression of mitochondrial antiviral signaling protein (MAVS) and mediator of IFN regulatory factor 3 activation (MITA). In the mechanism, ZIKV nonstructural (NS) 3 and NS2B3 negatively regulate IFN‐related retinoic acid‐inducible gene I‐like receptor signaling pathway by targeting MAVS and MITA, respectively. Overexpression of ZIKV NS3 and NS2B3 dramatically inhibits expression of IFN‐β. ZIKV NS3 interacts with MAVS, and NS2B3 interacts with MITA, which catalyzes K48‐linked polyubiquitination of MAVS and MITA for degradation. Further investigations suggest that ZIKV NS2B3 impairs polyinosinicpolycytidylic acid‐triggered K63‐linked polyubiquitination of MITA, thereby subverting the activation of downstream sensors. Our study reveals an undiscovered mechanism for ZIKV to escape the innate immune response, providing new insights into clinical study of vaccines or effective drugs.—Li, W., Li, N., Dai, S., Hou, G., Guo, K., Chen, X., Yi, C., Liu, W., Deng, F., Wu, Y., Cao, X. Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA. FASEB J. 33, 9929–9944 (2019). http://www.fasebj.org

Zika Virus Proteins NS2A and NS4A Are Major Antagonists that Reduce IFN-�� Promoter Activity Induced by the MDA5/RIG-I Signaling Pathway

“…1-3). The ZIKV NS3 and NS2B-NS3 complex are known to inhibit MAVS and mediator of IFN regulatory factor 3 activation (MITA) [56]. In contrast, our results showed no significant reduction in MAVS level by the NS3 and the NS2B-NS3 complex ( Fig.…”

Innate immune responses to duck Tembusu virus infection

“…It is suggested by the immune evasion strategies employed by DTMUV via targeting MAVS and STING were critical for host innate immune responses to DTMUV infection. Similarly, the Zika virus circumvented host innate immunity with NS3 and NS2B3 respectively targeting MAVS and STING [147]. The NS3/4A protein of HCV cleaves the MAVS and TRIF proteins, leading to the blocking of RLR and TLR3 signaling [148,149].…”

“…Similarly, the Zika virus circumvented host innate immunity with NS3 and NS2B3 respectively targeting MAVS and STING [ 147 ]. The NS3/4A protein of HCV cleaves the MAVS and TRIF proteins, leading to the blocking of RLR and TLR3 signaling [ 148 , 149 ].…”

Picking up a Fight: Fine Tuning Mitochondrial Innate Immune Defenses Against RNA Viruses

“…It is also known to disrupt mitochondrial dynamics which aids in infection ( Keystone Symposia, n.d. ). Further, the non-structural protein NS3 have been shown to target MAVs to proteasomal degradation via K48 linked polyubiquitination and subsequent downregulation of IFNβ pathway ( Li et al, 2019 ). Further, these responses vary among the different ZIKV strains isolated from different geographical locations.…”