Zika virus NS2A inhibits interferon signaling by degradation of STAT1 and STAT2

Abstract

The Interferon (IFN) response is crucial to restrain pathogenic infections. Investigations into flavivirus-host interactions reported that the high virulence is linked to innate immune evasion. Zika Virus (ZIKV) has developed diversified strategies to evade the innate immune system. We report that the viral protein NS2A counteracts the IFN response by strongly suppressing the IFN signaling. NS2A targets transcription factors STAT1 and STAT2, to impede their nuclear localization, thereby suppressing the transcription of ISRE promoter and IFN-stimulated genes. We found that NS2A promotes degradation of STAT1 and STAT2. Treatment of NS2A transfected cells with MG132 restores the levels of both transcription factors, suggesting the involvement of the proteasome system. Given the impact that the IFN antagonism has on flavivirus virulence, the knowledge gained by characterizing the mechanism through which ZIKV evades the IFN response paves the ground for new strategies to attenuate the pathogenesis and to develop countermeasures against effective pharmacological targets.

Variability in Susceptibility to Type I Interferon Response and Subgenomic RNA Accumulation Between Clinical Isolates of Dengue and Zika Virus From Oaxaca Mexico Correlate With Replication Efficiency in Human Cells and Disease Severity

“…There is evidence that regions of the viral genome that encode non-structural proteins present substantial variability ( Pollett et al., 2018 ). These differences could lead to critical phenotypic changes since these non-structural proteins are critical to the replication cycle, contain potential T cell epitopes, and have innate immune evasion capabilities ( Leung et al., 2008 ; Rastogi et al., 2016 ; Tian et al., 2019 ; Fanunza et al., 2021 ). Additionally, there is evidence of highly variable regions in the 3′UTR; variability in this region of the gRNA could impact the secondary and tertiary structures that are critical for the accumulation of subgenomic flaviviral RNAs (sfRNAs), which are small RNA products of the incomplete degradation of the gRNA by host 5′–3′ exonuclease XRN1, which have been associated with pathogenesis and type I interferon evasion ( Pijlman et al., 2008 ).…”

Rapid Construction of an Infectious Clone of the Zika Virus, Strain ZKC2

“…The innate immune response, especially the IFN pathway, is activated due to the presence of viral RNA, which is pathogen-associated molecular pattern (PAMP) that are recognized by pattern recognition receptors (PRRs; Green et al, 2014 ). However, host immune responses are weakened due to the degradation of STAT1 and STAT2 transcription factors that initiate the transcription of ISGs by NS2A during ZIKV infection ( Fanunza et al, 2021 ). Hence, we examined the ISGs transcript levels for DDX58 , IFIT1 , ISG15 , and IFNB1 , and analyzed the transcript levels of inflammatory cytokines including TNF-α and IL-6 that are associated with severe symptoms during ZIKV infection ( Abdalla et al, 2018 ).…”

Flaviviruses: Innate Immunity, Inflammasome Activation, Inflammatory Cell Death, and Cytokines

“…In addition, DENV NS2A, NS4A and NS4B can suppress the transcription of ISRE promoter and ISGs by blocking the phosphorylation of STAT1/STAT2 and hinder their nuclear localization to inhibit the IFN response (156), and the NS2A of ZIKV and the NS4B of WNV and YFV have similar functions (157)(158)(159). NS2A and NS4B from multiple DENV serotypes can also inhibit IFN production by targeting IRF3 and TBK1, but only NS4A from serotype-1 can inhibit TBK1 (160).…”