Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling

• Published in: Cell host & microbe Vol. 19; no. 6; pp. 882 - 890
• Main Authors: Grant, Alesha, Ponia, Sanket S., Tripathi, Shashank, Balasubramaniam, Vinod, Miorin, Lisa, Sourisseau, Marion, Schwarz, Megan C., Sánchez-Seco, Mari Paz, Evans, Matthew J., Best, Sonja M., García-Sastre, Adolfo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.06.2016
• Subjects: Animals; Base Sequence; Calmodulin-Binding Proteins; Calmodulin-Binding Proteins - metabolism; Chlorocebus aethiops; Cytoskeletal Proteins; Cytoskeletal Proteins - metabolism; Disease Models, Animal; HEK293 Cells; HEK293 Cells - drug effects; Humans; Interferon Type I; Interferon Type I - antagonists & inhibitors; Interferon Type I - metabolism; Life Sciences; Mice; Microbiology and Parasitology; Phylogeny; Signal Transduction; STAT2 Transcription Factor; STAT2 Transcription Factor - metabolism; Ubiquitin-Protein Ligases; Ubiquitin-Protein Ligases - metabolism; Vero Cells; Viral Nonstructural Proteins; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Virology; Zika Virus; Zika Virus - metabolism; Zika Virus Infection; Zika Virus Infection - metabolism; Zika Virus Infection - virology
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2016.05.009

The ongoing epidemic of Zika virus (ZIKV) illustrates the importance of flaviviruses as emerging human pathogens. All vector-borne flaviviruses studied thus far have to overcome type I interferon (IFN) to replicate and cause disease in vertebrates. The mechanism(s) by which ZIKV antagonizes IFN signaling is unknown. Here, we report that the nonstructural protein NS5 of ZIKV and other flaviviruses examined could suppress IFN signaling, but through different mechanisms. ZIKV NS5 expression resulted in proteasomal degradation of the IFN-regulated transcriptional activator STAT2 from humans, but not mice, which may explain the requirement for IFN deficiency to observe ZIKV-induced disease in mice. The mechanism of ZIKV NS5 resembles dengue virus (DENV) NS5 and not its closer relative, Spondweni virus (SPOV). However, unlike DENV, ZIKV did not require the E3 ubiquitin ligase UBR4 to induce STAT2 degradation. Hence, flavivirus NS5 proteins exhibit a remarkable functional convergence in IFN antagonism, albeit by virus-specific mechanisms. [Display omitted] •Flavivirus nonstructural NS5 proteins antagonize type I IFN by different mechanisms•Zika virus (ZIKV) NS5 targets the IFN-regulated transcriptional activator STAT2•ZIKV NS5 binds to and targets human, but not mouse, STAT2 for degradation•Unlike dengue, ZIKV NS5-mediated STAT2 degradation does not require E3 ligase UBR4 The mechanism(s) by which Zika virus (ZIKV) antagonizes IFN signaling is unknown. Grant et al. report that the nonstructural NS5 protein of ZIKV binds to and targets the IFN-regulated transcriptional activator STAT2 from humans for proteasomal degradation. Mouse STAT2 is refractory to ZIKV NS5.