Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling.
Alesha Grant, Sanket S Ponia, Shashank Tripathi, Vinod Balasubramaniam, Lisa Miorin, Marion Sourisseau, Megan C Schwarz, Mari Paz Sánchez-Seco, Matthew J Evans, Sonja M Best, Adolfo García-Sastre
Author Information
Alesha Grant: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Sanket S Ponia: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
Shashank Tripathi: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Vinod Balasubramaniam: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Lisa Miorin: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Marion Sourisseau: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Megan C Schwarz: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Mari Paz Sánchez-Seco: Laboratory of Arbovirus and Imported Viral Diseases, National Center of Microbiology, Institute of Health Carlos III, 28029 Madrid, Spain.
Matthew J Evans: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Sonja M Best: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
Adolfo García-Sastre: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: adolfo.garcia-sastre@mssm.edu.
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.
