A tunable immune-evasion function of Zika virus NS5 governs viral fitness and pathogenesis
8 affiliations
- 1Center for Infection Biology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China
- 2State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430062, China
- 3University of Chinese Academy of Sciences, Beijing 100049, China
- 4Strategic Pandemic Preparedness Action and Research Center (SPARC), Guangzhou National Laboratory, Guangzhou 510005, China
- 5School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- 6The High School Affiliated to Renmin University of China, Beijing 100080, China
- 7Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
- 8State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, National Centre for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510182, China
Abstract
Type I interferon (IFN) signaling is a central antiviral defense, with STAT2 driving the expression of IFN-stimulated genes (ISGs) to restrict viral infection. Zika virus (ZIKV) and dengue virus evade this pathway through nonstructural protein 5 (NS5)-mediated ubiquitination and proteasomal degradation of STAT2, yet the contribution of this immune-evasion strategy to viral fitness and pathogenesis remains incompletely defined. Here, using a multistep mutational scanning strategy that jointly assessed STAT2 degradation and viral RNA replication, we identified a single NS5 residue, L162, as uniquely permissive to substitution that abolishes STAT2 degradation without compromising intrinsic replication functions. Substitution of L162 with alanine or glycine (L162A or L162G) selectively disrupted NS5 recruitment of the ZSWIM8-CUL3 E3 ubiquitin ligase, thereby preserving STAT2 stability and restoring IFN signaling. Recombinant ZIKV carrying these mutations exhibited reduced replication and enhanced ISG induction in human cells, defects fully rescued by STAT2 knockout. In A129 mice (type I IFN receptor deficient), mutant and WT viruses replicated comparably, but in human STAT2 knock-in mice, ZIKV-NS5L162G exhibited markedly reduced viral loads and disease. In pregnant human STAT2 knock-in mice, the mutant also reduced placental and fetal viral burdens and adverse pregnancy outcomes. Notably, infection with ZIKV-NS5L162G elicited robust neutralizing antibody and T cell responses that conferred protection against WT challenge. Together, these findings establish NS5-mediated STAT2 degradation as a central determinant of ZIKV immune-evasion, viral fitness, and pathogenesis and highlight disruption of NS5–STAT2 antagonism as a promising strategy for antiviral intervention and rational attenuation.
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BibTeX
@article{zhang2026tunable,
title = {{A tunable immune-evasion function of Zika virus NS5 governs viral fitness and pathogenesis}},
author = {Yu Zhang and Yaqing Zhang and Chengyu Liu and Wenlin Ren and Yu Zhao and Chenhao Li and Yongqi Guo and Leyi Bai and Peigang Wang and Jing An and Jun Liu and Qiang Ding},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2630605123},
url = {https://doi.org/10.1073/pnas.2630605123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - A tunable immune-evasion function of Zika virus NS5 governs viral fitness and pathogenesis
AU - Yu Zhang
AU - Yaqing Zhang
AU - Chengyu Liu
AU - Wenlin Ren
AU - Yu Zhao
AU - Chenhao Li
AU - Yongqi Guo
AU - Leyi Bai
AU - Peigang Wang
AU - Jing An
AU - Jun Liu
AU - Qiang Ding
PY - 2026
DA - 2026/10/20
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2630605123
UR - https://doi.org/10.1073/pnas.2630605123
AB - Type I interferon (IFN) signaling is a central antiviral defense, with STAT2 driving the expression of IFN-stimulated genes (ISGs) to restrict viral infection. Zika virus (ZIKV) and dengue virus evade this pathway through nonstructural protein 5 (NS5)-mediated ubiquitination and proteasomal degradation of STAT2, yet the contribution of this immune-evasion strategy to viral fitness and pathogenesis remains incompletely defined. Here, using a multistep mutational scanning strategy that jointly assessed STAT2 degradation and viral RNA replication, we identified a single NS5 residue, L162, as uniquely permissive to substitution that abolishes STAT2 degradation without compromising intrinsic replication functions. Substitution of L162 with alanine or glycine (L162A or L162G) selectively disrupted NS5 recruitment of the ZSWIM8-CUL3 E3 ubiquitin ligase, thereby preserving STAT2 stability and restoring IFN signaling. Recombinant ZIKV carrying these mutations exhibited reduced replication and enhanced ISG induction in human cells, defects fully rescued by STAT2 knockout. In A129 mice (type I IFN receptor deficient), mutant and WT viruses replicated comparably, but in human STAT2 knock-in mice, ZIKV-NS5L162G exhibited markedly reduced viral loads and disease. In pregnant human STAT2 knock-in mice, the mutant also reduced placental and fetal viral burdens and adverse pregnancy outcomes. Notably, infection with ZIKV-NS5L162G elicited robust neutralizing antibody and T cell responses that conferred protection against WT challenge. Together, these findings establish NS5-mediated STAT2 degradation as a central determinant of ZIKV immune-evasion, viral fitness, and pathogenesis and highlight disruption of NS5–STAT2 antagonism as a promising strategy for antiviral intervention and rational attenuation.
SN - 0027-8424
SN - 1091-6490
ER -