Article Dans Une Revue Veterinary Research Année : 2025

Getah virus nonstructural protein 2 suppresses interferon-beta production by interrupting interferon regulatory factor 3 activation

Hua Liu
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Zhao Qi
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Lan Tian
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Zhe Chen
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Haonan Li
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Le Liu
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Sicong Liu
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Shuai Li
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Jiumeng Sun
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Ying Shao
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Xiangjun Song
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Jian Tu
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Liangqiang Zhu
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Kezong Qi
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Zhenyu Wang
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Résumé

AbstractGetah virus (GETV), a neglected and re-emerging mosquito-borne alphavirus, has become more serious and poses a potential threat to animal safety and public health. The innate immune response is critical for host defence against viral infection, and the dysregulation of host innate immune responses likely aggravates GETV infection. In this study, we use unbiased screening to identify GETV proteins that antagonise type I interferon (IFN-I) response. We found that GETV Nsp2 could inhibit Sendai virus or poly(I:C)-induced IFN-β promoter activation, potently suppressing primary interferon production— a key component of the host’s innate immunity antiviral response. Remarkably, Nsp2 showed efficient inhibition of the IRF3-responsive promoter, but not AP-1 or NF-κB. Further examination revealed that Nsp2 significantly suppressed luciferase activity when RIG-I-CARD, MDA5, MAVS, or IRF3 activated the IFN-β promoter. By contrast, IRF3/5D led to less suppression of luciferase expression, partially restoring luciferase activity, suggesting that Nsp2 interferes with the biological function of IRF3 as a crucial strategy in its antagonism of IFN-β production. Mechanistically, Nsp2 binds TBK1 to suppress IRF3 phosphorylation. Meanwhile, Nsp2 competitively inhibited the interaction of pIRF3 with KPNA3 and KPNA4, to inhibit IRF3 nuclear translocation. Overall, we demonstrated that GETV suppresses antiviral innate immunity by inhibiting the activation of IRF3, and Nsp2 plays a crucial role in this process. These findings reveal a novel strategy by which GETV evades the host innate immune response, providing new insights into the pathogenesis of GETV.

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hal-05103375 , version 1 (09-06-2025)

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Hua Liu, Zhao Qi, Lan Tian, Zhe Chen, Haonan Li, et al.. Getah virus nonstructural protein 2 suppresses interferon-beta production by interrupting interferon regulatory factor 3 activation. Veterinary Research, 2025, 56 (1), pp.110. ⟨10.1186/s13567-025-01547-3⟩. ⟨hal-05103375⟩
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