Nuclear localization of Zika virus NS5 contributes to suppression of type I interferon production and response

Author:

Zhao Zikai123,Tao Mengying123,Han Wei2,Fan Zijing123,Imran Muhammad123,Cao Shengbo123,Ye Jing132ORCID

Affiliation:

1. The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, PR China

2. Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PR China

3. State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, PR China

Abstract

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus, which caused an unprecedented epidemic in Latin America. Among all viral non-structural proteins in flavivirus, NS5 is the most highly conserved and has multiple crucial functions, including participating in viral RNA replication and suppressing host innate immunity. Although ZIKV NS5 prominently localizes in the nucleus during infection, its specific nuclear localization signal (NLS), and its role in viral replication and pathogenesis remain controversial. Here, we identified aa 11–90 and aa 370–406 regions that contain NLSs, which are critical for nuclear localization of ZIKV NS5. Further experiments demonstrated that nuclear localization of ZIKV NS5 predominantly participates in suppression of interferon regulatory factor 3 (IRF3)-mediated activation of type I IFN (IFN-I) transcription and inhibition of IFN-I downstream response independent of its effect on signal transducers and activators of transcription 2 (STAT2) degradation. These results suggest that subcellular localization of NS5 is important for its function on innate immune suppression, which provides new insight into ZIKV pathogenesis.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Fundamental Research Funds for the Central Universities

Natural Science Foundation of Hubei Province

Publisher

Microbiology Society

Subject

Virology

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