The Capsid Protein of Nervous Necrosis Virus Antagonizes Host Type I IFN Production by a Dual Strategy to Negatively Regulate Retinoic Acid–Inducible Gene-I–like Receptor Pathways

Author:

Jia Peng123ORCID,Zhang Wanwan13ORCID,Xiang Yangxi134ORCID,Lu Xiaobing13,Chen Xiaoqi1,Pan Hongbo1,Yi Meisheng13ORCID,Jia Kuntong13ORCID

Affiliation:

1. *Guangdong Provincial Key Laboratory of Marine Resources and Coastal Engineering, Pearl River Estuary Marine Ecosystem Research Station, Ministry of Education, School of Marine Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China;

2. †Fuzhou Medical College of Nanchang University, Fuzhou, Jiangxi, China;

3. ‡Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, Guangdong, China; and

4. §State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, China

Abstract

Abstract Nervous necrosis virus (NNV), a highly pathogenic RNA virus, is a major pathogen in the global aquaculture industry. To efficiently infect fish, NNV must evade or subvert the host IFN for their replication; however, the precise mechanisms remain to be elucidated. In this study, we reported that capsid protein (CP) of red-spotted grouper NNV (RGNNV) suppressed the IFN antiviral response to promote RGNNV replication in Lateolabrax japonicus brain cells, which depended on the ARM, S, and P domains of CP. CP showed an indirect or direct association with the key components of retinoic acid–inducible gene-I–like receptors signaling, L. japonicus TNFR-associated factor 3 (LjTRAF3) and IFN regulatory factor (LjIRF3), respectively, and degraded LjTRAF3 and LjIRF3 through the ubiquitin-proteasome pathway in HEK293T cells. Furthermore, we found that CP potentiated LjTRAF3 K48 ubiquitination degradation in a L. japonicus ring finger protein 114–dependent manner. LjIRF3 interacted with CP through the S domain of CP and the transcriptional activation domain or regulatory domain of LjIRF3. CP promoted LjIRF3 K48 ubiquitination degradation, leading to the reduced phosphorylation level and nuclear translocation of LjIRF3. Taken together, we demonstrated that CP inhibited type I IFN response by a dual strategy to potentiate the ubiquitination degradation of LjTRAF3 and LjIRF3. This study reveals a novel mechanism of RGNNV evading host immune response via its CP protein that will provide insights into the complex pathogenesis of NNV.

Funder

Bureau of Science and Information Technology of Guangzhou Municipality | Pearl River S and T Nova Program of Guangzhou

NSF | Foundation for Innovative Research Groups of the National Natural Science Foundation of China

China Postdoctoral Science Foundation

Natural Science Foundation of Guangdong Province

Natural Science Foundation of Guangxi Province

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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