A fish-specific E3 ubiquitin ligase NHRE3 suppresses antiviral immunity by degrading ISG15 via ubiquitination
- 1Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
- 2College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
Abstract
Grass carp (Ctenopharyngodon Idella) hemorrhagic diseases (GCHD), caused by grass carp reovirus (GCRV), has posed a serious threat to the grass carp aquaculture industry in China. Ubiquitination plays a central role in viral evasion of the host interferon response; therefore, elucidating the mechanisms by which viruses exploit ubiquitination to achieve immune escape is of significant scientific importance and translational value. In a previous study, we identified an E3 ubiquitin ligase–like gene associated with susceptibility to hemorrhagic disease through random mutagenesis in rare minnow (Gobiocypris rarus). In this study, domain and amino acid sequence analyses confirmed that this gene encodes a fish-specific E3 ubiquitin ligase, designated NHRE3. nhre3−/− rare minnows exhibited significantly enhanced resistance to GCRV. Interferon-stimulated gene 15 (ISG15) was identified as an NHRE3-interacting protein via Immunoprecipitation–Mass Spectrometry (IP–MS). Furthermore, NHRE3 possessed E3 ubiquitin ligase activity, catalyzing K48-linked polyubiquitination of ISG15 and leading to its degradation via the proteasome pathway. Given that the antiviral mechanism of ISG15 in fish remains poorly understood, we further investigated its function and found that ISG15 can interact with IRF3 and promote the expression of innate immune factors downstream of IRF3, thereby exerting its anti-GCRV effect. Taken together, NHRE3 promotes GCRV infection by mediating the ubiquitin–proteasome–dependent degradation of ISG15, may represent a mechanism unique to fish viruses. In mammals, viral immune evasion strategies targeting ISG15 primarily involve the inhibition of ISGylation or induction of deISGylation. The immune evasion mechanism identified in this study, in which a virus promotes degradation of ISG15 via a fish-specific ubiquitin ligase, may represent a more primitive or diverse form of innate immune regulation, revealing the ancient origins of the immunological arms race in vertebrates. Author summary: Hemorrhagic disease caused by grass carp reovirus (GCRV) infection is a major problem affecting the grass carp (Ctenopharyngodon Idella) aquaculture industry. We previously identified the susceptibility gene nhre3 for GCRV. In this study, we generated homozygous rare minnow lines resistant to GCRV by knocking out this gene and conducted a preliminary assessment of their growth and development. These findings provide valuable references and potential targets for breeding grass carp resistant to hemorrhagic disease. Further investigation revealed that NHRE3 is a fish-specific E3 ubiquitin ligase. In subsequent mechanistic studies, we identified ISG15 as an interacting partner of NHRE3 and demonstrated that NHRE3 degrades ISG15 via the K48-linked ubiquitin-proteasome pathway. This represents a mechanism for downregulating ISG15 distinct from that observed in mammals, thereby contributing to our understanding of the evolution of the vertebrate immune system. The function and mechanism of ISG15 in combating GCRV remain unclear. We found that ISG15 can interact with the host IRF3 and promote the expression of downstream innate immune factors to exert its antiviral effect against GCRV. Consequently, we conclude that the fish-specific E3 ubiquitin ligase NHRE3 suppresses antiviral immunity by ubiquitinating and degrading ISG15.
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BibTeX
@article{xie2026fishspecific,
title = {{A fish-specific E3 ubiquitin ligase NHRE3 suppresses antiviral immunity by degrading ISG15 via ubiquitination}},
author = {Juhong Xie and Jiayi Lei and Qinxue Zhu and Bin Gui and Yongming Li and Yaping Wang and Rong Huang},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014544},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014544},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A fish-specific E3 ubiquitin ligase NHRE3 suppresses antiviral immunity by degrading ISG15 via ubiquitination
AU - Juhong Xie
AU - Jiayi Lei
AU - Qinxue Zhu
AU - Bin Gui
AU - Yongming Li
AU - Yaping Wang
AU - Rong Huang
PY - 2026
DA - 2026/09/29
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014544
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014544
AB - Grass carp (Ctenopharyngodon Idella) hemorrhagic diseases (GCHD), caused by grass carp reovirus (GCRV), has posed a serious threat to the grass carp aquaculture industry in China. Ubiquitination plays a central role in viral evasion of the host interferon response; therefore, elucidating the mechanisms by which viruses exploit ubiquitination to achieve immune escape is of significant scientific importance and translational value. In a previous study, we identified an E3 ubiquitin ligase–like gene associated with susceptibility to hemorrhagic disease through random mutagenesis in rare minnow (Gobiocypris rarus). In this study, domain and amino acid sequence analyses confirmed that this gene encodes a fish-specific E3 ubiquitin ligase, designated NHRE3. nhre3−/− rare minnows exhibited significantly enhanced resistance to GCRV. Interferon-stimulated gene 15 (ISG15) was identified as an NHRE3-interacting protein via Immunoprecipitation–Mass Spectrometry (IP–MS). Furthermore, NHRE3 possessed E3 ubiquitin ligase activity, catalyzing K48-linked polyubiquitination of ISG15 and leading to its degradation via the proteasome pathway. Given that the antiviral mechanism of ISG15 in fish remains poorly understood, we further investigated its function and found that ISG15 can interact with IRF3 and promote the expression of innate immune factors downstream of IRF3, thereby exerting its anti-GCRV effect. Taken together, NHRE3 promotes GCRV infection by mediating the ubiquitin–proteasome–dependent degradation of ISG15, may represent a mechanism unique to fish viruses. In mammals, viral immune evasion strategies targeting ISG15 primarily involve the inhibition of ISGylation or induction of deISGylation. The immune evasion mechanism identified in this study, in which a virus promotes degradation of ISG15 via a fish-specific ubiquitin ligase, may represent a more primitive or diverse form of innate immune regulation, revealing the ancient origins of the immunological arms race in vertebrates. Author summary: Hemorrhagic disease caused by grass carp reovirus (GCRV) infection is a major problem affecting the grass carp (Ctenopharyngodon Idella) aquaculture industry. We previously identified the susceptibility gene nhre3 for GCRV. In this study, we generated homozygous rare minnow lines resistant to GCRV by knocking out this gene and conducted a preliminary assessment of their growth and development. These findings provide valuable references and potential targets for breeding grass carp resistant to hemorrhagic disease. Further investigation revealed that NHRE3 is a fish-specific E3 ubiquitin ligase. In subsequent mechanistic studies, we identified ISG15 as an interacting partner of NHRE3 and demonstrated that NHRE3 degrades ISG15 via the K48-linked ubiquitin-proteasome pathway. This represents a mechanism for downregulating ISG15 distinct from that observed in mammals, thereby contributing to our understanding of the evolution of the vertebrate immune system. The function and mechanism of ISG15 in combating GCRV remain unclear. We found that ISG15 can interact with the host IRF3 and promote the expression of downstream innate immune factors to exert its antiviral effect against GCRV. Consequently, we conclude that the fish-specific E3 ubiquitin ligase NHRE3 suppresses antiviral immunity by ubiquitinating and degrading ISG15.
SN - 1553-7374
ER -