Article ; Online: PEDV nucleocapsid antagonizes zinc-finger antiviral protein by disrupting the interaction with its obligate co-factor, TRIM25.
2024 Volume 291, Page(s) 110033
Abstract: The genomes of many pathogens contain high-CpG content, which is less common in most vertebrate host genomes. Such a distinct di-nucleotide composition in a non-self invader constitutes a special feature recognized by its host's immune system. The zinc- ... ...
| Abstract | The genomes of many pathogens contain high-CpG content, which is less common in most vertebrate host genomes. Such a distinct di-nucleotide composition in a non-self invader constitutes a special feature recognized by its host's immune system. The zinc-finger antiviral protein (ZAP) is part of the pattern recognition receptors (PRRs) that recognize CpG-rich viral RNA and subsequently initiate RNA degradation as an antiviral defense measure. To counteract such ZAP-mediated restriction, some viruses evolve to either suppress the CpG content in their genome or produce an antagonistic factor to evade ZAP sensing. We have previously shown that a coronavirus, Porcine epidermic diarrhea virus (PEDV), employs its nucleocapsid protein (PEDV-N) to suppress the ZAP-dependent antiviral activity. Here, we propose a mechanism by which PEDV-N suppresses ZAP function by interfering with the interaction between ZAP and its essential cofactor, Tripartite motif-containing protein 25 (TRIM25). PEDV-N was found to interact with ZAP through its N-terminal domain and with TRIM25 through its C-terminal domain. We showed that PEDV-N and ZAP compete for binding to the SPla and the RYanodine Receptor (SPRY) domain of TRIM25, resulting in PEDV-N preventing TRIM25 from interacting with and promoting ZAP. Our result also showed that the presence of PEDV-N in the complex reduces the E3 ligase activity of TRIM25 on ZAP, which is required for the antiviral activity of ZAP. The host-pathogen interaction mechanism presented herein provides an insight into the new function of this abundant and versatile viral protein from a coronavirus which could be a key target for development of antiviral interventions. |
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| MeSH term(s) | Animals ; Swine ; Ubiquitin-Protein Ligases/genetics ; Ubiquitination ; Viruses ; Antiviral Agents/pharmacology ; Antiviral Agents/metabolism ; Nucleocapsid ; Zinc |
| Chemical Substances | Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Antiviral Agents ; Zinc (J41CSQ7QDS) |
| Language | English |
| Publishing date | 2024-02-29 |
| Publishing country | Netherlands |
| Document type | Journal Article |
| ZDB-ID | 753154-0 |
| ISSN | 1873-2542 ; 0378-1135 |
| ISSN (online) | 1873-2542 |
| ISSN | 0378-1135 |
| DOI | 10.1016/j.vetmic.2024.110033 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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