{ "abstract": "Background: Coronaviruses have evolved intricate mechanisms to evade host RNA surveillance systems and sustain efficient replication. The feline infectious peritonitis virus (FIPV), a highly lethal feline coronavirus that causes systemic vasculitis and fatal peritonitis, represents a major challenge in veterinary medicine and serves as a valuable model for studying conserved coronavirus–host interactions. Among coronavirus structural proteins, the nucleocapsid (N) protein not only packages the viral genome but also modulates host antiviral responses, yet its role in counteracting RNA restriction remains incompletely understood. Results: Using co-immunoprecipitation coupled with mass spectrometry screening, we identified the host RNA-binding antiviral factor ZC3HAV1 (also known as ZAP or PARP13) as a prominent N-associated host protein. ZC3HAV1 restricted FIPV replication by associating with viral RNA and reducing viral RNA accumulation and persistence. We show that the FIPV N protein associates with the RBD-containing region of ZC3HAV1 and that the ZC3HAV1-associated region of N contributes to efficient viral counter-restriction activity. Through coordinated protein–protein and protein–RNA interactions, FIPV N interferes with ZC3HAV1–viral RNA association, thereby supporting viral RNA accumulation and replication. Expression of FIPV N in a heterologous Japanese encephalitis virus system also alleviated ZC3HAV1-mediated RNA-level restriction, indicating that this antagonism activity is functionally transferable and not entirely dependent on FIPV-specific replication machinery. Despite the low CpG content of FIPV RNA, ZC3HAV1 efficiently associated with multiple viral transcripts, suggesting that ZC3HAV1–FIPV RNA recognition is not fully explained by overall CpG abundance and may also be influenced by subgenomic RNA context or structural features. Conclusions: These findings reveal a previously unrecognized mechanism by which a highly pathogenic feline coronavirus circumvents host RNA restriction. By engaging the RBD-containing region of ZC3HAV1 and disrupting ZC3HAV1–viral RNA association, the FIPV N protein effectively attenuates ZC3HAV1-associated antiviral restriction and helps preserve viral RNA accumulation and persistence. This work expands the functional understanding of coronavirus N proteins beyond genome packaging and immune modulation, and provides new insight into FIPV–host interactions that may inform future studies of RNA-level counter-restriction mechanisms in other animal and human coronaviruses. Author summary: Feline infectious peritonitis virus (FIPV) is a deadly coronavirus that causes severe disease in cats and is difficult to treat. One reason FIPV is so challenging to control is its ability to escape the host’s immune response. In this study, we found that FIPV uses its nucleocapsid (N) protein to interfere with a host antiviral protein called ZC3HAV1, which normally helps defend cells by binding to viral RNA and limiting viral RNA accumulation and persistence. We found that ZC3HAV1 can restrict FIPV replication even though FIPV has a low-CpG genome, a feature that might be expected to reduce recognition by a CpG-biased RNA-binding antiviral factor. Instead, ZC3HAV1 association with FIPV RNA appears to be influenced by viral RNA context, including the abundance of certain viral transcripts. Importantly, the FIPV N protein counteracts this restriction by interacting with ZC3HAV1 and disrupting ZC3HAV1–viral RNA association through coordinated protein–protein and protein–RNA interactions. This hijacking of a host defense protein represents a previously unrecognized immune evasion strategy used by FIPV. Our findings provide new insights into how coronaviruses evade RNA-level antiviral restriction and may help inform future studies aimed at identifying antiviral targets.", "abstract_shown": true, "affiliations": [ "Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences (CAAS), Shanghai, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 14, "authors": [ { "affs": [ 0 ], "name": "Miao Zhang" }, { "name": "Na Li" }, { "name": "Kelimujiang Aishanjiang" }, { "name": "Aoxing Tang" }, { "name": "Meng Zhu" }, { "name": "Shiqiang Zhu" }, { "name": "Da Zhang" }, { "name": "Lingxue Yu" }, { "name": "Jie Zhu" }, { "name": "Chuanfeng Li" }, { "name": "Chunchun Meng" }, { "name": "Yingqi Zhu" }, { "name": "Guoxin Li" }, { "name": "Guangqing Liu" } ], "bibtex": "https://research.draconitic.com/paper/4s8rq8r3te9r7.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014616", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014616", "id": "4s8rq8r3te9r7", "issns": [ "1553-7374" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014616", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2403|interferon and immune responses" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Guide RNA" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Non-coding RNA/Small interfering RNA" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Gene regulation/Small interfering RNA" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Coronaviruses" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Molecular biology assays and analysis techniques/Nucleic acid analysis/RNA analysis" ], [ "plos", "/Biology and life sciences/Molecular biology/Molecular biology techniques/Transfection" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Coronaviruses" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Coronaviruses" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Coronaviruses" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Molecular biology assays and analysis techniques/Nucleic acid analysis/RNA analysis" ], [ "plos", "/Research and analysis methods/Molecular biology techniques/Transfection" ], [ "plos", "/Research and analysis methods/Precipitation techniques/Immunoprecipitation" ], [ "plos", "/Research and analysis methods/Precipitation techniques/Immunoprecipitation/Co-immunoprecipitation" ] ], "openalex": "W7213556824", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014616&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-18", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/4s8rq8r3te9r7.ris", "sources": [ { "first_seen": "2026-10-30T12:17:49Z", "native_id": "10.1371/journal.ppat.1014616", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014616" } ], "subjects": [ { "field": "biochemistry", "origin": "plos:gene expression", "subfield": "molecular-biology" }, { "field": "biology", "origin": "plos:microbiology", "subfield": "microbiology" } ], "title": "A feline coronavirus nucleocapsid protein disrupts ZC3HAV1–viral RNA association to counteract host RNA-level restriction", "title_text": "A feline coronavirus nucleocapsid protein disrupts ZC3HAV1–viral RNA association to counteract host RNA-level restriction", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:49Z", "url": "https://research.draconitic.com/paper/4s8rq8r3te9r7", "venue": "PLOS Pathogens", "versions": [] }