{
  "abstract": "Rabies virus (RABV), the prototypical lyssavirus, suppresses neuronal ferroptosis through lipid droplet (LD) biogenesis, which is a critical immune evasion strategy we previously identified. However, the mechanistic link between LD formation and ferroptosis regulation during RABV infection remains poorly defined. Here, we report that RABV upregulate Regulator of G Protein Signaling 4 (RGS4), a ferroptosis-associated regulator, and this induction is strictly dependent on triglyceride synthesis and subsequent LD formation. Functionally, genetic or pharmacological inhibition of RGS4 elevates ferroptosis susceptibility, thereby restricting viral replication. Mechanistically, RGS4 depletion reduces HERC2, impairing the assembly of branched K48/K63 ubiquitin chains on NCOA4, which is essential for its proteasomal degradation, thereby enhancing NCOA4 stability. Stabilized NCOA4 promotes ferritinophagy, leading to degradation of ferritin heavy chain (FTH) and ultimately inducing ferroptosis. Critically, we identified that the lyssavirus matrix (M) protein directly counteracts this pathway: M protein inhibits RGS4 degradation via the Cys/N-degron system through incomplete autophagy, stabilizing RGS4 to maintain HERC2 expression, promote NCOA4 ubiquitination, and attenuate ferritinophagy. This mechanism reduces ferroptosis susceptibility and enables viral replication. Our findings unveil a novel lyssavirus-specific regulatory axis, RGS4-HERC2-NCOA4-FTH, that modulates ferroptosis, highlighting the critical role of ferroptosis in lyssavirus infection and pathogenesis. Author summary: Rabies virus (RABV) evades the immune system by suppressing neuronal ferroptosis through lipid droplet (LD) biogenesis. Here, we uncover a novel regulatory axis through which RABV orchestrates this process: RABV infection upregulate the ferroptosis-associated regulator RGS4, which depends on triglyceride synthesis and LD formation. Mechanistically, RGS4 maintains the expression of the E3 ubiquitin ligase HERC2, which promotes branched K48/K63-linked ubiquitination and subsequent proteasomal degradation of NCOA4. This inhibits ferritinophagy and blocks ferritin heavy chain (FTH) degradation, thereby reducing ferroptosis susceptibility and enabling viral replication. Critically, RABV matrix (M) protein directly stabilizes RGS4 by interfering with its degradation via the Cys/N-degron system through incomplete autophagy. Furthermore, we identified this mechanism as a conserved pathway across lyssaviruses. In summary, our findings demonstrate that lyssavirus hijacks the RGS4-HERC2-NCOA4-FTH axis to reduce ferroptosis susceptibility, thereby revealing how lyssavirus M protein modulates ferroptosis to facilitate viral replication. This work elucidates a previously undefined mechanism of viral evasion and provides novel avenues for developing interventions against lyssavirus.",
  "abstract_shown": true,
  "affiliations": [
    "National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China",
    "Key Laboratory of Preventive Veterinary Medicine of Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China",
    "Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, China",
    "Hubei Hongshan Laboratory, Wuhan, China"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Jianqing Zhao"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Pingping Chen"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Meixin Sun"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Chuan Liang"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Zhen F. Fu"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Ling Zhao",
      "orcid": "0000-0003-0569-8105"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Ming Zhou"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8mz682tq2zsdw.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.ppat.1014726",
  "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014726",
  "id": "8mz682tq2zsdw",
  "issns": [
    "1553-7374",
    "1553-7366"
  ],
  "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014726",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Autophagic Cell Death"
    ],
    [
      "heading",
      "Biochemistry"
    ],
    [
      "heading",
      "Biology and Life Sciences"
    ],
    [
      "heading",
      "Biology and life sciences"
    ],
    [
      "heading",
      "Cell Biology"
    ],
    [
      "heading",
      "Cell Death"
    ],
    [
      "heading",
      "Cell Processes"
    ],
    [
      "heading",
      "Immunoblot Analysis"
    ],
    [
      "heading",
      "Lipid Peroxidation"
    ],
    [
      "heading",
      "Lipids"
    ],
    [
      "heading",
      "Lyssavirus"
    ],
    [
      "heading",
      "Medical Microbiology"
    ],
    [
      "heading",
      "Medicine and Health Sciences"
    ],
    [
      "heading",
      "Microbial Pathogens"
    ],
    [
      "heading",
      "Microbiology"
    ],
    [
      "heading",
      "Molecular Biology"
    ],
    [
      "heading",
      "Molecular Biology Techniques"
    ],
    [
      "heading",
      "Molecular Probe Techniques"
    ],
    [
      "heading",
      "Organisms"
    ],
    [
      "heading",
      "Pathogens"
    ],
    [
      "heading",
      "Pathology and Laboratory Medicine"
    ],
    [
      "heading",
      "Post-Translational Modification"
    ],
    [
      "heading",
      "Proteins"
    ],
    [
      "heading",
      "RNA viruses"
    ],
    [
      "heading",
      "Rabies Virus"
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    [
      "heading",
      "Research and Analysis Methods"
    ],
    [
      "heading",
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    ],
    [
      "heading",
      "Ubiquitination"
    ],
    [
      "heading",
      "Viral Pathogens"
    ],
    [
      "heading",
      "Viral Replication"
    ],
    [
      "heading",
      "Virology"
    ],
    [
      "heading",
      "Viruses"
    ],
    [
      "openalex",
      "2406|Rabies epidemiology and control"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Lipids/Lipid peroxidation"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Proteins/Post-translational modification/Ubiquitination"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cell processes/Cell death/Autophagic cell death"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Lyssavirus"
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    [
      "plos",
      "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Lyssavirus/Rabies virus"
    ],
    [
      "plos",
      "/Biology and life sciences/Microbiology/Virology/Viral replication"
    ],
    [
      "plos",
      "/Biology and life sciences/Molecular biology/Molecular biology techniques/Molecular probe techniques/Immunoblot analysis"
    ],
    [
      "plos",
      "/Biology and life sciences/Molecular biology/Molecular biology techniques/Transfection"
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    [
      "plos",
      "/Biology and life sciences/Organisms/Viruses/RNA viruses/Lyssavirus"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Viruses/RNA viruses/Lyssavirus/Rabies virus"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Lyssavirus"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Lyssavirus/Rabies virus"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Lyssavirus"
    ],
    [
      "plos",
      "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Lyssavirus/Rabies virus"
    ],
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      "plos",
      "/Research and analysis methods/Molecular biology techniques/Molecular probe techniques/Immunoblot analysis"
    ],
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      "plos",
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  "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014726&type=printable",
  "pmcid": "PMC13712672",
  "pmid": "42905767",
  "published": "2026-10-21",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/8mz682tq2zsdw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:23Z",
      "native_id": "10.1371/journal.ppat.1014726",
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      "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014726"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "plos:molecular biology",
      "subfield": "molecular-biology"
    },
    {
      "field": "biology",
      "origin": "heading:Cell Biology",
      "subfield": "cell-biology"
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    {
      "field": "biology",
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      "field": "medicine",
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  ],
  "title": "Lyssavirus matrix protein stabilizes RGS4 to suppress ferroptosis via incomplete autophagy and iron metabolic reprogramming",
  "title_text": "Lyssavirus matrix protein stabilizes RGS4 to suppress ferroptosis via incomplete autophagy and iron metabolic reprogramming",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:23:12Z",
  "url": "https://research.draconitic.com/paper/8mz682tq2zsdw",
  "venue": "PLOS Pathogens",
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}