{
  "abstract": "Detection of viral RNA by the RIG-I-like receptors (RLRs) RIG-I and MDA5 triggers assembly of a MAVS-dependent signalosome that activates the TBK1-IRF3 and IKK{beta}-NF-{kappa}B axes together with the JNK and p38 MAPK modules, driving type I and type III interferon (IFN) and inflammatory cytokine production. Because unrestrained activity of this pathway is a major cause of immunopathology, host-encoded negative regulators are essential, yet the full complement of these brakes remains incompletely defined. Here we identify interleukin-17 receptor D (IL-17RD, also known as SEF), an orphan member of the IL-17 receptor family previously characterized as an antagonist of FGF and Toll-like receptor signaling, as a negative regulator of RLR-driven antiviral innate immunity. Using a CRISPR-engineered and shRNA-depleted human airway epithelial-derived lung carcinoma A549 cell line, we show that loss of IL-17RD amplifies and prolongs phosphorylation of TBK1 and IRF3 in response to poly I:C transfection and to infection with encephalomyocarditis virus (EMCV) or Sendai virus (SeV), and likewise potentiates the IKK{beta}-I{kappa}B module and the TAK1-JNK1/2 and p38 MAPK branches. This translates into increased nuclear accumulation of IRF3 and p65, and markedly elevated induction of IFNB1, IFNL1-3, CCL5, IL6, and NFKBIA transcripts, as well as secreted IFN-{beta} and IL-6. Silencing IL-17RD in ACE2-expressing A549 cells similarly derepresses the antiviral and inflammatory transcriptional programme following SARS-CoV-2 infection. Epistasis experiments place IL-17RD at the level of MAVS, downstream of the RLR sentinels. Mechanistically, IL-17RD localizes to the ER-to-Golgi intermediate compartment (ERGIC), the membrane platform on which the MAVS signalosome is present, and associates with RIG-I, MDA5, MAVS, TBK1 and IRF3. Its re-expression in depleted cells redistributes RLR effectors and TRAF proteins across low-molecular-weight signalosome fractions, reducing the amount of IRF3 recruited to the 670 kDa MAVS signalosome complex. Complementation of IL-17RD-deficient cells also indicates that the intracellular TIR subdomain is sufficient to confer this antagonistic activity. Finally, Il17rd-/- mice display a splenic transcriptome enriched for antiviral response signatures, and, following intranasal infection with a moderate dose of SARS-CoV-2, they mount an exaggerated pulmonary cytokine response and develop significantly greater lung inflammation and fibrosis than wild-type littermates. Together, these data establish IL-17RD as a bona fide brake on the RLR-MAVS axis that limits virus-induced immunopathology, and identify the SEFIR/TIR subdomain as the module responsible for this activity.",
  "abstract_shown": true,
  "affiliations": [
    "Universite de Montreal"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "F. El-Mortada"
    },
    {
      "name": "J. Roy"
    },
    {
      "name": "C. Girondel"
    },
    {
      "name": "F. Do"
    },
    {
      "name": "A. C. Dos Santos Pereira Andrade"
    },
    {
      "name": "E. Lacasse"
    },
    {
      "name": "I. Dubuc"
    },
    {
      "name": "P. P. Roux"
    },
    {
      "name": "G. St-Jean"
    },
    {
      "name": "B. Demey"
    },
    {
      "name": "N. Labrecque"
    },
    {
      "name": "L. Flamand"
    },
    {
      "name": "S. Meloche"
    },
    {
      "affs": [
        0
      ],
      "name": "M. J. Servant"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/be03qgh2rnxb7.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.01.747870",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.747870v1.full",
  "id": "be03qgh2rnxb7",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.747870v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "microbiology"
    ],
    [
      "openalex",
      "2403|interferon and immune responses"
    ]
  ],
  "openalex": "W7208728283",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.747870v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/be03qgh2rnxb7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:19Z",
      "native_id": "10.64898/2026.09.01.747870",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.01.747870v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:microbiology",
      "subfield": "microbiology"
    }
  ],
  "title": "The orphan receptor IL-17RD is a negative regulator of RIG-I-like receptor-dependent antiviral innate immunity and restrains SARS-CoV-2-induced lung inflammation",
  "title_text": "The orphan receptor IL-17RD is a negative regulator of RIG-I-like receptor-dependent antiviral innate immunity and restrains SARS-CoV-2-induced lung inflammation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:30Z",
  "url": "https://research.draconitic.com/paper/be03qgh2rnxb7",
  "venue": "bioRxiv",
  "versions": []
}