{
  "abstract": "Type III interferon (IFN3, IFN{lambda}) drives antiviral defense at epithelial barriers with a more favorable safety profile than Type I interferon (IFN1), but weaker signaling limits its therapeutic potential. To identify small molecules that potentiate IFN-JAK-STAT signaling, we developed a high-throughput live-cell assay measuring STAT1/STAT2 phosphorylation in A549 cells and screened ~8,640 compounds. This identified proteasome inhibitors (MG132, delanzomib, ixazomib, oprozomib, bortezomib) as selective potentiators of IFN3-induced STAT activation, with minimal effect on IFN1 signaling. Proteasome inhibition enhanced IFN3 antiviral activity to levels approaching IFN1. Mechanistically, proteasome inhibition increased cell-surface IL10R{beta}, the limiting IFN3 receptor subunit, thereby increasing receptor JAK-STAT signaling. It did not alter IFN1 receptor levels but protected IFNAR2 from late ligand-induced downregulation. These findings establish receptor subunit availability as a rate-limiting, druggable node governing IFN3 signaling strength and demonstrate a scalable platform for identifying cytokine-selective signaling potentiators, with implications for mucosal antiviral therapeutics.",
  "abstract_shown": true,
  "affiliations": [
    "University of Chicago"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "J.-P. Parisien"
    },
    {
      "name": "C. O Leary"
    },
    {
      "name": "S. Shabani"
    },
    {
      "name": "S. Fernandez-Dunne"
    },
    {
      "name": "L. T. Huynh"
    },
    {
      "name": "A. K. Kurowska"
    },
    {
      "name": "C. M. Horvath"
    },
    {
      "affs": [
        0
      ],
      "name": "J. L. Mendoza"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/851eq4esmjj7b.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.12.758093",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.12.758093v1.full",
  "id": "851eq4esmjj7b",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.12.758093v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2403|interferon and immune responses"
    ]
  ],
  "openalex": "W7222971923",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.12.758093v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-12",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/851eq4esmjj7b.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:28:32Z",
      "native_id": "10.64898/2026.10.12.758093",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.12.758093v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "High-Throughput Screening Identifies Proteasome Inhibitors as Potentiators of Type III Interferon JAK-STAT Signaling and Antiviral Immunity",
  "title_text": "High-Throughput Screening Identifies Proteasome Inhibitors as Potentiators of Type III Interferon JAK-STAT Signaling and Antiviral Immunity",
  "type": "preprint",
  "updated_at": "2026-10-30T12:28:32Z",
  "url": "https://research.draconitic.com/paper/851eq4esmjj7b",
  "venue": "bioRxiv",
  "versions": []
}