{
  "abstract": "Interferons (IFNs) are secreted during virus infection and induce antiviral responses through receptor-mediated phosphorylation of signal transducer and activator of transcription (STAT) proteins, leading to IFN-stimulated gene expression with antiviral activity. We previously reported that the SARS-CoV-2 main protease, 3CLpro, is secreted from infected cells through gasdermin D/E pores and retains proteolytic activity in human serum against extracellular substrates. Here, we show that 3CLpro selectively cleaves glycosylated IFN-L1, IFN-L2, and a rare naturally occurring variant of IFN-{gamma} (Arg160Gln), but does not cleave wild-type IFN-{gamma}, IFN-L3, IFN-L4, IFN-alpha proteins or IFN-{beta}. We identified sites of O-linked glycosylation of IFN-L1 at Thr137 and one or more threonines or serine in the sequence 24TSKPTTT30, and N-linked glycosylation at Asn65 that were indispensable for signaling. Unexpectedly, O-glycosylation was also required for the cleavage and inactivation of IFN-L1 by 3CLpro at two sites. Cleavage reduced STAT1 phosphorylation and impaired the induction of the IFN-stimulated proteins MX1, OAS2, and IFIT1. Although 3CLpro cleaved IFN-L2 proximal to its N-terminus at ARLH32{downarrow}GALP, cleavage neither disrupted signaling nor antiviral activity against SARS-CoV-2 and vesicular stomatitis virus. We further show that matrix metalloproteinases (MMPs) 2, 7, 8, and 12 degrade 3CLpro, whereas 3CLpro shows no activity against these MMPs.",
  "abstract_shown": true,
  "affiliations": [
    "The University of British Columbia"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "P. M. Grin"
    },
    {
      "name": "H. C. R. de Jesus"
    },
    {
      "name": "I. Pablos"
    },
    {
      "name": "R. Kappelhoff"
    },
    {
      "name": "G. S. Butler"
    },
    {
      "name": "B. Charaf"
    },
    {
      "affs": [
        0
      ],
      "name": "C. M. Overall"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/26933a5dhz29t.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.07.749787",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749787v1.full",
  "id": "26933a5dhz29t",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749787v1",
  "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",
      "biochemistry"
    ],
    [
      "openalex",
      "2403|interferon and immune responses"
    ]
  ],
  "openalex": "W7211946448",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749787v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/26933a5dhz29t.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:11Z",
      "native_id": "10.64898/2026.09.07.749787",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749787v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|interferon and immune responses",
      "subfield": "immunology"
    }
  ],
  "title": "Interferon redundancy counteracts proteolytic inactivation by SARS-CoV-2 3CL main protease",
  "title_text": "Interferon redundancy counteracts proteolytic inactivation by SARS-CoV-2 3CL main protease",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:11Z",
  "url": "https://research.draconitic.com/paper/26933a5dhz29t",
  "venue": "bioRxiv",
  "versions": []
}