{
  "abstract": "Rheumatoid arthritis (RA) is characterized by a loss of immunological tolerance to synovial self-proteins, yet the initial triggers generating novel neo-antigens remain incompletely defined. Here, we demonstrate that human cathepsin K (hCatK), a key cysteine protease driving joint degradation in RA, catalyzes covalent cis- and trans-splicing of peptides from major RA-associated self-proteins and foreign antigens, including type II collagen, fibrinogen, and SARS-CoV-2 Spike protein. Using high-resolution LC-MS/MS and database-assisted de novo sequencing, we identified over 90 unique spliced peptides. Splicing efficiency peaked at near-neutral pH (6.5-7.5), contrasting with classic hydrolytic profiles. Biochemical profiling revealed strong subsite selectivity, with a striking enrichment for small, aliphatic and/or hydroxyl-containing residues (Gly, Thr, Ser) at the P1 position. Furthermore, splicing preferentially targeted flexible, intrinsically disordered protein regions, with 81% of fibrinogen splicing events clustering within its C domain. In silico binding predictions for the RA-susceptibility allele HLA-DRB1*04:01 harboring the shared epitope revealed that numerous hCatK-generated spliced peptides exhibit predicted affinities exceeding those of established immunogenic and genomic sequences, uncovering protease-mediated transpeptidation as a novel post-translational modification capable of generating potent MHC class II autoantigens in RA.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "O. Hinse"
    },
    {
      "name": "S. Y. Tabatabaei Dakhili"
    },
    {
      "name": "L. Freiburger"
    },
    {
      "name": "E. Mar"
    },
    {
      "name": "J. Rogalski"
    },
    {
      "name": "S. Subramaniam"
    },
    {
      "name": "E. A. James"
    },
    {
      "name": "L. J. Foster"
    },
    {
      "name": "D. Brömme"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/a1jjxsk59z7ka.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.06.749279",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749279v1.full",
  "id": "a1jjxsk59z7ka",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749279v1",
  "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",
      "2745|Rheumatoid Arthritis Research and Therapies"
    ]
  ],
  "openalex": "W7212169432",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749279v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/a1jjxsk59z7ka.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:55Z",
      "native_id": "10.64898/2026.09.06.749279",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.06.749279v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biochemistry",
      "subfield": "general"
    }
  ],
  "title": "Cathepsin K Mediates the Formation of Potential Rheumatoid Arthritis-Relevant Cis- and Trans-Spliced Peptides Compatible With HLA-DR4 Presentation",
  "title_text": "Cathepsin K Mediates the Formation of Potential Rheumatoid Arthritis-Relevant Cis- and Trans-Spliced Peptides Compatible With HLA-DR4 Presentation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:55Z",
  "url": "https://research.draconitic.com/paper/a1jjxsk59z7ka",
  "venue": "bioRxiv",
  "versions": []
}