---
title: "Cathepsin K Generates Cis- and Trans-Spliced Peptides That May Form HLA-DR4–Restricted RA Autoanti"
id: "biorxiv-4-cathepsin-k-mediates-the-formation-of-potential-rheumatoid-arthritis-relevant"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-4-cathepsin-k-mediates-the-formation-of-potential-rheumatoid-arthritis-relevant"
content_type: "clinical_feed_article"
specialty: "Rheumatology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.06.749279v1?rss=1"
published_at: "2026-09-10T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Cathepsin K Generates Cis- and Trans-Spliced Peptides That May Form HLA-DR4–Restricted RA Autoanti
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-4-cathepsin-k-mediates-the-formation-of-potential-rheumatoid-arthritis-relevant
- **Specialty:** [Rheumatology](https://medichelpline.com/clinical-feed/rheumatology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.06.749279v1?rss=1)
- **Published At:** 2026-09-10T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Rheumatoid arthritis (RA) involves loss of tolerance to synovial self-proteins; the initial neoantigen sources are incompletely defined. This study shows human **cathepsin K** (hCatK) can catalyze covalent cis- and trans-splicing of peptides from self and foreign proteins that are relevant to RA. - The authors used high-resolution LC-MS/MS and database-assisted de novo sequencing to identify more than **90 unique spliced peptides** generated by hCatK from substrates including type II collagen, fibrinogen, and the SARS-CoV-2 Spike protein. - Splicing efficiency differed from classic hydrolysis, peaking at near-neutral pH (6.5–7.5), indicating a distinct reaction profile for transpeptidation under these conditions. - Biochemical profiling revealed strong subsite selectivity with marked enrichment for small, aliphatic or hydroxyl-containing residues at the P1 position—notably **Gly, Thr, Ser**. - Splicing events preferentially occurred in flexible, intrinsically disordered protein regions; for fibrinogen, **81%** of splicing clustered within the αC domain. - In silico binding predictions for the RA-susceptibility allele **HLA-DRB1*04:01** (shared epitope) indicated that many hCatK-generated spliced peptides have predicted affinities that exceed those of known immunogenic and canonical genomic sequences. - The findings identify protease-mediated transpeptidation as a potential post-translational mechanism that can generate potent MHC class II autoantigens in RA. - Data and code resources reported by the authors include a GitHub repository and a PRIDE archive accession; funding was declared from CIHR (PJT-155979). The authors declared no competing interests.
## Clinical Analysis & Structured Key Points
Cathepsin K Mediates the Formation of Potential Rheumatoid Arthritis-Relevant Cis- and Trans-Spliced Peptides Compatible With HLA-DR4 Presentation | bioRxiv Skip to main content New Results Cathepsin K Mediates the Formation of Potential Rheumatoid Arthritis-Relevant Cis- and Trans-Spliced Peptides Compatible With HLA-DR4 Presentation View ORCID Profile Olivier Hinse , S. Yasin Tabatabaei Dakhili , Lee Freiburger , Eliot Mar , Jason Rogalski , Sriram Subramaniam , Eddie A. James , Leonard J. Foster , Dieter Brömme doi: https://doi.org/10.64898/2026.09.06.749279 Olivier Hinse 1 University of British Columbia; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Olivier Hinse S. Yasin Tabatabaei Dakhili 1 University of British Columbia; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lee Freiburger 1 University of British Columbia; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eliot Mar 1 University of British Columbia; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jason Rogalski 1 University of British Columbia; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sriram Subramaniam 1 University of British Columbia; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eddie A. James 2 Benaroya Research Institute Find this author on Google Scholar Find this author on PubMed Search for this author on this site Leonard J. Foster 1 University of British Columbia; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dieter Brömme 1 University of British Columbia; Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: dbromme{at}dentistry.ubc.ca Abstract Info/History Metrics Supplementary material Data/Code Preview PDF 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 αC 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. Competing Interest Statement The authors have declared no competing interest. Footnotes https://github.com/D4rk1705/catk-splicing-ra https://www.ebi.ac.uk/pride/archive/projects/PXD083738 Funder Information Declared Canadian Institutes of Health Research (CIHR) , PJT-155979 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 10, 2026. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Foster , Dieter Brömme bioRxiv 2026.09.06.749279; doi: https://doi.org/10.64898/2026.09.06.749279 Share This Article: Copy Citation Tools Cathepsin K Mediates the Formation of Potential Rheumatoid Arthritis-Relevant Cis- and Trans-Spliced Peptides Compatible With HLA-DR4 Presentation Olivier Hinse , S. Yasin Tabatabaei Dakhili , Lee Freiburger , Eliot Mar , Jason Rogalski , Sriram Subramaniam , Eddie A. James , Leonard J. Foster , Dieter Brömme bioRxiv 2026.09.06.749279; doi: https://doi.org/10.64898/2026.09.06.749279 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (7976) Biochemistry (18662) Bioengineering (14784) Bioinformatics (44219) Biophysics (22488) Cancer Biology (19612) Cell Biology (26768) Clinical Trials (138) Developmental Biology (13907) Ecology (20901) Epidemiology (2067) Evolutionary Biology (25342) Genetics (16109) Genomics (23417) Immunology (18631) Microbiology (42297) Molecular Biology (17964) Neuroscience (93025) Paleontology (694) Pathology (2973) Pharmacology and Toxicology (5069) Physiology (8079) Plant Biology (15918) Scientific Communication and Education (2093) Synthetic Biology (4539) Systems Biology (10193) Zoology (2376)
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