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Lookup NU author(s): Dr Sally Johnson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.Dysregulated proteolysis is central to autoimmune pathogenesis. The complement cascade, a major protease network, generates fragments that modulate immunity and tissue injury. We developed a scalable blood plasma N-terminomics workflow that markedly expands detection of proteolytic events in vitro and in vivo. Applied to 143 systemic lupus erythematosus (SLE) patients, Multi-Omics Factor Analysis (MOFA) linked N-terminal signatures to immunological and clinical heterogeneity. This revealed a previously unrecognized complement fragment, C3-LHF1, encompassing the C345C domain and rivaling, based on intensity detected by mass spectrometry, the abundance of canonical fragments like C3a and C3b. C3-LHF1 associated with renal function and remission in lupus nephritis, and exhibited dual functions: inhibiting classical and lectin complement pathways and acting as a partial IL6ST (gp130) agonist, independent of IL6Rα. In human kidney organoids, C3-LHF1 induced JAK/STAT3 signaling, amplified TNFα-driven CXCL10 secretion, and reduced podocyte marker expression, suggesting a role in tissue remodeling. These findings reveal unanticipated complexity in complement-mediated signaling and provide a comprehensive atlas of protein N-termini in human plasma, which enables discovery of novel immunoregulatory mechanisms and therapeutic targets in inflammatory disease.
Author(s): Demir F, Kovalenko E, Lasse M, Svenningsen EB, Bernth Jensen JM, Billing AM, Groeneveld K, Hutzfeldt A, Nilges L, Guerra JPL, Pietrzak-Lichwa KJ, Tan Y, Colby E, Hansen AG, Kurmasheva N, Olagnier D, Choi D, Richter MM, Laufer SD, Braun F, Johnson SA, Kruger M, Huber TB, Hoxha E, Steinmetz OM, Mrowka R, Melderis S, Saleem MA, Poulsen TB, Andersen GR, Thiel S, Troldborg A, Rinschen MM
Publication type: Article
Publication status: Published
Journal: EMBO Journal
Year: 2025
Pages: 1-38
Online publication date: 27/10/2025
Acceptance date: 30/09/2025
Date deposited: 11/11/2025
ISSN (print): 0261-4189
ISSN (electronic): 1460-2075
Publisher: Springer Science and Business Media Deutschland GmbH
URL: https://doi.org/10.1038/s44318-025-00598-8
DOI: 10.1038/s44318-025-00598-8
Data Access Statement: Proteome data for the 13C6-lysine labeled mouse serum N-terminome is available under the PRIDE accession PXD051273 (https://www.ebi.ac.uk/pride/archive/projects/PXD051273). Extended data regarding the human cohorts is present in the supplemental data. The corresponding authors cannot publish individual patient resolved spectral data as raw files due to the General Data Protection Regulation (GDPR) but will grant access to the human raw data upon reasonable request, following a data transfer agreement. The Opentrons OT-2 protocols are available under https://figshare.com/s/b2fcca1a34918ed46c3c. The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44318-025-00598-8. Expanded view data, supplementary information, appendices are available for this paper at https://doi.org/10.1038/s44318-025-00598-8
PubMed id: 41145914
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