Proteolytic profiling of human plasma reveals an immunoactive complement C3 fragment

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.

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Publication Details

Journal
The EMBO Journal
Published
2025-10-27
DOI
https://doi.org/10.1038/s44318-025-00598-8
Citations
2
Primary Topic
Complement system in diseases
Type
article
Field-Weighted Citation Impact
1.59
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article

Proteolytic profiling of human plasma reveals an immunoactive complement C3 fragment

David Olagnier, Steffen Thiel, João P. L. Guerra, Simon Melderis et al.
2 citations
The EMBO Journal
Complement system in diseases
1.59
article

Proteolytic profiling of human plasma reveals an immunoactive complement C3 fragment

David Olagnier, Steffen Thiel, João P. L. Guerra, Simon Melderis, Fabian Braun, Thomas B. Poulsen, Jens Magnus Bernth Jensen, Marcus Krüger, Elizabeth Colby, Yifan Tan, Markus Matthias Rinschen, Esben B. Svenningsen, Sally Johnson, Naziia Kurmasheva, Moin A. Saleem, Anne Troldborg, Gregers Rom Andersen, Moritz Lassé, Dennis W. Choi, Oliver M. Steinmetz, Kathrin Groeneveld, Arvid Hutzfeldt, Tobias B. Huber, Ralf Mrowka, Fatih Demir, Elion Hoxha, A. Billing, Krzysztof J Pietrzak-Lichwa, Sandra D. Laufer, Annette Gudmann Hansen, Elina Kovalenko, M Richter, Lars Nilges
article en
2 citations

Abstract

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.

The EMBO JournalVol. 44(24)
Universität Hamburg (DE), Aarhus University (DK), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Aarhus University Hospital (DK), University of Bristol (GB), MSH Medical School Hamburg – University of Applied Sciences and Medical University (DE), University Medical Center Hamburg-Eppendorf (DE), Newcastle upon Tyne Hospital (GB), Jena University Hospital (DE), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
Openalex Percentile: Top 14%
Complement system in diseases
1.59
DOIOpen Access PDFOpenAlex
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