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<p>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.</p>

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Proteolytic profiling of human plasma reveals an immunoactive complement C3 fragment

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月27日

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

摘要

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.