Proteolytic profiling of human plasma reveals an immunoactive complement C3 fragment

Area of Science:

• Proteomics
• Immunology
• Systems Biology

Background:

• Dysregulated proteolysis and complement cascade activation are key in autoimmune diseases like systemic lupus erythematosus (SLE).
• Existing methods have limitations in detecting proteolytic events in complex biological samples like blood plasma.

Purpose of the Study:

• To develop an advanced N-terminomics workflow for comprehensive detection of proteolytic events.
• To identify novel complement fragments and their roles in SLE pathogenesis and clinical manifestations.

Main Methods:

• Development of a scalable blood plasma N-terminomics workflow.
• Application of Multi-Omics Factor Analysis (MOFA) to plasma from 143 SLE patients.
• Mass spectrometry-based quantification and functional assays in human kidney organoids.

Main Results:

• Identification of a novel complement fragment, C3-LHF1, comparable in abundance to known fragments.
• C3-LHF1 correlates with renal function and remission in lupus nephritis.
• C3-LHF1 demonstrates dual functions: inhibiting complement pathways and acting as a partial IL6ST (gp130) agonist.
• C3-LHF1 modulates kidney cell signaling and gene expression, suggesting a role in tissue remodeling.

Conclusions:

• The study reveals novel complexity in complement-mediated signaling in SLE.
• C3-LHF1 represents a potential biomarker and therapeutic target for lupus nephritis.
• The developed N-terminomics platform provides a comprehensive atlas for discovering immunoregulatory mechanisms.