Decoding chemerin proteolytic processing and isoform signaling across disease contexts.

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• Chemerin (RARRES2) is a key adipokine involved in metabolic, inflammatory, cardiovascular, and neoplastic diseases.
• Current clinical interpretations of chemerin are limited by measuring total levels, masking crucial proteoform-specific signaling.
• Chemerin is secreted as an inactive precursor and processed into active isoforms with varying receptor affinities and tissue distribution.

Purpose of the Study:

• To decode the functional duality of chemerin by examining its isoform processing and receptor interactions.
• To establish a framework for interpreting chemerin's role in disease by considering its specific proteoforms and localization.
• To highlight methods for isoform-resolved quantification and potential therapeutic targeting strategies.

Main Methods:

• Review of existing literature on chemerin processing, bioactivity, and receptor interactions (CMKLR1, GPR1, CCRL2).
• Emphasis on targeted/MRM-MS for isoform-specific quantification.
• Development of a compartment-aware framework for clinical data interpretation.

Main Results:

• Chemerin bioactivity is determined by protease-encoded isoform "barcodes."
• Distinct isoform landscapes exist in human biofluids and disease microenvironments.
• Receptor context (CMKLR1, GPR1, CCRL2) modulates chemerin signaling output.

Conclusions:

• Measuring total chemerin is mechanistically misleading; isoform-specific analysis is essential.
• A compartment-aware framework improves the interpretation of complex disease associations linked to chemerin.
• Isoform-resolved quantification and understanding localization offer new avenues for targeted therapeutic interventions.