Hepcidin, still an antimicrobial peptide in fish: Exploring sequence diversity, functions and therapeutic potential

Hepcidin is an important antimicrobial peptide (AMP), yet the structural based classification of AMPs can be debated due to the additional role of hepcidin in iron homeostasis. Sequence analyses showed that the pro-peptide region of fish hepcidin exhibits substantial diversification, and the mature peptide remains comparatively conserved in fish, characterized by eight cysteine residues forming four intramolecular disulfide bonds. These conserved cysteines are essential for stabilizing a hairpin structure composed of two antiparallel β-sheets, an amphipathic configuration that is believed to facilitate interaction with microbial membranes. However, this structural conserveness is also observed in isoforms dedicated for iron homeostasis, which has become a primary role in higher vertebrates predicted through evolution because the mature peptide also showed substantial difference in amino acid sequence in higher vertebrates compared to fish. Positive Darwinian selection observed in fish hepcidins, likely due to pathogen-driven evolutionary pressure in diverse aquatic environments. Although hepcidin is predominantly expressed in the liver, induced expression was also noticed in spleen, gills, intestine, and skin. Recent studies have demonstrated that after cleavage from the propeptide, the mature peptide predominantly localizes to mucosal surfaces, including the skin and gills, indicating its role as a first line of defense. Nevertheless, fish hepcidin exhibits broad-spectrum antimicrobial activity against Gram-negative and Gram-positive bacteria, viruses, and parasites. It interacts with the specific microbial membrane, resulting in membrane disruption and ultimately death of the microorganism. Beyond direct antimicrobial action, evidence of interaction of hepcidin with various immune pathways, including inflammatory responses, complement, Toll-like receptors, and lysozyme and involvement in iron homeostasis gives evidence of physiological networks of hepcidin. Therefore, instead of categorizing AMPs on the basis of function or structure, we need to open up our understanding of physiological systems. Although fish hepcidin is well established as a potent antimicrobial peptide, and its involvement in complex physiological networks highlights the sophistication of living systems still it's a perfect example how genes evolve to perform different function.