Identification of a new antimicrobial peptide from the histone variant MacroH2A1 of large yellow croaker (Larimichthys crocea): insights into the diversity of histone-derived antimicrobial peptides.

Abstract

Histones, fundamental components of eukaryotic nucleosomes, comprise canonical histones (e.g., H1, H2A, H2B, H3, H4) and histone variants (e.g., H2A.Z, MacroH2A, H3.3), which critically regulate embryonic development and cellular reprogramming. Although histone-derived antimicrobial peptides (AMPs) from canonical histones have been extensively documented across vertebrates and invertebrates, no AMPs originating from histone variants have been identified to date. This study addresses this gap by characterizing a histone variant MacroH2A1 in large yellow croaker (Larimichthys crocea) and subsequently synthesizing its 26-amino acid N-terminal derivative peptide RMR26. In vitro analyses revealed that RMR26 exhibits a broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria and a low cytotoxicity and minimal hemolytic activity. The RMR26 demonstrated stability across diverse temperature and pH conditions, suggesting its applicability as an aquaculture feed additive. Mechanistic investigations demonstrated that RMR26 exerts bactericidal effects by disrupting bacterial membrane integrity. Besides, antimicrobial efficacy was further confirmed in vivo using a zebrafish challenge model. This study reports the first histone variant-derived AMP, expanding the diversity of histone-based antimicrobial agents and providing a promising therapeutic candidate for bacterial disease management in aquaculture.