Abstract
Human Ribonuclease 6 is a secreted protein belonging to the ribonuclease A (RNaseA) superfamily, a vertebrate specific family suggested to arise with an ancestral host defense role. Tissue distribution analysis revealed its expression in innate cell types, showing abundance in monocytes and neutrophils. Recent evidence of induction of the protein expression by bacterial infection suggested an antipathogen function in vivo. In our laboratory, the antimicrobial properties of the protein have been evaluated against Gram-negative and Gram-positive species and its mechanism of action was characterized using a membrane model. Interestingly, our results indicate that RNase6, as previously reported for RNase3, is able to specifically agglutinate Gram-negative bacteria as a main trait of its antimicrobial activity. Moreover, a side by side comparative analysis with the RN6(1–45) derived peptide highlights that the antimicrobial activity is mostly retained at the protein N-terminus. Further work by site directed mutagenesis and structural analysis has identified two residues involved in the protein antimicrobial action (Trp1 and Ile13) that are essential for the cell agglutination properties. This is the first structure-functional characterization of RNase6 antimicrobial properties, supporting its contribution to the infection focus clearance.
Highlights
The ribonuclease A (RNaseA) superfamily is a vertebrate-specific gene family that comprises a wide set of secreted ribonucleases displaying a variety of biological properties [1,2]
In order to evaluate the antimicrobial mechanism of action of RNase6, we used different experimental approaches that combined the analysis of the protein activity in synthetic lipid bilayers with its action on bacteria cultures
The results demonstrated that the hydrophobic patch at the N-terminal region of the protein is related to the interaction with bacterial cell wall components
Summary
The RNaseA superfamily is a vertebrate-specific gene family that comprises a wide set of secreted ribonucleases displaying a variety of biological properties [1,2]. Distant related members were reported to share innate immunity properties, suggesting that the vertebrate RNases have evolved as a host-defense family [3,4,5]. RNase is another RNase secreted by a variety of epithelial tissues [24] and displaying a high antimicrobial activity against a wide range of bacteria, regarded as a major contributor to the skin barrier protection [25,26,27,28]. RNase has been related with the host immune system protection, being expressed in neutrophils and monocytes and displaying a high antimicrobial activity [29]. Our understanding of the antimicrobial mechanism of action of the RNase is still poor
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