Rnase a ribonucleases and host defense: An evolving story

the founding member an extensive family of diver-gent proteins that share specific elements of se-quence homology, a unique disulfide-bonded ter-tiary structure, and the ability to hydrolyze poly-meric RNA. Among the more intriguing and perhaps counterintuitive findings, at the current state of the art, the connection between RNase activity and characterized host defense functions is quite weak; whether this is a scientific reality or more a reflection of what has been chosen for study remains to be determined. Several of the RNase A family RNases are highly cationic and have cyto-toxic and bactericidal properties that are clearly (eosinophil cationic protein, leukocyte RNase A-2) or are probably (RNase 7) unrelated to their enzy-matic activity. Interestingly, peptides derived from the leukocyte RNase A-2 sequence are nearly as bactericidal as the entire protein, suggesting that among other functions, the RNase A superfamily may be serving as a source of gene scaffolds for the generation of novel cytotoxic peptides. Other RNase A ribonucleases are somewhat less cationic (mouse angiogenin 4, zebrafish RNases) and have moderate bactericidal activities that have not yet been explored mechanistically. Additional host de-fense functions characterized specifically for the RNase eosinophil-derived neurotoxin include re-ducing infectivity of RNA viruses for target cells in culture, which does require RNase activity, che-moattraction of immature human dendritic cells via a G-protein-coupled receptor-dependent mech-anism, and activation of TLR2. The properties of individual RNase A ribonucleases, recent experi-mental findings, and important questions for the near and distant future will be reviewed. J. Leukoc