Ongoing research provides further understanding of the biology of RNase A ribonucleases that promote innate immunity (the eosinophil RNase 2 and RNase 3, tissue RNases 7 and 8, and leukocyte RNase A-2) with efforts focused toward understanding their mechanisms of action in health and disease. Eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP) are prominent, evolutionarily divergent secretory mediators of human eosinophils with antiviral activity. The mouse orthologs of these proteins, the eosinophil-associated ribonucleases, or EARs, have undergone an unusual pattern of evolution called rapid birth-death and gene sorting, which has also been documented in the T-cell receptor, immunoglobulin, and major-histocompatability complex gene families. This rapidly expanded gene family consists of 15 genes of which mEar-1, -2, -6/7, -5/11 have been positively identified within eosinophil secondary granules. Mouse EAR11 has retained the RNase A family characteristic sequence motifs but has a unique expression pattern, as it responds to Th2 stimulation, and is produced by alternatively-activated macrophages in the lung in response to IL-4 or IL-13. As part of a larger effort to evaluate the unique properties of mEAR11, we have compared the enzymatic activity of this protein to the predominant paralogs, mEAR1 and mEAR2. Despite similar isoelectric points (pI), mEAR11 has approximately 100-fold less activity against a standard tRNA substrate. Among the interpretations, it is conceivable that mEAR 11 has diverged to support functions other than enzymatic activity. Other evaluations of the bioactivity of mEAR 11 are currently in progress. We also report a mouse model that includes the first successful deletion of a mouse eosinophil ribonuclease (relevant also for report AI000941). The characterization of this mouse will have profound impact on our understanding of the role of these enzymes in promoting homeostasis in vivo and at the cellular level.

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