Functional roles of the human ribonuclease A superfamily in RNA metabolism and membrane receptor biology

The human ribonuclease A (hRNase A) superfamily is comprised of 13 members of secretory RNases, most of which are recognized as catabolic enzymes for their ribonucleolytic activity to degrade ribonucleic acids (RNAs) in the extracellular space, where they play a role in innate host defense and physiological homeostasis. Interestingly, human RNases 9–13, which belong to a non-canonical subgroup of the hRNase A superfamily, are ribonucleolytic activity-deficient proteins with unclear biological functions. Moreover, accumulating evidence indicates that secretory RNases, such as human RNase 5, can be internalized into cells facilitated by membrane receptors like the epidermal growth factor receptor to regulate intracellular RNA species, in particular non-coding RNAs, and signaling pathways by either a ribonucleolytic activity-dependent or -independent manner. In this review, we summarize the classical role of hRNase A superfamily in the metabolism of extracellular and intracellular RNAs and update its non-classical function as a cognate ligand of membrane receptors. We further discuss the biological significance and translational potential of using secretory RNases as predictive biomarkers or therapeutic agents in certain human diseases and the pathological settings for future investigations.