Immune Modulation by Human Secreted RNases at the Extracellular Space

Abstract

The ribonuclease A superfamily is a vertebrate-specific family of proteins that encompasses eight functional members in humans. The proteins are secreted by diverse innate immune cells, from blood cells to epithelial cells and their levels in our body fluids correlate with infection and inflammation processes. Recent studies ascribe a prominent role to secretory RNases in the extracellular space. Extracellular RNases endowed with immuno-modulatory and antimicrobial properties can participate in a wide variety of host defense tasks, from performing cellular housekeeping to maintaining body fluid sterility. Their expression and secretion are induced in response to a variety of injury stimuli. The secreted proteins can target damaged cells and facilitate their removal from the focus of infection or inflammation. Following tissue damage, RNases can participate in clearing RNA from cellular debris or work as signaling molecules to regulate the host response and contribute to tissue remodeling and repair. We provide here an overall perspective on the current knowledge of human RNases’ biological properties and their role in health and disease. The review also includes a brief description of other vertebrate family members and unrelated extracellular RNases that share common mechanisms of action. A better knowledge of RNase mechanism of actions and an understanding of their physiological roles should facilitate the development of novel therapeutics.

Phospho‐RNA‐seq: a modified small RNA‐seq method that reveals circulating mRNA and lncRNA fragments as potential biomarkers in human plasma

“…We hypothesized that mRNA and lncRNA transcripts in the blood circulation are likely to be acted upon by different classes of ribonucleases that may not produce ends conducive to sequencing by standard small RNA‐seq library protocols. Specifically, abundant RNases in human circulation such as those belonging to the ribonuclease superfamily A (Lu et al , ) degrade RNA dinucleotide bonds leaving a 5′ OH and 3′ P product (Cuchillo et al , ), thus rendering cleavage products unsuitable for standard ligation‐based library preparation protocols.…”

“…In contrast, the 5′ and 3′ ends of RNA cleavage products generated by other ribonucleases vary substantially, which might prevent efficient adapter ligation with typical small RNA‐seq methods. For example, abundant RNases in human blood circulation, such as those belonging to the ribonuclease A superfamily (Lu et al , ), degrade RNA dinucleotide bonds, leaving a 5′ OH and 3′ P product (Cuchillo et al , ). Therefore, we reasoned that in order to sequence a broader space of exRNAs beyond microRNAs, it would be essential to develop modifications to small RNA‐seq protocols that can enable capture of RNA fragments that may have these alternate 5′ and 3′ phosphorylation states.…”

Antimicrobial Role of RNASET2 Protein During Innate Immune Response in the Medicinal Leech Hirudo verbana

“…Although the molecular mechanisms by which T2 RNase enzymes act in the antimicrobial process are still unknown, this ability is reminiscent to that previously described for some members of the RNase A superfamily, which, unlike T2 RNases, has been described only in vertebrates (18). For instance, the class A human RNase3 protein, also called eosinophil cationic protein (ECP) (19), acts as a strong eosinophil-mediated antimicrobial protein or peptide (AMPs) independently from its ribonucleolytic activity (20). ECP is released during eosinophil activation from the inner secondary cytoplasmatic granules to the extracellular environment and, after specific interaction with bacterial cells, it permeabilizes their external membranes in order to disrupt them (21)(22)(23).…”

“…ECP is active against different types of bacteria (24) and shows a high affinity to LPS, a component of the outer membrane of Gram-negative bacteria. By binding to bacterial cell membranes and subsequently destabilizing them, ECP shows a carpet-like anti-bacterial mechanism that recalls many host defense antimicrobial proteins or peptides (20). In addition, its N-terminal region induces the formation of bacterial clumps, thus promoting a systematic elimination by immune cells (25).…”

Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases

“…32 Furthermore, ubiquitously present blood and tissue RNases are a significant hindrance to the systemic applicability of naked mRNA. 33 At the cell surface, the next barrier that needs to be overcome is the negatively charged lipid bilayer. Molecules smaller than 1,000 Da can passively diffuse across the membrane, while naked RNA is a large and negatively charged molecule that is hardly transported into the cell without a carrier.…”