Introduction of RNase A
The ribonuclease A (RNase A) protein, originally derived from the bovine pancreas, stands out as a well-explored mammalian protein in scientific literature. Through ongoing research, numerous proteins sharing significant sequence homology have been identified in mammals and other vertebrates, culminating in the establishment of the vertebrate-specific RNase A superfamily. Distinguished from other ribonucleases, the superfamily exhibits distinct distributions and properties.
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In humans, eight secreted RNases, collectively known as canonical RNases, have been extensively studied. These RNases share common features in terms of sequences, conformations, phylogenesis, biochemical characterization, and regulation. They possess a tertiary structure stabilized by eight disulfide bridges, except for RNase 5, which has six cysteine residues. Catalytic activity is determined by two histidine residues and one lysine residue within the CKxxNTF motif. Each RNase carries an N-terminal signal sequence directing endoplasmic reticulum-mediated biosynthesis, with the mature form being secretory. The N-terminal portion of extracellular RNase is implicated in antimicrobial activity, demonstrated by peptides derived from the N-terminus exhibiting similar antimicrobial effects.
Fig. 1 A schematic overview of the human canonical ribonucleases (RNases) in the host defence system (Koczera P., et al. 2016).
The RNase A superfamily, in contrast to other immune-associated proteins/genes, exhibits high rates of duplication and amino acid substitution, accompanied by high isoelectric points and positive net charges. These properties contribute to antibacterial activity and strong interactions with polynucleotide substrates. Canonical RNases display variations in ribonuclease activity and substrate cleavage preferences.
Distinct regulatory patterns for RNases at transcriptional or secretory levels are recognized, with the ribonuclease inhibitor (RI) present in all mammalian cells playing a crucial role. RI binds to ribonucleases with femtomolar affinity, forming an inhibitory complex that attenuates the biological effects of RNases. Cytosolic RI serves as protection against the cytotoxic activity of RNases in host cells.
Despite extensive evaluation of the biochemical properties and the evolutionary emergence of the RNase A gene superfamily, their physiological functions require further clarification.
Individual Canonical RNases
RNase 1: Ubiquitous in various organs, RNase 1 plays a vital role in host defense, angiogenesis, and serum viscosity normalization. It exhibits antiviral activity against HIV-1 and induces dendritic cell activation.
RNase 2: Known as eosinophil-derived neurotoxin (EDN), RNase 2 has antiviral effects against HIV and RSV, with potential roles in allergic inflammation and antibacterial responses.
RNase 3: RNase 3, shows antiviral, antibacterial, anthelmintic, and cytotoxic effects. Its antibacterial mechanism involves amyloid-like aggregation and disruption of bacterial membranes.
RNase 4: Limited studies on RNase 4 suggest potential antimicrobial activity, particularly against Candida albicans, possibly in conjunction with RNase 5.
RNase 5: Also known as angiogenin, RNase 5 exhibits angiogenic properties, antiviral effects against HIV-1, and antimicrobial activities against various pathogens.
RNase 6: Recently studied, RNase 6 shows elevated levels during urinary tract infections, demonstrating antimicrobial activity against uropathogenic bacteria and inhibiting HIV infection.
RNase 7: Abundant in the skin, RNase 7 contributes to cutaneous host defense against bacteria and fungi. It exhibits broad-spectrum antimicrobial activity by disrupting bacterial membranes.
RNase 8: Found in the placenta, lung, spleen, and testis, RNase 8 displays antimicrobial properties against Gram-positive and Gram-negative bacteria and Candida albicans, suggesting a role in pregnancy-related host defense.
The canonical RNases play multifaceted roles in host defense, exhibiting diverse antimicrobial activities and immunomodulatory effects. Further research is essential to elucidate their specific mechanisms, potential therapeutic applications, and contributions to human health in various physiological contexts.
Reference
- Koczera P., et al. The ribonuclease a superfamily in humans: canonical RNases as the buttress of innate immunity. International Journal of Molecular Sciences. 2016, 17(8): 1278.
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