Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.5 (RNase)
17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the identification and characterization of the gene encoding the eighth and final human ribonuclease (RNase) of the highly diversified RNase A superfamily. The RNase 8 gene is linked to seven other RNase A superfamily genes on chromosome 14. It is expressed prominently in the placenta, but is not detected in any other tissues examined. Phylogenetic analysis suggests that RNase 7 is the closest relative of RNase 8 and that the pair likely resulted from a recent gene duplication event in primates. Further analysis reveals that the RNase 8 gene has incorporated non-silent mutations at an elevated rate (1.3 x 10(-9) substitutions/site/year) and that orthologous RNase 8 genes from 6 of 10 primate species examined have been deactivated by frameshifting deletions or point mutations at crucial structural or catalytic residues. The ribonucleolytic activity of recombinant human RNase 8 is among the lowest of members of this superfamily and it exhibits neither antiviral nor antibacterial activities characteristic of some other RNase A ribonucleases. The rapid evolution, species-limited deactivation and tissue-specific expression of RNase 8 suggest a unique physiological function and reiterates the evolutionary plasticity of the RNase A superfamily.
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PMID:RNase 8, a novel RNase A superfamily ribonuclease expressed uniquely in placenta. 1186 8

We analyzed healthy human skin for the presence of endogenous antimicrobial proteins that might explain the unusually high resistance of human skin against infections. A novel 14.5-kDa antimicrobial ribonuclease, termed RNase 7, was isolated from skin-derived stratum corneum. RNase 7 exhibited potent ribonuclease activity and thus may contribute to the well known ribonuclease activity of human skin. RNase 7 revealed broad spectrum antimicrobial activity against many pathogenic microorganisms and remarkably potent activity (lethal dose of 90% < 30 nm) against a vancomycin-resistant Enterococcus faecium. Molecular cloning from skin-derived primary keratinocytes and purification of RNase 7 from supernatants of cultured primary keratinocytes indicate that keratinocytes represent the major cellular source in skin and that RNase 7 is secreted. RNase 7 mRNA expression was detected in various epithelial tissues including skin, respiratory tract, genitourinary tract, and at a low level, in the gut. In addition to a constitutive expression, RNase 7 mRNA was induced in cultured primary keratinocytes by interleukin-1beta, interferon-gamma, and bacterial challenge. This is the first report demonstrating RNases as a novel class of epithelial inducible antimicrobial proteins, which may play an important role in the innate immune defense system of human epithelia.
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PMID:RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin. 1224 54

Here we report on the expression and function of RNase 7, one of the final RNase A superfamily ribonucleases identified in the human genome sequence. The human RNase 7 gene is expressed in various somatic tissues including the liver, kidney, skeletal muscle and heart. Recombinant RNase 7 is ribonucleolytically active against yeast tRNA, as expected from the presence of eight conserved cysteines and the catalytic histidine-lysine- histidine triad which are signature motifs of this superfamily. The protein is atypically cationic with an isoelectric point (pI) of 10.5. Expression of recombinant RNase 7 in Escherichia coli completely inhibits the growth of the host bacteria, similar to what has been observed for the cationic RNase, eosinophil cationic protein (ECP/RNase 3, pI 11.4). An in vitro assay demonstrates dose-dependent cytotoxicity of RNase 7 against bacteria E.coli, Pseudomonas aeruginosa and Staphylococcus aureus. While RNase 7 and ECP/RNase 3 are both cationic and share this particular aspect of functional similarity, their protein sequence identity is only 40%. Of particular interest, ECP/RNase 3's cationicity is based on an (over)abundance of arginine residues, whereas RNase 7 includes an excess of lysine. This difference, in conjunction with the independent origins and different expression patterns, suggests that RNase 7 and ECP/RNase 3 may have been recruited to target different pathogens in vivo, if their physiological functions are indeed host defenses.
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PMID:Human RNase 7: a new cationic ribonuclease of the RNase A superfamily. 1252 68

The Ribonuclease A superfamily includes an extensive network of distinct and divergent gene lineages. Although all ribonucleases of this superfamily share invariant structural and catalytic elements and some degree of enzymatic activity, the primary sequences have diverged significantly, ostensibly to promote novel function. We will review the literature on the evolution and biology of the RNase A ribonuclease lineages that have been characterized specifically as involved in host defense including: (1) RNases 2 and RNases 3, also known as the eosinophil ribonucleases, which are rapidly-evolving cationic proteins released from eosinophilic leukocytes, (2) RNase 7, an anti-pathogen ribonuclease identified in human skin, and (3) RNase 5, also known as angiogenin, another rapidly-evolving ribonuclease known to promote blood vessel growth with recently-discovered antibacterial activity. Interestingly, some of the characterized anti-pathogen activities do not depend on ribonuclease activity per se. We discuss the ways in which the anti-pathogen activities characterized in vitro might translate into experimental confirmation in vivo. We will also consider the possibility that other ribonucleases, such as the dimeric bovine seminal ribonuclease and the frog oocyte ribonucleases, may have host defense functions and therapeutic value that remain to be explored. (190 words).
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PMID:The RNase a superfamily: generation of diversity and innate host defense. 1696 22

RNase A (bovine pancreatic RNase) is the founding member an extensive family of divergent proteins that share specific elements of sequence homology, a unique disulfide-bonded tertiary structure, and the ability to hydrolyze polymeric 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 cytotoxic and bactericidal properties that are clearly (eosinophil cationic protein, leukocyte RNase A-2) or are probably (RNase 7) unrelated to their enzymatic 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 defense functions characterized specifically for the RNase eosinophil-derived neurotoxin include reducing infectivity of RNA viruses for target cells in culture, which does require RNase activity, chemoattraction of immature human dendritic cells via a G-protein-coupled receptor-dependent mechanism, and activation of TLR2. The properties of individual RNase A ribonucleases, recent experimental findings, and important questions for the near and distant future will be reviewed.
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PMID:RNase A ribonucleases and host defense: an evolving story. 1821 64

The antimicrobial defense of the skin is partially mediated by RNase 7, an abundant ribonuclease of the stratum corneum (SC). Here, we investigated the expression and regulation of members of the RNase A family and of the endogenous RNase inhibitor (RI) protein in epidermal keratinocytes (KCs). Reverse transcription-PCR screening revealed that KCs expressed not only RNase 7 but also RNase 5, which was shown earlier to kill the yeast Candida albicans, as well as RNase 1, RNase 4, and RI. The mRNA and protein levels of RNase 5, RNase 7, and RI increased during KC differentiation. When RNase 5 and RNase 7 were incubated with RI in vitro, not only their ribonucleolytic activities but also their antimicrobial activities were strongly suppressed. Immunochemical analyses revealed that SC contains RNase 5, whereas RI was not detectable. Unlike recombinant RNase 5, recombinant RI was degraded when exposed to SC extract. The addition of aprotinin prevented the degradation of RI, indicating that serine proteases of the SC cleave RI. Taken together, this study adds RNase 5 to the list of antimicrobial factors present in the SC and suggests that proteases contribute indirectly to the defense function of the SC by releasing the RI-mediated inhibition of RNase 5 and RNase 7.
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PMID:Degradation by stratum corneum proteases prevents endogenous RNase inhibitor from blocking antimicrobial activities of RNase 5 and RNase 7. 1980 22

Eosinophil cationic protein (ECP/RNase 3) and the skin derived ribonuclease 7 (RNase 7) are members of the RNase A superfamily. RNase 3 is mainly expressed in eosinophils whereas RNase 7 is primarily secreted by keratinocytes. Both proteins present a broad-spectrum antimicrobial activity and their bactericidal mechanism is dependent on their membrane destabilizing capacities. Using phospholipid vesicles as membrane models, we have characterized the protein membrane association process. Confocal microscopy experiments using giant unilamellar vesicles illustrate the morphological changes of the liposome population. By labelling both lipid bilayers and proteins we have monitored the kinetic of the process. The differential protein ability to release the liposome aqueous content was evaluated together with the micellation and aggregation processes. A distinct morphology of the protein/lipid aggregates was visualized by transmission electron microscopy and the proteins overall secondary structure in a lipid microenvironment was assessed by FTIR. Interestingly, for both RNases the membrane interaction events take place in a different behaviour and timing: RNase 3 triggers first the vesicle aggregation, while RNase 7 induces leakage well before the aggregation step. Their distinct mechanism of action at the membrane level may reflect different in vivo antipathogen functions.
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PMID:Comparison of the membrane interaction mechanism of two antimicrobial RNases: RNase 3/ECP and RNase 7. 1936 93

The eosinophil cationic protein/RNase 3 and the skin-derived RNase 7 are two human antimicrobial RNases involved in host innate immunity. Both belong to the RNase A superfamily and share a high cationicity and a common structural architecture. However, they present significant divergence at their primary structures, displaying either a high number of Arg or Lys residues, respectively. Previous comparative studies with a membrane model revealed two distinct mechanisms of action for lipid bilayer disruption. We have now compared their bactericidal activity, identifying some features that confer specificity at the bacterial cell wall level. RNase 3 displays a specific Escherichia coli cell agglutination activity, which is not shared by RNase 7. The RNase 3 agglutination process precedes the bacterial death and lysis event. In turn, RNase 7 can trigger the release of bacterial cell content without inducing any cell aggregation process. We hypothesize that the RNase 3 agglutination activity may depend on its high affinity for lipopolysaccharides and the presence of an N-terminal hydrophobic patch, and thus could facilitate host clearance activity at the infection focus by phagocytic cells. The present study suggests that the membrane disruption abilities do not solely explain the protein bacterial target preferences and highlights the key role of antimicrobial action at the bacterial cell wall level. An understanding of the interaction between antimicrobial proteins and their target at the bacterial envelope should aid in the design of alternative peptide-derived antibiotics.
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PMID:Comparison of human RNase 3 and RNase 7 bactericidal action at the Gram-negative and Gram-positive bacterial cell wall. 2018 Aug 4

Antimicrobial proteins (AMP) are small endogenous proteins which are capable of rapidly inactivating microorganisms at low micro- and nanomolar concentrations. Their significance in host defense is reflected by their wide distribution in nature. Several AMP have been isolated from human skin, and there is increasing evidence that AMP may play an important role in cutaneous defense. One important human AMP class comprises several antimicrobial members of the RNase A superfamily. Of these, two members, RNase 7 and RNase 5, have been implicated in cutaneous defense. This review gives an overview about our current knowledge on the potential role of RNase 7 and RNase 5 in protecting human skin from infection.
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PMID:Antimicrobial RNases in cutaneous defense. 2232 69

Recent studies stress the importance of antimicrobial peptides in protecting the urinary tract from infection. Previously, we have shown that ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that has a broad-spectrum antimicrobial activity against uropathogenic bacteria. The urothelium of the lower urinary tract and intercalated cells of the kidney produce RNase 7, but regulation of its antimicrobial activity has not been well defined. Here, we characterize the expression of an endogenous inhibitor, ribonuclease inhibitor (RI), in the urinary tract and evaluate its effect on the antimicrobial activity of RNase 7. Using RNA isolated from non-infected human bladder and kidney tissue, quantitative real-time polymerase chain reaction showed that RNH1, the gene encoding RI, is constitutively expressed throughout the urinary tract. With pyelonephritis, RNH1 expression and RI peptide production significantly decrease. Immunostaining localized RI production to the umbrella cells of the bladder and intercalated cells of the renal collecting tubule. In vitro assays showed that RI bound to RNase 7 and suppressed its antimicrobial activity by blocking its ability to bind the cell wall of uropathogenic bacteria. Thus, these results demonstrate a new immunomodulatory role for RI and identified a unique regulatory pathway that may affect how RNase 7 maintains urinary tract sterility.
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PMID:An endogenous ribonuclease inhibitor regulates the antimicrobial activity of ribonuclease 7 in the human urinary tract. 2410 47


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