A Review of Ribonuclease 7’s Structure, Regulation, and Contributions to Host Defense

Becknell, Brian; Spencer, John David

doi:10.3390/ijms17030423

Cited by 39 publications

(34 citation statements)

References 52 publications

(91 reference statements)

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“…It is also one of the most abundant antimicrobial proteins purified from skin ( 44 , 79 ). RNase7 is secreted by a variety of epithelial cells (Table 2 ) and mostly contributes to urinary tract sterility and epidermis protection ( 43 , 80 – 82 ). Together with high antimicrobial activity against a variety of infective microorganisms ( 82 , 87 , 89 , 193 ), some immuno-modulatory properties were reported.…”

Section: The Rnase a Superfamilymentioning

confidence: 99%

Immune Modulation by Human Secreted RNases at the Extracellular Space

et al. 2018

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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.

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Section: The Rnase a Superfamilymentioning

confidence: 99%

Immune Modulation by Human Secreted RNases at the Extracellular Space

et al. 2018

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“…The hRNase A superfamily consists of 13 members which genes encoding both canonical RNases 1–8 and noncanonical RNases 9–13 (Table 1 ). All genes are closely linked on chromosome 14 and encode secretory proteins containing a classical hydrophobic signal peptide at the N-terminus [ 19 – 21 ]. Each RNase maintains an invariant catalytic triad of two histidine (His) residues located at the C-terminus and one lysine (Lys) residue within a consensus CKXXNTF motif, and contains six to eight conserved cysteine residues that form three to four disulfide bonds [ 1 , 22 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

A novel ligand-receptor relationship between families of ribonucleases and receptor tyrosine kinases

2018

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Pancreatic ribonuclease is known to participate in host defense system against pathogens, such as parasites, bacteria, and virus, which results in innate immune response. Nevertheless, its potential impact to host cells remains unclear. Of interest, several ribonucleases do not act as catalytically competent enzymes, suggesting that ribonucleases may be associated with certain intrinsic functions other than their ribonucleolytic activities. Most recently, human pancreatic ribonuclease 5 (hRNase5; also named angiogenin; hereinafter referred to as hRNase5/ANG), which belongs to the human ribonuclease A superfamily, has been demonstrated to function as a ligand of epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase family. As a newly identified EGFR ligand, hRNase5/ANG associates with EGFR and stimulates EGFR and the downstream signaling in a catalytic-independent manner. Notably, hRNase5/ANG, whose level in sera of pancreatic cancer patients, serves as a non-invasive serum biomarker to stratify patients for predicting the sensitivity to EGFR-targeted therapy. Here, we describe the hRNase5/ANG-EGFR pair as an example to highlight a ligand-receptor relationship between families of ribonucleases and receptor tyrosine kinases, which are thought as two unrelated protein families associated with distinct biological functions. The notion of serum biomarker-guided EGFR-targeted therapies will also be discussed. Furthering our understanding of this novel ligand-receptor interaction will shed new light on the search of ligands for their cognate receptors, especially those orphan receptors without known ligands, and deepen our knowledge of the fundamental research in membrane receptor biology and the translational application toward the development of precision medicine.

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“…12, 14 RNase 7’s bactericidal properties are independent of its catalytic activity and are dependent on its ability to disrupt the microbial cell wall. 13, 15–18 RNase 7 has been described as the most potent human AMP. 13, 19, 20 When it is neutralized in human urine specimens, urinary bacterial growth increases – suggesting that deficient urinary RNase 7 production increases UTI susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract

Eichler

Becknell

Easterling

et al. 2016

Kidney International

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Diabetes mellitus is a systemic disease associated with a deficiency of insulin production or action. Diabetic patients have an increased susceptibility to infection with the urinary tract being the most common site of infection. Recent studies suggest that Ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that plays an important role in protecting the urinary tract from bacterial insult. The impact of diabetes on RNase 7 expression and function are unknown. Here, we investigate the effects of insulin on RNase 7. Using human urine specimens, we measured urinary RNase 7 concentrations in healthy control patients and insulin-deficient type 1 diabetics before and after starting insulin therapy. Compared to controls, diabetic patients had suppressed urinary RNase 7 concentrations, which increased with insulin. Using primary human urothelial cells, we explored the mechanisms by which insulin induces RNase 7. Insulin induces RNase 7 production via the phosphatidylinositide 3-kinase signaling pathway (PI3K/AKT) to shield urothelial cells from uropathogenic E. coli. In contrast, we show that uropathogenic E. coli suppresses PI3K/AKT and RNase 7. Together, these results indicate that insulin and PI3K/AKT signaling are essential for RNase 7 expression. They also suggest that increased infection risks in diabetic patients may be secondary to suppressed RNase 7 production. These data may provide unique insight into novel UTI therapeutic strategies in at risk populations.

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A Review of Ribonuclease 7’s Structure, Regulation, and Contributions to Host Defense

Cited by 39 publications

References 52 publications

Immune Modulation by Human Secreted RNases at the Extracellular Space

Immune Modulation by Human Secreted RNases at the Extracellular Space

A novel ligand-receptor relationship between families of ribonucleases and receptor tyrosine kinases

Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract

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