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3692 KiB

Open AccessArticle

Insights into the Antimicrobial Mechanism of Action of Human RNase6: Structural Determinants for Bacterial Cell Agglutination and Membrane Permeation

by David Pulido, Javier Arranz-Trullén, Guillem Prats-Ejarque, Diego Velázquez, Marc Torrent, Mohammed Moussaoui and Ester Boix

Int. J. Mol. Sci. 2016, 17(4), 552; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040552 - 13 Apr 2016

Cited by 39 | Viewed by 5699

Abstract

Human Ribonuclease 6 is a secreted protein belonging to the ribonuclease A (RNaseA) superfamily, a vertebrate specific family suggested to arise with an ancestral host defense role. Tissue distribution analysis revealed its expression in innate cell types, showing abundance in monocytes and neutrophils. [...] Read more.

Human Ribonuclease 6 is a secreted protein belonging to the ribonuclease A (RNaseA) superfamily, a vertebrate specific family suggested to arise with an ancestral host defense role. Tissue distribution analysis revealed its expression in innate cell types, showing abundance in monocytes and neutrophils. Recent evidence of induction of the protein expression by bacterial infection suggested an antipathogen function in vivo. In our laboratory, the antimicrobial properties of the protein have been evaluated against Gram-negative and Gram-positive species and its mechanism of action was characterized using a membrane model. Interestingly, our results indicate that RNase6, as previously reported for RNase3, is able to specifically agglutinate Gram-negative bacteria as a main trait of its antimicrobial activity. Moreover, a side by side comparative analysis with the RN6(1–45) derived peptide highlights that the antimicrobial activity is mostly retained at the protein N-terminus. Further work by site directed mutagenesis and structural analysis has identified two residues involved in the protein antimicrobial action (Trp1 and Ile13) that are essential for the cell agglutination properties. This is the first structure-functional characterization of RNase6 antimicrobial properties, supporting its contribution to the infection focus clearance. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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1804 KiB

Open AccessArticle

The Human Host Defense Ribonucleases 1, 3 and 7 Are Elevated in Patients with Sepsis after Major Surgery—A Pilot Study

by Lukas Martin, Patrick Koczera, Nadine Simons, Elisabeth Zechendorf, Janine Hoeger, Gernot Marx and Tobias Schuerholz

Int. J. Mol. Sci. 2016, 17(3), 294; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17030294 - 26 Feb 2016

Cited by 19 | Viewed by 5415

Abstract

Sepsis is the most common cause of death in intensive care units and associated with widespread activation of host innate immunity responses. Ribonucleases (RNases) are important components of the innate immune system, however the role of RNases in sepsis has not been investigated. [...] Read more.

Sepsis is the most common cause of death in intensive care units and associated with widespread activation of host innate immunity responses. Ribonucleases (RNases) are important components of the innate immune system, however the role of RNases in sepsis has not been investigated. We evaluated serum levels of RNase 1, 3 and 7 in 20 surgical sepsis patients (Sepsis), nine surgical patients (Surgery) and 10 healthy controls (Healthy). RNase 1 and 3 were elevated in Sepsis compared to Surgery (2.2- and 3.1-fold, respectively; both p < 0.0001) or compared to Healthy (3.0- and 15.5-fold, respectively; both p < 0.0001). RNase 1 showed a high predictive value for the development of more than two organ failures (AUC 0.82, p = 0.01). Patients with renal dysfunction revealed higher RNase 1 levels than without renal dysfunction (p = 0.03). RNase 1 and 3 were higher in respiratory failure than without respiratory failure (p < 0.0001 and p = 0.02, respectively). RNase 7 was not detected in Healthy patients and only in two patients of Surgery, however RNase 7 was detected in 10 of 20 Sepsis patients. RNase 7 was higher in renal or metabolic failure than without failure (p = 0.04 and p = 0.02, respectively). In conclusion, RNase 1, 3 and 7 are secreted into serum under conditions with tissue injury, such as major surgery or sepsis. Thus, RNases might serve as laboratory parameters to diagnose and monitor organ failure in sepsis. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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8651 KiB

Open AccessArticle

RNase L Cleavage Products Promote Switch from Autophagy to Apoptosis by Caspase-Mediated Cleavage of Beclin-1

by Mohammad Adnan Siddiqui, Sushovita Mukherjee, Praveen Manivannan and Krishnamurthy Malathi

Int. J. Mol. Sci. 2015, 16(8), 17611-17636; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160817611 - 31 Jul 2015

Cited by 40 | Viewed by 10219

Abstract

Autophagy and apoptosis share regulatory molecules enabling crosstalk in pathways that affect cellular homeostasis including response to viral infections and survival of tumor cells. Ribonuclease L (RNase L) is an antiviral endonuclease that is activated in virus-infected cells and cleaves viral and cellular [...] Read more.

Autophagy and apoptosis share regulatory molecules enabling crosstalk in pathways that affect cellular homeostasis including response to viral infections and survival of tumor cells. Ribonuclease L (RNase L) is an antiviral endonuclease that is activated in virus-infected cells and cleaves viral and cellular single-stranded RNAs to produce small double-stranded RNAs with roles in amplifying host responses. Activation of RNase L induces autophagy and apoptosis in many cell types. However, the mechanism by which RNase L mediates crosstalk between these two pathways remains unclear. Here we show that small dsRNAs produced by RNase L promote a switch from autophagy to apoptosis by caspase-mediated cleavage of Beclin-1, terminating autophagy. The caspase 3-cleaved C-terminal fragment of Beclin-1 enhances apoptosis by translocating to the mitochondria along with proapoptotic protein, Bax, and inducing release of cytochrome C to the cytosol. Cleavage of Beclin-1 determines switch to apoptosis since expression of caspase-resistant Beclin-1 inhibits apoptosis and sustains autophagy. Moreover, inhibiting RNase L-induced autophagy promotes cell death and inhibiting apoptosis prolongs autophagy in a cross-inhibitory mechanism. Our results demonstrate a novel role of RNase L generated small RNAs in cross-talk between autophagy and apoptosis that impacts the fate of cells during viral infections and cancer. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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Review

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Open AccessReview

The Ribonuclease A Superfamily in Humans: Canonical RNases as the Buttress of Innate Immunity

by Patrick Koczera, Lukas Martin, Gernot Marx and Tobias Schuerholz

Int. J. Mol. Sci. 2016, 17(8), 1278; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17081278 - 05 Aug 2016

Cited by 94 | Viewed by 9058

Abstract

In humans, the ribonuclease A (RNase A) superfamily contains eight different members that have RNase activities, and all of these members are encoded on chromosome 14. The proteins are secreted by a large variety of different tissues and cells; however, a comprehensive understanding [...] Read more.

In humans, the ribonuclease A (RNase A) superfamily contains eight different members that have RNase activities, and all of these members are encoded on chromosome 14. The proteins are secreted by a large variety of different tissues and cells; however, a comprehensive understanding of these proteins’ physiological roles is lacking. Different biological effects can be attributed to each protein, including antiviral, antibacterial and antifungal activities as well as cytotoxic effects against host cells and parasites. Different immunomodulatory effects have also been demonstrated. This review summarizes the available data on the human RNase A superfamily and illustrates the significant role of the eight canonical RNases in inflammation and the host defence system against infections. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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793 KiB

Open AccessReview

RNase 7 in Cutaneous Defense

by Franziska Rademacher, Maren Simanski and Jürgen Harder

Int. J. Mol. Sci. 2016, 17(4), 560; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040560 - 14 Apr 2016

Cited by 27 | Viewed by 6140

Abstract

RNase 7 belongs to the RNase A superfamily and exhibits a broad spectrum of antimicrobial activity against various microorganisms. RNase 7 is expressed in human skin, and expression in keratinocytes can be induced by cytokines and microbes. These properties suggest that RNase 7 [...] Read more.

RNase 7 belongs to the RNase A superfamily and exhibits a broad spectrum of antimicrobial activity against various microorganisms. RNase 7 is expressed in human skin, and expression in keratinocytes can be induced by cytokines and microbes. These properties suggest that RNase 7 participates in innate cutaneous defense. In this review, we provide an overview about the role of RNase 7 in cutaneous defense with focus on the molecular mechanism of the antimicrobial activity of RNase 7, the regulation of RNase 7 expression, and the role of RNase 7 in skin diseases. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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1308 KiB

Open AccessReview

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

by Brian Becknell and John David Spencer

Int. J. Mol. Sci. 2016, 17(3), 423; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17030423 - 22 Mar 2016

Cited by 37 | Viewed by 6202

Abstract

The Ribonuclease A Superfamily is composed of a group of structurally similar peptides that are secreted by immune cells and epithelial tissues. Several members of the Ribonuclease A Superfamily demonstrate antimicrobial activity, and it has been suggested that some of these ribonucleases play [...] Read more.

The Ribonuclease A Superfamily is composed of a group of structurally similar peptides that are secreted by immune cells and epithelial tissues. Several members of the Ribonuclease A Superfamily demonstrate antimicrobial activity, and it has been suggested that some of these ribonucleases play an essential role in host defense. Ribonuclease 7 (RNase 7) is an epithelial-derived secreted peptide with potent broad-spectrum antimicrobial activity. This review summarizes the published literature on RNase 7’s antimicrobial properties, structure, regulation, and contributions to host defense. In doing so, we conclude by highlighting key knowledge gaps that must be investigated to completely understand the potential of developing RNase 7 as a novel therapeutic for human infectious diseases. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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1824 KiB

Open AccessReview

The Roles of RNase-L in Antimicrobial Immunity and the Cytoskeleton-Associated Innate Response

by Heather J. Ezelle, Krishnamurthy Malathi and Bret A. Hassel

Int. J. Mol. Sci. 2016, 17(1), 74; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17010074 - 08 Jan 2016

Cited by 29 | Viewed by 11201

Abstract

The interferon (IFN)-regulated endoribonuclease RNase-L is involved in multiple aspects of the antimicrobial innate immune response. It is the terminal component of an RNA cleavage pathway in which dsRNA induces the production of RNase-L-activating 2-5A by the 2′-5′-oligoadenylate synthetase. The active nuclease then [...] Read more.

The interferon (IFN)-regulated endoribonuclease RNase-L is involved in multiple aspects of the antimicrobial innate immune response. It is the terminal component of an RNA cleavage pathway in which dsRNA induces the production of RNase-L-activating 2-5A by the 2′-5′-oligoadenylate synthetase. The active nuclease then cleaves ssRNAs, both cellular and viral, leading to downregulation of their expression and the generation of small RNAs capable of activating retinoic acid-inducible gene-I (RIG-I)-like receptors or the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome. This leads to IFNβ expression and IL-1β activation respectively, in addition to broader effects on immune cell function. RNase-L is also one of a growing number of innate immune components that interact with the cell cytoskeleton. It can bind to several cytoskeletal proteins, including filamin A, an actin-binding protein that collaborates with RNase-L to maintain the cellular barrier to viral entry. This antiviral activity is independent of catalytic function, a unique mechanism for RNase-L. We also describe here the interaction of RNase-L with the E3 ubiquitin ligase and scaffolding protein, ligand of nump protein X (LNX), a regulator of tight junction proteins. In order to better understand the significance and context of these novel binding partners in the antimicrobial response, other innate immune protein interactions with the cytoskeleton are also discussed. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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1065 KiB

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Eosinophil-Derived Neurotoxin (EDN/RNase 2) and the Mouse Eosinophil-Associated RNases (mEars): Expanding Roles in Promoting Host Defense

by Helene F. Rosenberg

Int. J. Mol. Sci. 2015, 16(7), 15442-15455; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160715442 - 08 Jul 2015

Cited by 55 | Viewed by 7804

Abstract

The eosinophil-derived neurotoxin (EDN/RNase2) and its divergent orthologs, the mouse eosinophil-associated RNases (mEars), are prominent secretory proteins of eosinophilic leukocytes and are all members of the larger family of RNase A-type ribonucleases. While EDN has broad antiviral activity, targeting RNA viruses via mechanisms [...] Read more.

The eosinophil-derived neurotoxin (EDN/RNase2) and its divergent orthologs, the mouse eosinophil-associated RNases (mEars), are prominent secretory proteins of eosinophilic leukocytes and are all members of the larger family of RNase A-type ribonucleases. While EDN has broad antiviral activity, targeting RNA viruses via mechanisms that may require enzymatic activity, more recent studies have elucidated how these RNases may generate host defense via roles in promoting leukocyte activation, maturation, and chemotaxis. This review provides an update on recent discoveries, and highlights the versatility of this family in promoting innate immunity. Full article

(This article belongs to the Special Issue Antimicrobial RNases in Host Defense)

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