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Exploring the Multifunctional Roles of Host Defence RNases under Stress Conditions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 12106

Special Issue Editor

Prof. Dr. Ester Boix

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Faculty of Biosciences, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
Interests: host-pathogen interactions; antimicrobial peptides; enzymology; ribonucleases; eosinophil granule proteins; glycosaminoglycan binding proteins; innate immunity; protein crystallography
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ribonucleases (RNases) can participate in a variety of host defence processes and contribute to maintaining organism fitness in the context of potential injuries. We observe the selective expression of host RNases under stress conditions, such as infection, tissue damage, senescence, or cancer. In response to external threats, RNases can deploy a diversity of biological actions, including antipathogen, antitumour, anti-inflammatory, or tissue remodelling activities. Interestingly, RNases do not provide cell protection merely via their enzymatic activity but also thanks to additional immunomodulation properties. Among others, RNases can exert signalling roles not only by the selective targeting of RNA but also by direct interaction with cell receptors. Luckily, thanks to the latest advances within the protein structure and RNA world, we are starting to elucidate their mechanism of action. Novel methodologies on the analysis of cellular RNA population, together with the characterisation of supramolecular complexes involved in innate immunity, should contribute to dissecting the multifaceted properties of host defence RNases.

This Special Issue welcomes original or review articles focused on the multiple roles of host defence RNases during stress conditions, including infection, inflammation, aging, or cancer. The issue also covers any translational work on how RNases can be tailored to design novel structure-based drugs.

Prof. Dr. Ester Boix
Guest Editor

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Keywords

  • Host defence RNases
  • antimicrobial RNases
  • innate immunity
  • drug design
  • RNaseA superfamily
  • RNaseL
  • RNaseT2
  • secretory RNases
  • extracellular RNases

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Published Papers (4 papers)

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Research

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18 pages, 5509 KiB  
Article
Protective Effects of Recombinant Human Angiogenin in Keratinocytes: New Insights on Oxidative Stress Response Mediated by RNases
by Rosanna Culurciello, Andrea Bosso, Romualdo Troisi, Valentina Barrella, Ilaria Di Nardo, Margherita Borriello, Rosa Gaglione, Valeria Pistorio, Serena Aceto, Valeria Cafaro, Eugenio Notomista, Filomena Sica, Angela Arciello and Elio Pizzo
Int. J. Mol. Sci. 2022, 23(15), 8781; https://doi.org/10.3390/ijms23158781 - 7 Aug 2022
Cited by 7 | Viewed by 2254
Abstract
Human angiogenin (ANG) is a 14-kDa ribonuclease involved in different pathophysiological processes including tumorigenesis, neuroprotection, inflammation, innate immunity, reproduction, the regeneration of damaged tissues and stress cell response, depending on its intracellular localization. Under physiological conditions, ANG moves to the cell nucleus where [...] Read more.
Human angiogenin (ANG) is a 14-kDa ribonuclease involved in different pathophysiological processes including tumorigenesis, neuroprotection, inflammation, innate immunity, reproduction, the regeneration of damaged tissues and stress cell response, depending on its intracellular localization. Under physiological conditions, ANG moves to the cell nucleus where it enhances rRNA transcription; conversely, recent reports indicate that under stress conditions, ANG accumulates in the cytoplasmic compartment and modulates the production of tiRNAs, a novel class of small RNAs that contribute to the translational inhibition and recruitment of stress granules (SGs). To date, there is still limited and controversial experimental evidence relating to a hypothetical role of ANG in the epidermis, the outermost layer of human skin, which is continually exposed to external stressors. The present study collects compelling evidence that endogenous ANG is able to modify its subcellular localization on HaCaT cells, depending on different cellular stresses. Furthermore, the use of recombinant ANG allowed to determine as this special enzyme is effectively able to counter at various levels the alterations of cellular homeostasis in HaCaT cells, actually opening a new vision on the possible functions that this special enzyme can support also in the stress response of human skin. Full article
(This article belongs to the Special Issue Exploring the Multifunctional Roles of Host Defence RNases under Stress Conditions)
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18 pages, 10326 KiB  
Article
Upregulation of miR-34a-5p, miR-20a-3p and miR-29a-3p by Onconase in A375 Melanoma Cells Correlates with the Downregulation of Specific Onco-Proteins
by Elisa De Tomi, Rachele Campagnari, Elisa Orlandi, Alessia Cardile, Valentina Zanrè, Marta Menegazzi, Macarena Gomez-Lira and Giovanni Gotte
Int. J. Mol. Sci. 2022, 23(3), 1647; https://doi.org/10.3390/ijms23031647 - 31 Jan 2022
Cited by 3 | Viewed by 3181
Abstract
Onconase (ONC) is an amphibian secretory ribonuclease displaying cytostatic and cytotoxic activities against many mammalian tumors, including melanoma. ONC principally damages tRNA species, but also other non-coding RNAs, although its precise targets are not known. We investigated the ONC ability to modulate the [...] Read more.
Onconase (ONC) is an amphibian secretory ribonuclease displaying cytostatic and cytotoxic activities against many mammalian tumors, including melanoma. ONC principally damages tRNA species, but also other non-coding RNAs, although its precise targets are not known. We investigated the ONC ability to modulate the expression of 16 onco-suppressor microRNAs (miRNAs) in the A375 BRAF-mutated melanoma cell line. RT-PCR and immunoblots were used to measure the expression levels of miRNAs and their regulated proteins, respectively. In silico study was carried out to verify the relations between miRNAs and their mRNA targets. A375 cell transfection with miR-20a-3p and miR-34a-5p mimics or inhibitors was performed. The onco-suppressors miR-20a-3p, miR-29a-3p and miR-34a-5p were highly expressed in 48-h ONC-treated A375 cells. The cytostatic effect of ONC in A375 cells was mechanistically explained by the sharp inhibition of cyclins D1 and A2 expression level, as well as by downregulation of retinoblastoma protein and cyclin-dependent-kinase-2 activities. Remarkably, the expression of kinases ERK1/2 and Akt, as well as of the hypoxia inducible factor-1α, was inhibited by ONC. All these proteins control pro-survival pathways. Finally, many crucial proteins involved in migration, invasion and metastatic potential were downregulated by ONC. Results obtained from transfection of miR-20a-3p and miR-34a-5p inhibitors in the presence of ONC show that these miRNAs may participate in the antitumor effects of ONC in the A375 cell line. In conclusion, we identified many intracellular downregulated proteins involved in melanoma cell proliferation, metabolism and progression. All mRNAs coding these proteins may be targets of miR-20a-3p, miR-29a-3p and/or miR-34a-5p, which are in turn upregulated by ONC. Data suggest that several known ONC anti-proliferative and anti-metastatic activities in A375 melanoma cells might depend on the upregulation of onco-suppressor miRNAs. Notably, miRNAs stability depends on the upstream regulation by long-non-coding-RNAs or circular-RNAs that can, in turn, be damaged by ONC ribonucleolytic activity. Full article
(This article belongs to the Special Issue Exploring the Multifunctional Roles of Host Defence RNases under Stress Conditions)
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21 pages, 26207 KiB  
Article
Structure-Based Design of an RNase Chimera for Antimicrobial Therapy
by Guillem Prats-Ejarque, Helena Lorente, Clara Villalba, Raúl Anguita, Lu Lu, Sergi Vázquez-Monteagudo, Pablo Fernández-Millán and Ester Boix
Int. J. Mol. Sci. 2022, 23(1), 95; https://doi.org/10.3390/ijms23010095 - 22 Dec 2021
Cited by 6 | Viewed by 2966
Abstract
Bacterial resistance to antibiotics urges the development of alternative therapies. Based on the structure-function of antimicrobial members of the RNase A superfamily, we have developed a hybrid enzyme. Within this family, RNase 1 exhibits the highest catalytic activity and the lowest cytotoxicity; in [...] Read more.
Bacterial resistance to antibiotics urges the development of alternative therapies. Based on the structure-function of antimicrobial members of the RNase A superfamily, we have developed a hybrid enzyme. Within this family, RNase 1 exhibits the highest catalytic activity and the lowest cytotoxicity; in contrast, RNase 3 shows the highest bactericidal action, alas with a reduced catalytic activity. Starting from both parental proteins, we designed a first RNase 3/1-v1 chimera. The construct had a catalytic activity much higher than RNase 3, unfortunately without reaching an equivalent antimicrobial activity. Thus, two new versions were created with improved antimicrobial properties. Both of these versions (RNase 3/1-v2 and -v3) incorporated an antimicrobial loop characteristic of RNase 3, while a flexible RNase 1-specific loop was removed in the latest construct. RNase 3/1-v3 acquired both higher antimicrobial and catalytic activities than previous versions, while retaining the structural determinants for interaction with the RNase inhibitor and displaying non-significant cytotoxicity. Following, we tested the constructs’ ability to eradicate macrophage intracellular infection and observed an enhanced ability in both RNase 3/1-v2 and v3. Interestingly, the inhibition of intracellular infection correlates with the variants’ capacity to induce autophagy. We propose RNase 3/1-v3 chimera as a promising lead for applied therapeutics. Full article
(This article belongs to the Special Issue Exploring the Multifunctional Roles of Host Defence RNases under Stress Conditions)
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Review

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23 pages, 1019 KiB  
Review
Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections
by Marta Menegazzi and Giovanni Gotte
Int. J. Mol. Sci. 2022, 23(12), 6556; https://doi.org/10.3390/ijms23126556 - 12 Jun 2022
Cited by 4 | Viewed by 2982
Abstract
The majority of transcribed RNAs do not codify for proteins, nevertheless they display crucial regulatory functions by affecting the cellular protein expression profile. MicroRNAs (miRNAs) and transfer RNA-derived small RNAs (tsRNAs) are effectors of interfering mechanisms, so that their biogenesis is a tightly [...] Read more.
The majority of transcribed RNAs do not codify for proteins, nevertheless they display crucial regulatory functions by affecting the cellular protein expression profile. MicroRNAs (miRNAs) and transfer RNA-derived small RNAs (tsRNAs) are effectors of interfering mechanisms, so that their biogenesis is a tightly regulated process. Onconase (ONC) is an amphibian ribonuclease known for cytotoxicity against tumors and antiviral activity. Additionally, ONC administration in patients resulted in clinical effectiveness and in a well-tolerated feature, at least for lung carcinoma and malignant mesothelioma. Moreover, the ONC therapeutic effects are actually potentiated by cotreatment with many conventional antitumor drugs. This review not only aims to describe the ONC activity occurring either in different tumors or in viral infections but also to analyze the molecular mechanisms underlying ONC pleiotropic and cellular-specific effects. In cancer, data suggest that ONC affects malignant phenotypes by generating tRNA fragments and miRNAs able to downregulate oncogenes expression and upregulate tumor-suppressor proteins. In cells infected by viruses, ONC hampers viral spread by digesting the primer tRNAs necessary for viral DNA replication. In this scenario, new therapeutic tools might be developed by exploiting the action of ONC-elicited RNA derivatives. Full article
(This article belongs to the Special Issue Exploring the Multifunctional Roles of Host Defence RNases under Stress Conditions)
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