Biological Activities of Ribosome Inactivating Proteins II

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Plant Toxins".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 6211

Special Issue Editors


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Guest Editor
Department of Biochemistry, Molecular Biology and Physiology, Faculty of Sciences, University of Valladolid, E-47011 Valladolid, Spain
Interests: ribosome-inactivating proteins (RIPs); immunotoxins; protein synthesis inhibition; ribotoxins; structure–activity relationship
Special Issues, Collections and Topics in MDPI journals

E-Mail Website1 Website2
Guest Editor
Department of Biochemistry, Molecular Biology and Physiology, Faculty of Sciences, University of Valladolid, E-47011 Valladolid, Spain
Interests: ribosome-inactivating proteins (RIPs); immunotoxins; protein synthesis inhibition; ribotoxins; protein translocation; intracellular transport; apoptosis
Special Issues, Collections and Topics in MDPI journals

E-Mail Website1 Website2
Guest Editor
Department of Biochemistry and Molecular Biology and Physiology, Faculty of Sciences, University of Valladolid, E-47011 Valladolid, Spain
Interests: plant toxins; ribosome-inactivating proteins (RIPs); ribotoxins; immunotoxins; plant fungal pathogenesis; antifun-gal proteins

Special Issue Information

Dear Colleagues,

Ribosome-inactivating proteins (RIPs) are rRNA N-glycosylases (EC 3.2.2.22) that specifically catalyze the hydrolysis of the second N-glycosidic bond from the GAGA tetraloop located in the sarcin–ricin loop (SRL) of the large ribosomal RNA. Because the SRL is crucial for anchoring the elongation factors on the ribosome, depurination causes the irreversible inactivation of ribosomes. In addition, RIPs usually display other enzymatic activities, the most relevant being their adenine polynucleotide glycosylase activity on all kinds of nucleic acids. RIPs have been classified into two types depending on the presence (type 2 RIPs) or absence (type 1 RIPs) of a lectin chain (B chain). The presence of the B chain may turn type 2 RIPs into powerful toxins, such as ricin or abrin. Regardless, despite the absence of the B chain, type 1 RIPs at higher concentrations are also able to enter cells and display toxicity to cells and animals.

Most RIPs have been isolated from angiosperm plants, while one has been obtained from algae and a few from bacteria or fungi.

The exact biological role played by RIPs remains unknown, but it is thought to represent a defense mechanism of plants against pathogens and predators.

As a consequence of their enzymatic action, RIPs display several biological activities, including antiviral, antibacterial, antifungal, antifeedant, and antiproliferative activities, which may be relevant to their functions and biotechnological applications.

The most promising applications of RIPs in experimental medicine, especially in anticancer therapy, are related to their use as components of immunotoxins, in which the RIP is linked to antibodies that mediate their binding and internalization by malignant cells. In agriculture, RIPs have been shown to increase resistance against viruses, fungi, and insects in transgenic plants.

The focus of this Special Issue of Toxins will be on the biological activities of RIPs that may be relevant to their biological functions and biotechnological applications, and on the elucidation of the structure–activity relationships of these proteins.

Prof. Dr. José Miguel Ferreras
Prof. Dr. Lucía Citores
Prof. Dr. Rosario Iglesias
Guest Editors

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Keywords

  • antifeedant
  • antifungal
  • antitumoral
  • antiviral
  • apoptosis
  • immunotoxin
  • ribosome-inactivating protein (RIP)
  • rRNA N-glycosylase

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Published Papers (5 papers)

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Research

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23 pages, 3625 KiB  
Article
Mutational Analysis of RIP Type I Dianthin-30 Suggests a Role for Arg24 in Endocytosis
by Louisa Schlaak, Christoph Weise, Benno Kuropka and Alexander Weng
Toxins 2024, 16(5), 219; https://doi.org/10.3390/toxins16050219 - 10 May 2024
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Abstract
Saponin-mediated endosomal escape is a mechanism that increases the cytotoxicity of type I ribosome-inactivating proteins (type I RIPs). In order to actualize their cytotoxicity, type I RIPs must be released into the cytosol after endocytosis. Without release from the endosomes, type I RIPs [...] Read more.
Saponin-mediated endosomal escape is a mechanism that increases the cytotoxicity of type I ribosome-inactivating proteins (type I RIPs). In order to actualize their cytotoxicity, type I RIPs must be released into the cytosol after endocytosis. Without release from the endosomes, type I RIPs are largely degraded and cannot exert their cytotoxic effects. Certain triterpene saponins are able to induce the endosomal escape of these type I RIPs, thus increasing their cytotoxicity. However, the molecular mechanism underlying the endosomal escape enhancement of type I RIPs by triterpene saponins has not been fully elucidated. In this report, we investigate the involvement of the basic amino acid residues of dianthin-30, a type I RIP isolated from the plant Dianthus caryophyllus L., in endosomal escape enhancement using alanine scanning. Therefore, we designed 19 alanine mutants of dianthin-30. Each mutant was combined with SO1861, a triterpene saponin isolated from the roots of Saponaria officinalis L., and subjected to a cytotoxicity screening in Neuro-2A cells. Cytotoxic screening revealed that dianthin-30 mutants with lysine substitutions did not impair the endosomal escape enhancement. There was one particular mutant dianthin, Arg24Ala, that exhibited significantly reduced synergistic cytotoxicity in three mammalian cell lines. However, this reduction was not based on an altered interaction with SO1861. It was, rather, due to the impaired endocytosis of dianthin Arg24Ala into the cells. Full article
(This article belongs to the Special Issue Biological Activities of Ribosome Inactivating Proteins II)
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17 pages, 10327 KiB  
Article
Edodin: A New Type of Toxin from Shiitake Mushroom (Lentinula edodes) That Inactivates Mammalian Ribosomes
by Lucía Citores, Sara Ragucci, Claudia C. Gay, Rosita Russo, Angela Chambery, Antimo Di Maro, Rosario Iglesias and José M. Ferreras
Toxins 2024, 16(4), 185; https://doi.org/10.3390/toxins16040185 - 10 Apr 2024
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Abstract
Ribosome-inactivating proteins (RIPs) are a group of proteins with rRNA N-glycosylase activity that irreversibly inhibit protein synthesis and consequently cause cell death. Recently, an RIP called ledodin has been found in shiitake; it is cytotoxic, strongly inhibits protein synthesis, and shows rRNA N-glycosylase [...] Read more.
Ribosome-inactivating proteins (RIPs) are a group of proteins with rRNA N-glycosylase activity that irreversibly inhibit protein synthesis and consequently cause cell death. Recently, an RIP called ledodin has been found in shiitake; it is cytotoxic, strongly inhibits protein synthesis, and shows rRNA N-glycosylase activity. In this work, we isolated and characterized a 50 kDa cytotoxic protein from shiitake that we named edodin. Edodin inhibits protein synthesis in a mammalian cell-free system, but not in insect-, yeast-, and bacteria-derived systems. It exhibits rRNA N-glycosylase and DNA-nicking activities, which relate it to plant RIPs. It was also shown to be toxic to HeLa and COLO 320 cells. Its structure is not related to other RIPs found in plants, bacteria, or fungi, but, instead, it presents the characteristic structure of the fold type I of pyridoxal phosphate-dependent enzymes. Homologous sequences have been found in other fungi of the class Agaricomycetes; thus, edodin could be a new type of toxin present in many fungi, some of them edible, which makes them of great interest in health, both for their involvement in food safety and for their potential biomedical and biotechnological applications. Full article
(This article belongs to the Special Issue Biological Activities of Ribosome Inactivating Proteins II)
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14 pages, 3491 KiB  
Article
Hortensins, Type 1 Ribosome-Inactivating Proteins from Seeds of Red Mountain Spinach: Isolation, Characterization, and Their Effect on Glioblastoma Cells
by Sara Ragucci, Veronica Russo, Angela Clemente, Maria Giuseppina Campanile, Maria Antonietta Oliva, Nicola Landi, Paolo Vincenzo Pedone, Antonietta Arcella and Antimo Di Maro
Toxins 2024, 16(3), 135; https://doi.org/10.3390/toxins16030135 - 4 Mar 2024
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Abstract
Ribosome inactivating proteins (RIPs) are specific N-β-glycosylases that are well-characterized in plants. Their enzymatic action is to damage ribosomes, thereby blocking protein translation. Recently, several research groups have been working on the screening for these toxins in edible plants to facilitate the use [...] Read more.
Ribosome inactivating proteins (RIPs) are specific N-β-glycosylases that are well-characterized in plants. Their enzymatic action is to damage ribosomes, thereby blocking protein translation. Recently, several research groups have been working on the screening for these toxins in edible plants to facilitate the use of RIPs as biotechnological tools and biopesticides and to overcome public prejudice. Here, four novel monomeric (type 1) RIPs have been isolated from the seeds of Atriplex hortensis L. var. rubra, which is commonly known as edible red mountain spinach. These enzymes, named hortensins 1, 2, 4, and 5, are able to release the β-fragment and, like many other RIPs, adenines from salmon sperm DNA, thus, acting as polynucleotide:adenosine glycosidases. Structurally, hortensins have a different molecular weight and are purified with different yields (hortensin 1, ~29.5 kDa, 0.28 mg per 100 g; hortensin 2, ~29 kDa, 0.29 mg per 100 g; hortensin 4, ~28.5 kDa, 0.71 mg per 100 g; and hortensin 5, ~30 kDa, 0.65 mg per 100 g); only hortensins 2 and 4 are glycosylated. Furthermore, the major isoforms (hortensins 4 and 5) are cytotoxic toward human continuous glioblastoma U87MG cell line. In addition, the morphological change in U87MG cells in the presence of these toxins is indicative of cell death triggered by the apoptotic pathway, as revealed by nuclear DNA fragmentation (TUNEL assay). Full article
(This article belongs to the Special Issue Biological Activities of Ribosome Inactivating Proteins II)
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13 pages, 3927 KiB  
Article
Heterophyllin: A New Adenia Toxic Lectin with Peculiar Biological Properties
by Massimo Bortolotti, Francesco Biscotti, Andrea Zanello, Letizia Polito and Andrea Bolognesi
Toxins 2024, 16(1), 1; https://doi.org/10.3390/toxins16010001 - 19 Dec 2023
Viewed by 1439
Abstract
Ribosome-inactivating proteins (RIPs) are plant toxins that were identified for their ability to irreversibly damage ribosomes, thereby causing arrest of protein synthesis and induction of cell death. The RIPs purified from Adenia plants are the most potent ones. Here, we describe a novel [...] Read more.
Ribosome-inactivating proteins (RIPs) are plant toxins that were identified for their ability to irreversibly damage ribosomes, thereby causing arrest of protein synthesis and induction of cell death. The RIPs purified from Adenia plants are the most potent ones. Here, we describe a novel toxic lectin from Adenia heterophylla caudex, which has been named heterophyllin. Heterophyllin shows the enzymatic and lectin properties of type 2 RIPs. Interestingly, in immunoreactivity experiments, heterophyllin poorly cross-reacts with sera against all other tested RIPs. The cytotoxic effects and death pathways triggered by heterophyllin were investigated in three human-derived cell lines: NB100, T24, and MCF7, and compared to ricin, the most known and studied type 2 RIP. Heterophyllin was able to completely abolish cell viability at nM concentration. A strong induction of apoptosis, but not necrosis, and the involvement of oxidative stress and necroptosis were observed in all the tested cell lines. Therefore, the enzymatic, immunological, and biological activities of heterophyllin make it an interesting molecule, worthy of further in-depth analysis to verify its possible pharmacological application. Full article
(This article belongs to the Special Issue Biological Activities of Ribosome Inactivating Proteins II)
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Review

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20 pages, 901 KiB  
Review
Antifungal Activity of Ribosome-Inactivating Proteins
by Rosario Iglesias, Lucía Citores, Claudia C. Gay and José M. Ferreras
Toxins 2024, 16(4), 192; https://doi.org/10.3390/toxins16040192 - 15 Apr 2024
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Abstract
The control of crop diseases caused by fungi remains a major problem and there is a need to find effective fungicides that are environmentally friendly. Plants are an excellent source for this purpose because they have developed defense mechanisms to cope with fungal [...] Read more.
The control of crop diseases caused by fungi remains a major problem and there is a need to find effective fungicides that are environmentally friendly. Plants are an excellent source for this purpose because they have developed defense mechanisms to cope with fungal infections. Among the plant proteins that play a role in defense are ribosome-inactivating proteins (RIPs), enzymes obtained mainly from angiosperms that, in addition to inactivating ribosomes, have been studied as antiviral, fungicidal, and insecticidal proteins. In this review, we summarize and discuss the potential use of RIPs (and other proteins with similar activity) as antifungal agents, with special emphasis on RIP/fungus specificity, possible mechanisms of antifungal action, and the use of RIP genes to obtain fungus-resistant transgenic plants. It also highlights the fact that these proteins also have antiviral and insecticidal activity, which makes them very versatile tools for crop protection. Full article
(This article belongs to the Special Issue Biological Activities of Ribosome Inactivating Proteins II)
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