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Constance Mehlgarten, Heike Prochaska, Alexander Hammermeister, Wael Abdel-Fattah, Melanie Wagner, Rościsław Krutyhołowa, Sang Eun Jun, Gyung-Tae Kim, Sebastian Glatt, Karin D Breunig, Michael J R Stark, Raffael Schaffrath
Saccharomyces cerevisiae cells are killed by zymocin, a tRNase ribotoxin complex from Kluyveromyces lactis, which cleaves anticodons and inhibits protein synthesis. Zymocin's action requires specific chemical modification of uridine bases in the anticodon wobble position (U34) by the Elongator complex (Elp1-Elp6). Hence, loss of anticodon modification in mutants lacking Elongator or related KTI (K. lactis Toxin Insensitive) genes protects against tRNA cleavage and confers resistance to the toxin. Here, we show that zymocin can be used as a tool to genetically analyse KTI12, a gene previously shown to code for an Elongator partner protein...
September 5, 2017: Toxins
Jo Marie Bacusmo, Silvia S Orsini, Jennifer Hu, Michael DeMott, Patrick C Thiaville, Ameer Elfarash, Mellie June Paulines, Diego Rojas-Benítez, Birthe Meineke, Chris Deutsch, Dirk Iwata-Reuyl, Patrick A Limbach, Peter C Dedon, Kelly C Rice, Stewart Shuman, Valérie de Crécy-Lagard
Endoribonuclease toxins (ribotoxins) are produced by bacteria and fungi to respond to stress, eliminate non-self competitor species, or interdict virus infection. PrrC is a bacterial ribotoxin that targets and cleaves tRNA(Lys)UUU in the anticodon loop. In vitro studies suggested that the post-transcriptional modification threonylcarbamoyl adenosine (t(6)A) is required for PrrC activity but this prediction had never been validated in vivo. Here, by using t(6)A-deficient yeast derivatives, it is shown that t(6)A is a positive determinant for PrrC proteins from various bacterial species...
July 20, 2017: RNA Biology
Moisés Maestro-López, Miriam Olombrada, Lucía García-Ortega, Daniel Serrano-González, Javier Lacadena, Mercedes Oñaderra, José G Gavilanes, Álvaro Martínez-Del-Pozo
Fungal ribotoxins are highly specific extracellular RNases which cleave a single phosphodiester bond at the ribosomal sarcin-ricin loop, inhibiting protein biosynthesis by interfering with elongation factors. Most ribotoxins show high degree of conservation, with similar sizes and amino acid sequence identities above 85%. Only two exceptions are known: hirsutellin A and anisoplin, produced by the entomopathogenic fungi Hirsutella thompsonii and Metarhizium anisopliae, respectively. Both proteins are similar but smaller than the other known ribotoxins (130 vs 150 amino acids), displaying only about 25% sequence identity with them...
April 1, 2017: Archives of Biochemistry and Biophysics
Miriam Olombrada, Rodrigo Lázaro-Gorines, Juan C López-Rodríguez, Álvaro Martínez-Del-Pozo, Mercedes Oñaderra, Moisés Maestro-López, Javier Lacadena, José G Gavilanes, Lucía García-Ortega
Fungi establish a complex network of biological interactions with other organisms in nature. In many cases, these involve the production of toxins for survival or colonization purposes. Among these toxins, ribotoxins stand out as promising candidates for their use in biotechnological applications. They constitute a group of highly specific extracellular ribonucleases that target a universally conserved sequence of RNA in the ribosome, the sarcin-ricin loop. The detailed molecular study of this family of toxic proteins over the past decades has highlighted their potential in applied research...
February 21, 2017: Toxins
Amanda E Jetzt, Xiao-Ping Li, Nilgun E Tumer, Wendie S Cohick
Ricin is a potent ribotoxin that is considered a bioterror threat due to its ease of isolation and possibility of aerosolization. In yeast, mutation of arginine residues away from the active site results in a ricin toxin A chain (RTA) variant that is unable to bind the ribosome and exhibits reduced cytotoxicity. The goal of the present work was to determine if these residues contribute to ribosome binding and cytotoxicity of RTA in mammalian cells. The RTA mutant R193A/R235A did not interact with mammalian ribosomes, while a G212E variant with a point mutation near its active site bound ribosomes similarly to wild-type (WT) RTA...
November 1, 2016: Toxicology and Applied Pharmacology
Tim D Jones, Arron R Hearn, Robert G E Holgate, Dorota Kozub, Mark H Fogg, Francis J Carr, Matthew P Baker, Javier Lacadena, Kurt R Gehlsen
Fungal ribotoxins that block protein synthesis can be useful warheads in the context of a targeted immunotoxin. α-Sarcin is a small (17 kDa) fungal ribonuclease produced by Aspergillus giganteus that functions by catalytically cleaving a single phosphodiester bond in the sarcin-ricin loop of the large ribosomal subunit, thus making the ribosome unrecognisable to elongation factors and leading to inhibition of protein synthesis. Peptide mapping using an ex vivo human T cell assay determined that α-sarcin contained two T cell epitopes; one in the N-terminal 20 amino acids and the other in the C-terminal 20 amino acids...
August 29, 2016: Protein Engineering, Design & Selection: PEDS
Miriam Olombrada, Pilar Medina, Flor Budia, José G Gavilanes, Álvaro Martínez-Del-Pozo, Lucía García-Ortega
Metarhizium anisopliae is an entomopathogenic fungus relevant in biotechnology with applications like malaria vector control. Studies of its virulence factors are therefore of great interest. Fungal ribotoxins are toxic ribonucleases with extraordinary efficiency against ribosomes and suggested as potential insecticides. Here we describe this ribotoxin characteristic activity in M. anisopliae cultures. Anisoplin has been obtained as a recombinant protein and further characterized. It is structurally similar to hirsutellin A, the ribotoxin from the entomopathogen Hirsutella thompsonii...
January 1, 2017: Biological Chemistry
Miriam Olombrada, Lucía García-Ortega, Javier Lacadena, Mercedes Oñaderra, José G Gavilanes, Álvaro Martínez-del-Pozo
Ribotoxins are cytotoxic members of the family of fungal extracellular ribonucleases best represented by RNase T1. They share a high degree of sequence identity and a common structural fold, including the geometric arrangement of their active sites. However, ribotoxins are larger, with a well-defined N-terminal β-hairpin, and display longer and positively charged unstructured loops. These structural differences account for their cytotoxic properties. Unexpectedly, the discovery of hirsutellin A (HtA), a ribotoxin produced by the invertebrate pathogen Hirsutella thompsonii, showed how it was possible to accommodate these features into a shorter amino acid sequence...
January 1, 2016: Biological Chemistry
Elías Herrero-Galán, Lucía García-Ortega, Miriam Olombrada, Javier Lacadena, Álvaro Martínez Del Pozo, José G Gavilanes, Mercedes Oñaderra
The fungal pathogen Hirsutella thompsonii produces an insecticidal protein named hirsutellin A (HtA), which has been described to be toxic to several species of mites, insect larvae, and cells. On the other hand, on the basis of an extensive biochemical and structural characterization, HtA has been considered to be a member of the ribotoxins family. Ribotoxins are fungal extracellular ribonucleases, which inactivate ribosomes by specifically cleaving a single phosphodiester bond located at the large rRNA. Although ribotoxins were brought to light in the 1960s as antitumor agents, their biological function has remained elusive...
July 9, 2013: Insects
Tanis Hogg, Jameson T Mendel, Jonathan L Lavezo
Pokeweed antiviral protein (PAP) belongs to the family of type I ribosome‑inactivating proteins (RIPs): Ribotoxins, which function by depurinating the sarcin‑ricin loop of ribosomal RNA. In addition to its antibacterial and antifungal properties, PAP has shown promise in antiviral and targeted tumor therapy owing to its ability to depurinate viral RNA and eukaryotic rRNA. Several PAP genes are differentially expressed across pokeweed tissues, with natively isolated seed forms of PAP exhibiting the greatest cytotoxicity...
October 2015: Molecular Medicine Reports
Joshua C Bunger, Angela R Melton-Celsa, Ernest L Maynard, Alison D O'Brien
Shiga toxin (Stx) is an AB5 ribotoxin made by Stx-producing Escherichia coli (STEC). These organisms cause diarrhea, hemorrhagic colitis and the hemolytic uremic syndrome. STEC make two types of Stxs, Stx1 and/or Stx2. Stx2 has one prototype (a) and six subtypes (b-g), but only STEC that make Stx2a, and/or Stx2c, or Stx2d are associated with severe disease. However, Stx2c is about 10-fold less toxic than Stx2d in vivo despite only two amino acid differences in the A subunit at positions 291 and 297. We made mutations at these two sites to create intermediate toxins between Stx2c and Stx2d, and determined the 50% cytotoxic dose on Vero cells before and after heat treatment, and the 50% lethal dose in mice of the toxins...
June 23, 2015: Toxins
Jaime Tomé-Amat, Miriam Olombrada, Javier Ruiz-de-la-Herrán, Eduardo Pérez-Gómez, Clara Andradas, Cristina Sánchez, Leopoldo Martínez, Álvaro Martínez-Del-Pozo, José G Gavilanes, Javier Lacadena
Tagging of RNases, such as the ribotoxin α-sarcin, with the variable domains of antibodies directed to surface antigens that are selectively expressed on tumor cells endows cellular specificity to their cytotoxic action. A recombinant single-chain immunotoxin based on the ribotoxin α-sarcin (IMTXA33αS), produced in the generally regarded as safe (GRAS) yeast Pichia pastoris, has been recently described as a promising candidate for the treatment of colorectal cancer cells expressing the glycoprotein A33 (GPA33) antigen, due to its high specific and effective cytotoxic effect on in vitro assays against targeted cells...
2015: SpringerPlus
Pei Wang, Kiruthika Selvadurai, Raven H Huang
Ribotoxins cleave essential RNAs for cell killing, and RNA repair neutralizes the damage inflicted by ribotoxins for cell survival. Here we report a new bacterial RNA repair complex that performs RNA repair linked to immunity. This new RNA repair complex is a 270-kDa heterohexamer composed of three proteins-Pnkp1, Rnl and Hen1-that are required to repair ribotoxin-cleaved RNA in vitro. The crystal structure of the complex reveals the molecular architecture of the heterohexamer as two rhomboid-shaped ring structures of Pnkp1-Rnl-Hen1 heterotrimer fused at the Pnkp1 dimer interface...
April 17, 2015: Nature Communications
Fabien Graziani, Ange Pujol, Cendrine Nicoletti, Philippe Pinton, Loriane Armand, Eric Di Pasquale, Isabelle P Oswald, Josette Perrier, Marc Maresca
The intestinal epithelium possesses active immune functions including the production of proinflammatory cytokines and antimicrobial molecules such as nitric oxide (NO). As observed with immune cells, the production of NO by the intestinal epithelium is mainly due to the expression of the inducible NO synthase (iNOS or NOS2). Epithelial immune functions could be affected by many factors including pathogenic microorganisms and food-associated toxins (bacterial and fungal). Among the various mycotoxins, deoxynivalenol (DON) is known to alter the systemic and intestinal immunity...
June 2015: Toxicological Sciences: An Official Journal of the Society of Toxicology
Jaime Tomé-Amat, Elías Herrero-Galán, Mercedes Oñaderra, Álvaro Martínez-Del-Pozo, José G Gavilanes, Javier Lacadena
Immunotoxins are chimeric proteins composed of an antibody domain that specifically directs the action of the toxic domain, resulting in the death of the targeted cells. Over recent years, immunotoxins have been widely studied and the number of different constructions has increased exponentially. Protein engineering has allowed the design of optimized versions of immunotoxins with an improved tumor binding affinity, stability or cytotoxic efficacy, although sometimes this has compromised the safety of the patient in terms of undesirable adverse secondary reactions...
June 2015: FEBS Journal
Santosh K Yadav, Janendra K Batra
Restrictocin, a highly specific ribonuclease produced by Aspergillus restrictus, cleaves a single phosphodiester bond in a universally conserved stem and loop structure termed sarcin/ricin loop within the large ribosomal RNA of all organisms. In the current study, we demonstrate restrictocin to manifest anti-HIV-1 activity in two model cell systems. Using two mutants of restrictocin, we further show that the anti-HIV-1 activity of restrictocin is due to its specific ribonucleolytic activity. The study suggests that restrictocin is able to recognize region(s) within HIV-1 genome as its target...
May 2015: International Journal of Biological Macromolecules
Carlos Castaño-Rodríguez, Miriam Olombrada, Angélica Partida-Hanon, Javier Lacadena, Mercedes Oñaderra, José G Gavilanes, Lucía García-Ortega, Álvaro Martínez-Del-Pozo
Ribotoxins are a family of fungal ribosome-inactivating proteins displaying highly specific ribonucleolytic activity against the sarcin/ricin loop (SRL) of the larger rRNA, with α-sarcin as its best-characterized member. Their toxicity arises from the combination of this activity with their ability to cross cell membranes. The involvement of α-sarcin's loops 2 and 3 in SRL and ribosomal proteins recognition, as well as in the ribotoxin-lipid interactions involving cell penetration, has been suggested some time ago...
March 2015: Toxicon: Official Journal of the International Society on Toxinology
Hui-Ren Zhou, Kaiyu He, Jeff Landgraf, Xiao Pan, James J Pestka
Double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a critical upstream mediator of the ribotoxic stress response (RSR) to the trichothecene deoxynivalenol (DON) and other translational inhibitors. Here, we employed HeLa cell lysates to: (1) characterize PKR's interactions with the ribosome and ribosomal RNA (rRNA); (2) demonstrate cell-free activation of ribosomal-associated PKR and (3) integrate these findings in a unified model for RSR. Robust PKR-dependent RSR was initially confirmed in intact cells...
December 16, 2014: Toxins
Jaime Tomé-Amat, Javier Ruiz-de-la-Herrán, Álvaro Martínez-del-Pozo, José G Gavilanes, Javier Lacadena
Toxins have been thoroughly studied for their use as therapeutic agents in search of an improvement in toxic efficiency together with a minimization of their undesired side effects. Different studies have shown how toxins can follow different intracellular pathways which are connected with their cytotoxic action inside the cells. The work herein presented describes the different pathways followed by the ribotoxin α-sarcin and the fungal RNase T1, as toxic domains of immunoconjugates with identical binding domain, the single chain variable fragment of a monoclonal antibody raised against the glycoprotein A33...
February 2015: FEBS Journal
M Sheikh Mohamed, Srivani Veeranarayanan, Ankur Baliyan, Aby Cheruvathoor Poulose, Yutaka Nagaoka, Hiroaki Minegishi, Seiki Iwai, Yasuhiro Shimane, Yasuhiko Yoshida, Toru Maekawa, D Sakthi Kumar
A nanoformulation composed of a ribosome inactivating protein-curcin and a hybrid solid lipid nanovector has been devised against glioblastoma. The structurally distinct nanoparticles were highly compatible to human endothelial and neuronal cells. A sturdy drug release from the particles, recorded upto 72 h, was reflected in the time-dependent toxicity. Folate-targeted nanoparticles were specifically internalized by glioma, imparting superior toxicity and curbed an aggressively proliferating in vitro 3D cancer mass in addition to suppressing the anti-apoptotic survivin and cell matrix protein vinculin...
December 2014: Macromolecular Bioscience
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