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Photorhabdus luminescens Tc toxins are large tripartite ABC‐type toxin complexes, composed of TcA, TcB and TcC proteins. Tc toxins are widespread and have shown a tropism for a variety of targets including insect, mammalian and human cells. However, their receptors and the specific mechanisms of uptake into target cells remain unknown. Here, we show that the TcA protein TcdA1 interacts with N‐glycans, particularly Lewis X/Y antigens. This is confirmed using N‐acetylglucosamine transferase I (Mgat1 gene product) deficient Chinese hamster ovary (CHO) Lec1 cells, which are highly resistant to intoxication by the Tc toxin complex most likely due to the absence of complex N‐glycans. Restoring Mgat1 gene activity, and hence complex N‐glycan biosynthesis, recapitulated the sensitivity of these cells to the toxin. Exogenous addition of Lewis X trisaccharide partially inhibits intoxication in wildtype cells. Additionally, sialic acid also largely reduced binding of the Tc toxin. Moreover, proteolytic activation of TcdA1 alters glycan‐binding and uptake into target cells. The data suggest that TcdA1‐binding is most likely multivalent and carbohydrates probably work cooperatively to facilitate binding and intoxication. This article is protected by copyright. All rights reserved.
Peter Njenga Ng'Ang'A; Lina Siukstaite; Alexander E. Lang; Hans Bakker; Winfried Römer; Klaus Aktories; Gudula Schmidt. Involvement of N‐glycans in binding of Photorhabdus luminescens Tc toxin. Cellular Microbiology 2021, 1 .
AMA StylePeter Njenga Ng'Ang'A, Lina Siukstaite, Alexander E. Lang, Hans Bakker, Winfried Römer, Klaus Aktories, Gudula Schmidt. Involvement of N‐glycans in binding of Photorhabdus luminescens Tc toxin. Cellular Microbiology. 2021; ():1.
Chicago/Turabian StylePeter Njenga Ng'Ang'A; Lina Siukstaite; Alexander E. Lang; Hans Bakker; Winfried Römer; Klaus Aktories; Gudula Schmidt. 2021. "Involvement of N‐glycans in binding of Photorhabdus luminescens Tc toxin." Cellular Microbiology , no. : 1.
Open access funding provided by Projekt DEAL. Lee, H. et al. Recognition of semaphorin proteins by P. sordellii lethal toxin reveals principles of receptor specificity in clostridial toxins. Cell 182, 345–356.e16 (2020). CAS Article Google Scholar Aktories, K., Schwan, C. & Jank, T. Clostridium difficile toxin biology. Annu. Rev. Microbiol. 71, 281–307 (2017). CAS Article Google Scholar Geny, B. et al. Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability. Am. J. Pathol. 170, 1003–1017 (2007). CAS Article Google Scholar Tian, S. et al. Genome-wide CRISPR screen identifies semaphorin 6A and 6B as receptors for Paeniclostridium sordellii toxin TcsL. Cell Host Microbe 27, 782–792.e787 (2020). CAS Article Google Scholar Chen, P. et al. Structural basis for recognition of frizzled proteins by Clostridium difficile toxin B. Science 360, 664–669 (2018). CAS Article Google Scholar Download references Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, Albertstr. 25, 79104, Freiburg, Germany Klaus Aktories You can also search for this author in PubMed Google Scholar Correspondence to Klaus Aktories. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions Aktories, K. Semaphorins or Frizzled –it is the receptor that direct the action of clostridial glucosylating toxins. Sig Transduct Target Ther 5, 206 (2020). https://doi.org/10.1038/s41392-020-00307-3 Download citation Received: 27 July 2020 Revised: 05 August 2020 Accepted: 19 August 2020 Published: 19 September 2020 DOI: https://doi.org/10.1038/s41392-020-00307-3
Klaus Aktories. Semaphorins or Frizzled –it is the receptor that direct the action of clostridial glucosylating toxins. Signal Transduction and Targeted Therapy 2020, 5, 1 -2.
AMA StyleKlaus Aktories. Semaphorins or Frizzled –it is the receptor that direct the action of clostridial glucosylating toxins. Signal Transduction and Targeted Therapy. 2020; 5 (1):1-2.
Chicago/Turabian StyleKlaus Aktories. 2020. "Semaphorins or Frizzled –it is the receptor that direct the action of clostridial glucosylating toxins." Signal Transduction and Targeted Therapy 5, no. 1: 1-2.
Clostridioides difficile infection (CDI) represents a significant burden on the health care system, one that is exacerbated by the emergence of binary toxin (CDT)-producing hypervirulent C. difficile strains. Previous work from our lab has shown that TLR2 recognizes CDT to induce inflammation. Here we explore the interactions of CDT with TLR2 and the impact on host immunity during CDI. We found that the TLR2/6 heterodimer, not TLR2/1, is responsible for CDT recognition, and that gene pathways including NF-κB and MAPK downstream of TLR2/6 are upregulated in mice with intact TLR2/6 signaling during CDI.
Morgan Simpson; Alyse Frisbee; Pankaj Kumar; Carsten Schwan; Klaus Aktories; William Petri. Clostridium difficile binary toxin (CDT) is recognized by the TLR2/6 heterodimer to induce an NF-κB response. 2020, 1 .
AMA StyleMorgan Simpson, Alyse Frisbee, Pankaj Kumar, Carsten Schwan, Klaus Aktories, William Petri. Clostridium difficile binary toxin (CDT) is recognized by the TLR2/6 heterodimer to induce an NF-κB response. . 2020; ():1.
Chicago/Turabian StyleMorgan Simpson; Alyse Frisbee; Pankaj Kumar; Carsten Schwan; Klaus Aktories; William Petri. 2020. "Clostridium difficile binary toxin (CDT) is recognized by the TLR2/6 heterodimer to induce an NF-κB response." , no. : 1.
Anthrax toxin is the major virulence factor secreted by Bacillus anthracis, causing high mortality in humans and other mammals. It consists of a membrane translocase, known as protective antigen (PA), that catalyzes the unfolding of its cytotoxic substrates lethal factor (LF) and edema factor (EF), followed by translocation into the host cell. Substrate recruitment to the heptameric PA pre-pore and subsequent translocation, however, are not well understood. Here, we report three high-resolution cryo-EM structures of the fully-loaded anthrax lethal toxin in its heptameric pre-pore state, which differ in the position and conformation of LFs. The structures reveal that three LFs interact with the heptameric PA and upon binding change their conformation to form a continuous chain of head-to-tail interactions. As a result of the underlying symmetry mismatch, one LF binding site in PA remains unoccupied. Whereas one LF directly interacts with a part of PA called α-clamp, the others do not interact with this region, indicating an intermediate state between toxin assembly and translocation. Interestingly, the interaction of the N-terminal domain with the α-clamp correlates with a higher flexibility in the C-terminal domain of the protein. Based on our data, we propose a model for toxin assembly, in which the relative position of the N-terminal α-helices in the three LFs determines which factor is translocated first. Anthrax is a life-threatening infectious disease that affects primarily livestock and wild animals, but can also cause high mortality in humans. Due to its suitability as a bioweapon and the search for an antidote, it is important to understand the molecular mechanism of infection of the anthrax pathogen and in particular of the anthrax toxin. Although the process of poisoning by anthrax toxin has been extensively investigated, many details are still missing that are required to understand the mechanism of action in molecular detail. Here, we used single-particle electron cryo microscopy to determine structures of the fully-loaded asymmetric anthrax lethal toxin in its heptameric pre-pore state. The structures reveal that three lethal factors interact with the heptameric protective antigen and upon binding change their conformation to form a continuous chain of head-to-tail interactions. Based on our data, we propose a model for toxin assembly, in which the relative position of the N-terminal region in the three lethal factors determines which factor is translocated first. Our studies provide novel insights into the organization of the anthrax lethal toxin and advance our understanding of toxin assembly and translocation.
Claudia Antoni; Dennis Quentin; Alexander E. Lang; Klaus Aktories; Christos Gatsogiannis; Stefan Raunser. Cryo-EM structure of the fully-loaded asymmetric anthrax lethal toxin in its heptameric pre-pore state. PLOS Pathogens 2020, 16, e1008530 .
AMA StyleClaudia Antoni, Dennis Quentin, Alexander E. Lang, Klaus Aktories, Christos Gatsogiannis, Stefan Raunser. Cryo-EM structure of the fully-loaded asymmetric anthrax lethal toxin in its heptameric pre-pore state. PLOS Pathogens. 2020; 16 (8):e1008530.
Chicago/Turabian StyleClaudia Antoni; Dennis Quentin; Alexander E. Lang; Klaus Aktories; Christos Gatsogiannis; Stefan Raunser. 2020. "Cryo-EM structure of the fully-loaded asymmetric anthrax lethal toxin in its heptameric pre-pore state." PLOS Pathogens 16, no. 8: e1008530.
Anthrax toxin is the major virulence factor secreted by Bacillus anthracis, causing high mortality in humans and other mammals. It consists of a membrane translocase, known as protective antigen (PA), that catalyzes the unfolding of its cytotoxic substrates lethal factor (LF) and edema factor (EF), followed by translocation into the host cell. Substrate recruitment to the heptameric PA pre-pore and subsequent translocation, however, are not well understood. Here, we report three high-resolution cryo-EM structures of the fully-loaded anthrax lethal toxin in its heptameric pre-pore state, which differ in the position and conformation of LFs. The structures reveal that three LFs interact with the heptameric PA and upon binding change their conformation to form a continuous chain of head-to-tail interactions. As a result of the underlying symmetry mismatch, one LF binding site in PA remains unoccupied. Whereas one LF directly interacts with a part of PA called α-clamp, the others do not interact with this region, indicating an intermediate state between toxin assembly and translocation. Interestingly, the interaction of the N-terminal domain with the α-clamp correlates with a higher flexibility in the C-terminal domain of the protein. Based on our data, we propose a model for toxin assembly, in which the order of LF binding determines which factor is translocated first.
Claudia Antoni; Dennis Quentin; Alexander E. Lang; Klaus Aktories; Christos Gatsogiannis; Stefan Raunser. Cryo-EM structure of the fully-loaded asymmetric anthrax lethal toxin in its heptameric pre-pore state. 2020, 1 .
AMA StyleClaudia Antoni, Dennis Quentin, Alexander E. Lang, Klaus Aktories, Christos Gatsogiannis, Stefan Raunser. Cryo-EM structure of the fully-loaded asymmetric anthrax lethal toxin in its heptameric pre-pore state. . 2020; ():1.
Chicago/Turabian StyleClaudia Antoni; Dennis Quentin; Alexander E. Lang; Klaus Aktories; Christos Gatsogiannis; Stefan Raunser. 2020. "Cryo-EM structure of the fully-loaded asymmetric anthrax lethal toxin in its heptameric pre-pore state." , no. : 1.
We identified a glucosyltransferase (YGT) and an ADP-ribosyltransferase (YART) in Yersinia mollaretii, highly related to glucosylating toxins from Clostridium difficile, the cause of antibiotics-associated enterocolitis. Both Yersinia toxins consist of an amino-terminal enzyme domain, an autoprotease domain activated by inositol hexakisphosphate, and a carboxyl-terminal translocation domain. YGT N-acetylglucosaminylates Rab5 and Rab31 at Thr52 and Thr36, respectively, thereby inactivating the Rab proteins. YART ADP-ribosylates Rab5 and Rab31 at Gln79 and Gln64, respectively. This activates Rab proteins by inhibiting GTP hydrolysis. We determined the crystal structure of the glycosyltransferase domain of YGT (YGTG) in the presence and absence of UDP at 1.9- and 3.4-Å resolution, respectively. Thereby, we identified a previously unknown potassium ion–binding site, which explains potassium ion–dependent enhanced glycosyltransferase activity in clostridial and related toxins. Our findings exhibit a novel type of inverse regulation of Rab proteins by toxins and provide new insights into the structure-function relationship of glycosyltransferase toxins.
G. Stefan Ost; Christophe Wirth; Xenia Bogdanović; Wei-Chun Kao; Björn Schorch; Philipp J. K. Aktories; Panagiotis Papatheodorou; Carsten Schwan; Andreas Schlosser; Thomas Jank; Carola Hunte; Klaus Aktories. Inverse control of Rab proteins by Yersinia ADP-ribosyltransferase and glycosyltransferase related to clostridial glucosylating toxins. Science Advances 2020, 6, eaaz2094 .
AMA StyleG. Stefan Ost, Christophe Wirth, Xenia Bogdanović, Wei-Chun Kao, Björn Schorch, Philipp J. K. Aktories, Panagiotis Papatheodorou, Carsten Schwan, Andreas Schlosser, Thomas Jank, Carola Hunte, Klaus Aktories. Inverse control of Rab proteins by Yersinia ADP-ribosyltransferase and glycosyltransferase related to clostridial glucosylating toxins. Science Advances. 2020; 6 (11):eaaz2094.
Chicago/Turabian StyleG. Stefan Ost; Christophe Wirth; Xenia Bogdanović; Wei-Chun Kao; Björn Schorch; Philipp J. K. Aktories; Panagiotis Papatheodorou; Carsten Schwan; Andreas Schlosser; Thomas Jank; Carola Hunte; Klaus Aktories. 2020. "Inverse control of Rab proteins by Yersinia ADP-ribosyltransferase and glycosyltransferase related to clostridial glucosylating toxins." Science Advances 6, no. 11: eaaz2094.
The human disease fibrodysplasia ossificans progressiva (FOP) is a rare and highly disabling disorder of extensive heterotopic bone growth that is caused by a point mutation (R206H) in the activation domain of Alk2, a BMP (bone morphogenic protein) type 1 receptor. The mutation leads to extensive BMP-signaling induced by Activin A, which is normally an antagonist for wildtype receptors, resulting in excessive and uncontrolled bone formation. Here, we studied the effects of Pasteurella multocida toxin (PMT), which activates osteoclasts and inhibits osteoblast activity, in C2C12 myoblasts expressing the mutant Alk2(R206H) receptor as model of FOP. In our study, we mainly used alkaline phosphatase (ALP) activity as marker to determine osteoblast differentiation. BMP-4 stimulated an increase in ALP activity in C2C12-Alk2wt and C2C12-Alk2(R206H) cells. By contrast, Activin A only induced ALP activity in C2C12-Alk2(R206H) cells. In both cases, PMT acted as a potent inhibitor of ALP activity. PMT-induced inhibition of ALP activity was paralleled by a constitutive activation of the heterotrimeric Gq protein. Expression of a permanently active Gαq blocked Activin A/Alk2(R206H)-dependent increase in ALP activity. Inactivation of Gq by specific inhibitor FR900359 blocked the PMT effect. Similarly, canonical second messengers and effectors of Gαq (e.g. ionophore A23187-induced increase in intracellular Ca2+ and activation of PKC by PMA (phorbol 12-myristate 13-acetate)) inhibited Alk2(R206H)-mediated induction of ALP activity. Notably, Activin A-induced increase in ALP activity in C2C12-Alk2(R206H) cells was also inhibited by stimulation of the α1A-adrenoceptor, which couples to Gαq, by phenylephrine. PMT did not alter tail phosphorylation of the major downstream effectors of the Alk2 receptor, Smad1/5/9; neither did the toxin affect nuclear translocation of the Smad-complex. However, PMT diminished BMP responsive element-induced gene expression. The data indicate that PMT potently inhibits the induction of osteoblast markers in a FOP model via activation of G proteins. Moreover, our findings indicate that activation of G protein-coupled receptors and of G protein signaling might be a rationale for pharmacological therapy of FOP.
Julia K. Ebner; Gabriele M. König; Evi Kostenis; Peter Siegert; Klaus Aktories; Joachim H.C. Orth. Activation of Gq signaling by Pasteurella multocida toxin inhibits the osteoblastogenic-like actions of Activin A in C2C12 myoblasts, a cell model of fibrodysplasia ossificans progressiva. Bone 2019, 127, 592 -601.
AMA StyleJulia K. Ebner, Gabriele M. König, Evi Kostenis, Peter Siegert, Klaus Aktories, Joachim H.C. Orth. Activation of Gq signaling by Pasteurella multocida toxin inhibits the osteoblastogenic-like actions of Activin A in C2C12 myoblasts, a cell model of fibrodysplasia ossificans progressiva. Bone. 2019; 127 ():592-601.
Chicago/Turabian StyleJulia K. Ebner; Gabriele M. König; Evi Kostenis; Peter Siegert; Klaus Aktories; Joachim H.C. Orth. 2019. "Activation of Gq signaling by Pasteurella multocida toxin inhibits the osteoblastogenic-like actions of Activin A in C2C12 myoblasts, a cell model of fibrodysplasia ossificans progressiva." Bone 127, no. : 592-601.
Legionella pneumophila causes Legionnaires' disease, a severe form of pneumonia. L. pneumophila translocates more than 300 effectors into host cells via its Dot/Icm (Defective in organelle trafficking/Intracellular multiplication) type IV secretion system to enable its replication in target cells. Here, we studied the effector LtpM, which is encoded in a recombination hot spot in L. pneumophila Paris. We show that a C-terminal phosphoinositol 3-phosphate (PI3P)-binding domain, also found in otherwise unrelated effectors, targets LtpM to the Legionella-containing vacuole and to early and late endosomes. LtpM expression in yeast caused cytotoxicity. Sequence comparison and structural homology modeling of the N-terminal domain of LtpM uncovered a remote similarity to the glycosyltransferase (GT) toxin PaTox from the bacterium Photorhabdus asymbiotica; however, instead of the canonical DxD motif of GT-A type glycosyltransferases, essential for enzyme activity and divalent cation coordination, we found that a DxN motif is present in LtpM. Using UDP-glucose as sugar donor, we show that purified LtpM nevertheless exhibits glucohydrolase and autoglucosylation activity in vitro and demonstrate that PI3P binding activates LtpM's glucosyltransferase activity toward protein substrates. Substitution of the aspartate or the asparagine in the DxN motif abolished the activity of LtpM. Moreover, whereas all glycosyltransferase toxins and effectors identified so far depend on the presence of divalent cations, LtpM is active in their absence. Proteins containing LtpM-like GT domains are encoded in the genomes of other L. pneumophila isolates and species, suggesting that LtpM is the first member of a novel family of glycosyltransferase effectors employed to subvert hosts.
Nadezhda Levanova; Corinna Mattheis; Danielle Carson; Ka-Ning To; Thomas Jank; Gad Frankel; Klaus Aktories; Gunnar Neels Schroeder. The Legionella effector LtpM is a new type of phosphoinositide-activated glucosyltransferase. Journal of Biological Chemistry 2019, 294, 2862 -5740.
AMA StyleNadezhda Levanova, Corinna Mattheis, Danielle Carson, Ka-Ning To, Thomas Jank, Gad Frankel, Klaus Aktories, Gunnar Neels Schroeder. The Legionella effector LtpM is a new type of phosphoinositide-activated glucosyltransferase. Journal of Biological Chemistry. 2019; 294 (8):2862-5740.
Chicago/Turabian StyleNadezhda Levanova; Corinna Mattheis; Danielle Carson; Ka-Ning To; Thomas Jank; Gad Frankel; Klaus Aktories; Gunnar Neels Schroeder. 2019. "The Legionella effector LtpM is a new type of phosphoinositide-activated glucosyltransferase." Journal of Biological Chemistry 294, no. 8: 2862-5740.
The nematode mutualistic bacterium Photorhabdus asymbiotica produces a large virulence-associated multifunctional protein toxin named PaTox. A glycosyltransferase domain and a deamidase domain of this large toxin function as effectors that specifically target host Rho GTPases and heterotrimeric G proteins, respectively. Modification of these intracellular regulators results in toxicity toward insects and mammalian cells. In this study, we identified a cysteine protease-like domain spanning PaTox residues 1844–2114 (PaToxP), upstream of these two effector domains and characterized by three conserved amino acid residues (Cys-1865, His-1955, and Asp-1975). We determined the crystal structure of the PaToxP C1865A variant by native single-wavelength anomalous diffraction of sulfur atoms (sulfur-SAD). At 2.0 Å resolution, this structure revealed a catalytic site typical for papain-like cysteine proteases, comprising a catalytic triad, oxyanion hole, and typical secondary structural elements. The PaToxP structure had highest similarity to that of the AvrPphB protease from Pseudomonas syringae classified as a C58-protease. Furthermore, we observed that PaToxP shares structural homology also with non-C58-cysteine proteases, deubiquitinases, and deamidases. Upon delivery into insect larvae, PaToxP alone without full-length PaTox had no toxic effects. Yet, PaToxP expression in mammalian cells was toxic and enhanced the apoptotic phenotype induced by PaTox in HeLa cells. We propose that PaToxP is a C58-like cysteine protease module that is essential for full PaTox activity.
Xenia Bogdanovic; Silvia Schneider; Nadezhda Levanova; Christophe Wirth; Christoph Trillhaase; Marcus Steinemann; Carola Hunte; Klaus Aktories; Thomas Jank. A cysteine protease–like domain enhances the cytotoxic effects of the Photorhabdus asymbiotica toxin PaTox. Journal of Biological Chemistry 2019, 294, 1035 -1044.
AMA StyleXenia Bogdanovic, Silvia Schneider, Nadezhda Levanova, Christophe Wirth, Christoph Trillhaase, Marcus Steinemann, Carola Hunte, Klaus Aktories, Thomas Jank. A cysteine protease–like domain enhances the cytotoxic effects of the Photorhabdus asymbiotica toxin PaTox. Journal of Biological Chemistry. 2019; 294 (3):1035-1044.
Chicago/Turabian StyleXenia Bogdanovic; Silvia Schneider; Nadezhda Levanova; Christophe Wirth; Christoph Trillhaase; Marcus Steinemann; Carola Hunte; Klaus Aktories; Thomas Jank. 2019. "A cysteine protease–like domain enhances the cytotoxic effects of the Photorhabdus asymbiotica toxin PaTox." Journal of Biological Chemistry 294, no. 3: 1035-1044.
Clostridium difficile is associated with antibiotic-associated diarrhea and pseudomembranous colitis in humans. Its 2 major toxins, toxins A and B, enter host cells and inactivate GTPases of the Ras homologue/rat sarcoma family by glucosylation. Pore formation of the toxins in the endosomal membrane enables the translocation of their glucosyltransferase domain into the cytosol, and membrane cholesterol is crucial for this process. Here, we asked whether the activity of the sterol regulatory element–binding protein 2 (SREBP-2) pathway, which regulates the cholesterol content in membranes, affects the susceptibility of target cells toward toxins A and B. We show that the SREBP-2 pathway is crucial for the intoxication process of toxins A and B by using pharmacological inhibitors (PF-429242, 25-hydroxycholesterol) and cells that are specifically deficient in SREBP-2 pathway signaling. SREBP-2 pathway inhibition disturbed the cholesterol-dependent pore formation of toxin B in cellular membranes. Preincubation with the cholesterol-lowering drug simvastatin protected cells from toxin B intoxication. Inhibition of the SREBP-2 pathway was without effect when the enzyme portion of toxin B was introduced into target cells via the cell delivery property of anthrax protective antigen. Taken together, these findings allowed us to identify the SREBP-2 pathway as a suitable target for the development of antitoxin therapeutics against C. difficile toxins A and B.—Papatheodorou, P., Song, S., López-Ureña, D., Witte, A., Marques, F., Ost, G. S., Schorch, B., Chaves-Olarte, E., Aktories, K. Cytotoxicity of Clostridium difficile toxins A and B requires an active and functional SREBP-2 pathway. FASEB J. 33, 4883–4892 (2019). www.fasebj.org
Panagiotis Papatheodorou; Shuo Song; Diana López‐Ureña; Alexander Witte; Felícia Marques; Gerhard Stefan Ost; Björn Schorch; Esteban Chaves‐Olarte; Klaus Aktories. Cytotoxicity of Clostridium difficile toxins A and B requires an active and functional SREBP‐2 pathway. The FASEB Journal 2018, 33, 4883 -4892.
AMA StylePanagiotis Papatheodorou, Shuo Song, Diana López‐Ureña, Alexander Witte, Felícia Marques, Gerhard Stefan Ost, Björn Schorch, Esteban Chaves‐Olarte, Klaus Aktories. Cytotoxicity of Clostridium difficile toxins A and B requires an active and functional SREBP‐2 pathway. The FASEB Journal. 2018; 33 (4):4883-4892.
Chicago/Turabian StylePanagiotis Papatheodorou; Shuo Song; Diana López‐Ureña; Alexander Witte; Felícia Marques; Gerhard Stefan Ost; Björn Schorch; Esteban Chaves‐Olarte; Klaus Aktories. 2018. "Cytotoxicity of Clostridium difficile toxins A and B requires an active and functional SREBP‐2 pathway." The FASEB Journal 33, no. 4: 4883-4892.
Photorhabdus luminescens Tc toxins consist of the cell‐binding component TcA, the linker component TcB and the enzyme component TcC. TccC3, a specific isoform of TcC, ADP‐ribosylates actin and causes redistribution of the actin cytoskeleton. TccC5, another isoform of TcC, ADP‐ribosylates and activates Rho proteins. Here, we report that the proteasome inhibitor MG132 blocks the intoxication of cells by Tc toxin. The inhibitory effect of MG132 was not observed, when the ADP‐ribosyltransferase domain of the TcC component was introduced into target cells by protective antigen (PA), which is the binding and delivery component of anthrax toxin. Additionally, MG132 neither affected pore formation by TcA in artificial membranes, nor binding of the toxin to cells. Furthermore, the in vitro ADP‐ribosylation of actin by the enzyme domain of TccC3 was not affected by MG132. Similar to MG132, several calpain inhibitors blocked the action of the Tc toxin. Proteolytic cleavage of the binding component TcA induced by P. luminescens protease PrtA1 or by collagenase largely increased the toxicity of the Tc toxin. MG132 exhibited no inhibitory effect on the cleaved TcA component. Moreover, binding of TcA to target cells was largely increased after cleavage. The data indicate that Tc toxin is activated by proteolytic processing of the TcA component, resulting in increased receptor binding. Toxin processing is probably inhibited by MG132.
Gerhard Stefan Ost; Peter Ng'Ang'A; Alexander E. Lang; Klaus Aktories. Photorhabdus luminescens Tc toxin is inhibited by the protease inhibitor MG132 and activated by protease cleavage resulting in increased binding to target cells. Cellular Microbiology 2018, 21, e12978 .
AMA StyleGerhard Stefan Ost, Peter Ng'Ang'A, Alexander E. Lang, Klaus Aktories. Photorhabdus luminescens Tc toxin is inhibited by the protease inhibitor MG132 and activated by protease cleavage resulting in increased binding to target cells. Cellular Microbiology. 2018; 21 (3):e12978.
Chicago/Turabian StyleGerhard Stefan Ost; Peter Ng'Ang'A; Alexander E. Lang; Klaus Aktories. 2018. "Photorhabdus luminescens Tc toxin is inhibited by the protease inhibitor MG132 and activated by protease cleavage resulting in increased binding to target cells." Cellular Microbiology 21, no. 3: e12978.
Clostridium difficile infection causes antibiotics-associated diarrhea and pseudomembranous colitis. Major virulence factors of C. difficile are the Rho-glucosylating toxins TcdA and TcdB. In addition, many, so-called hypervirulent C. difficile strains produce the binary actin-ADP-ribosylating toxin CDT. CDT causes depolymerization of F-actin and rearrangement of the actin cytoskeleton. Thereby, many cellular functions, which depend on actin, are altered. CDT disturbs the dynamic balance between actin and microtubules in target cells. The toxin increases microtubule polymerization and induces the formation of microtubule-based protrusions at the plasma membrane of target cells. Moreover, CDT causes a redistribution of vesicles from the basolateral side to the apical side, where extracellular matrix proteins are released. These processes may increase the adherence of clostridia to target cells. Here, we review the effects of the action of CDT on the actin cytoskeleton and on the microtubule system.
Klaus Aktories; Panagiotis Papatheodorou; Carsten Schwan. Binary Clostridium difficile toxin (CDT) - A virulence factor disturbing the cytoskeleton. Anaerobe 2018, 53, 21 -29.
AMA StyleKlaus Aktories, Panagiotis Papatheodorou, Carsten Schwan. Binary Clostridium difficile toxin (CDT) - A virulence factor disturbing the cytoskeleton. Anaerobe. 2018; 53 ():21-29.
Chicago/Turabian StyleKlaus Aktories; Panagiotis Papatheodorou; Carsten Schwan. 2018. "Binary Clostridium difficile toxin (CDT) - A virulence factor disturbing the cytoskeleton." Anaerobe 53, no. : 21-29.
Legionella pneumophila glucosyltransferase SetA, which is introduced into target cells by a type IV secretion system, affects the intracellular traffic of host cells. Here, we characterized the enzyme activity of the Legionella effector. We report that Asp118 and Arg121 of SetA are essential for glucohydrolase and glucotransferase activities. Exchange of Trp36 to alanine reduced the enzyme activity of SetA. All three amino acids were crucial for the cytotoxic effects of SetA in yeast. We observed that phosphatidylinositol-3-phosphate (PI3P) increased the glucosyltransferase activity of SetA severalfold, while the glucohydrolase activity was not affected. In the presence of PI3P, we observed the glucosylation of actin, vimentin and the chaperonin CCT5 in the cytosolic fraction of target cells. Studies on the functional consequences of glucosylation of skeletal muscle α-actin in vitro revealed inhibition of actin polymerization by glucosylation.
Nadezhda Levanova; Marcus Steinemann; Kira E. Böhmer; Silvia Schneider; Yury Belyi; Andreas Schlosser; Klaus Aktories; Thomas Jank. Characterization of the glucosyltransferase activity of Legionella pneumophila effector SetA. Naunyn-Schmiedeberg's Archives of Pharmacology 2018, 392, 69 -79.
AMA StyleNadezhda Levanova, Marcus Steinemann, Kira E. Böhmer, Silvia Schneider, Yury Belyi, Andreas Schlosser, Klaus Aktories, Thomas Jank. Characterization of the glucosyltransferase activity of Legionella pneumophila effector SetA. Naunyn-Schmiedeberg's Archives of Pharmacology. 2018; 392 (1):69-79.
Chicago/Turabian StyleNadezhda Levanova; Marcus Steinemann; Kira E. Böhmer; Silvia Schneider; Yury Belyi; Andreas Schlosser; Klaus Aktories; Thomas Jank. 2018. "Characterization of the glucosyltransferase activity of Legionella pneumophila effector SetA." Naunyn-Schmiedeberg's Archives of Pharmacology 392, no. 1: 69-79.
Various bacterial protein toxins, includingClostridium difficiletoxins A (TcdA) and B (TcdB), attack intracellular target proteins of host cells by glucosylation. After receptor binding and endocytosis, the toxins are translocated into the cytosol, where they modify target proteins (e.g., Rho proteins). Here we report that the activity of translocated glucosylating toxins depends on the chaperonin TRiC/CCT. The chaperonin subunits CCT4/5 directly interact with the toxins and enhance the refolding and restoration of the glucosyltransferase activities of toxins after heat treatment. Knockdown of CCT5 by siRNA and HSF1A, an inhibitor of TRiC/CCT, blocks the cytotoxic effects of TcdA and TcdB. In contrast, HSP90, which is involved in the translocation and uptake of ADP ribosylating toxins, is not involved in uptake of the glucosylating toxins. We show that the actions of numerous glycosylating toxins from various toxin types and different species depend on TRiC/CCT. Our data indicate that the TRiC/CCT chaperonin system is specifically involved in toxin uptake and essential for the action of various glucosylating protein toxins acting intracellularly on target proteins.
Marcus Steinemann; Andreas Schlosser; Thomas Jank; Klaus Aktories. The chaperonin TRiC/CCT is essential for the action of bacterial glycosylating protein toxins likeClostridium difficiletoxins A and B. Proceedings of the National Academy of Sciences 2018, 115, 9580 -9585.
AMA StyleMarcus Steinemann, Andreas Schlosser, Thomas Jank, Klaus Aktories. The chaperonin TRiC/CCT is essential for the action of bacterial glycosylating protein toxins likeClostridium difficiletoxins A and B. Proceedings of the National Academy of Sciences. 2018; 115 (38):9580-9585.
Chicago/Turabian StyleMarcus Steinemann; Andreas Schlosser; Thomas Jank; Klaus Aktories. 2018. "The chaperonin TRiC/CCT is essential for the action of bacterial glycosylating protein toxins likeClostridium difficiletoxins A and B." Proceedings of the National Academy of Sciences 115, no. 38: 9580-9585.
Pasteurella multocida toxin (PMT) causes progressive atrophic rhinitis with severe turbinate bone degradation in pigs. It has been reported that the toxin deamidates and activates heterotrimeric G proteins, resulting in increased differentiation of osteoclasts and blockade of osteoblast differentiation. So far, the action of PMT on osteocytes, which is the most abundant cell type in bone tissue, is not known. In MLO-Y4 osteocytes, PMT deamidated heterotrimeric G proteins, resulting in loss of osteocyte dendritic processes, stress fiber formation, cell spreading and activation of RhoC but not of RhoA. Moreover, the toxin caused processing of membrane-bound receptor activator of NF-κB ligand (RANKL) to release soluble RANKL and enhanced the secretion of osteoclastogenic TNF-α. In a co-culture model of osteocytes and bone marrow cells, PMT-induced osteoclastogenesis was largely increased as compared to the mono-culture model. The enhancement of osteoclastogenesis observed in the co-culture was blocked by sequestering RANKL with osteoprotegerin and by an antibody against TNF-α indicating involvement of release of the osteoclastogenic factors from osteocytes. Data support the crucial role of osteocytes in bone metabolism and osteoclastogenesis and identify osteocytes as important target cells of PMT in progressive atrophic rhinitis.
Hannah Heni; Julia K. Ebner; Gudula Schmidt; Klaus Aktories; Joachim H. C. Orth. Involvement of Osteocytes in the Action of Pasteurella multocida Toxin. Toxins 2018, 10, 328 .
AMA StyleHannah Heni, Julia K. Ebner, Gudula Schmidt, Klaus Aktories, Joachim H. C. Orth. Involvement of Osteocytes in the Action of Pasteurella multocida Toxin. Toxins. 2018; 10 (8):328.
Chicago/Turabian StyleHannah Heni; Julia K. Ebner; Gudula Schmidt; Klaus Aktories; Joachim H. C. Orth. 2018. "Involvement of Osteocytes in the Action of Pasteurella multocida Toxin." Toxins 10, no. 8: 328.
Salmonella enterica serotype Typhimurium (S. Typhimurium) is one of the most frequent causes of food-borne illness in humans and usually associated with acute self-limiting gastroenteritis. However, in immunocompromised patients, the pathogen can disseminate and lead to severe systemic diseases. S. Typhimurium are facultative intracellular bacteria. For uptake and intracellular life, Salmonella translocate numerous effector proteins into host cells using two type-III secretion systems (T3SS), which are encoded within Salmonella pathogenicity islands 1 (SPI-1) and 2 (SPI-2). While SPI-1 effectors mainly promote initial invasion, SPI-2 effectors control intracellular survival and proliferation. Here, we elucidate the mode of action of Salmonella SPI-2 effector SseI, which is involved in control of systemic dissemination of S. Typhimurium. SseI deamidates a specific glutamine residue of heterotrimeric G proteins of the Gαi family, resulting in persistent activation of the G protein. Gi activation inhibits cAMP production and stimulates PI3-kinase γ by Gαi-released Gβγ subunits, resulting in activation of survival pathways by phosphorylation of Akt and mTOR. Moreover, SseI-induced deamidation leads to non-polarized activation of Gαi and, thereby, to loss of directed migration of dendritic cells. Salmonella Typhimurium is one of the most common causes of gastroenteritis in humans. In immunocompromised patients, the pathogen can cause systemic infections. Crucial virulence factors are encoded on two Salmonella pathogenicity islands SPI-1 and SPI-2. While SPI-1 encodes virulence factors essential for host cell invasion, intracellular proliferation of the pathogen depends mainly on SPI-2 effectors. Here, we elucidate the mode of action of Salmonella SPI-2 effector SseI. SseI activates heterotrimeric G proteins of the Gαi family by deamidation of a specific glutamine residue. Deamidation blocks GTP hydrolysis by Gαi, resulting in a persistently active G protein. Gi activation inhibits cAMP production and stimulates PI3Kγ by Gαi-released Gβγ subunits, resulting in activation of survival pathways by phosphorylation of Akt and mTOR. Moreover, deamidation of Gαi leads to a loss of directed migration in dendritic cells. The data offers a new perspective in the understanding of the actions of SseI.
Thorsten Brink; Veronika Leiss; Peter Siegert; Doris Jehle; Julia K. Ebner; Carsten Schwan; Aliaksei Shymanets; Sebastian Wiese; Bernd Nürnberg; Michael Hensel; Klaus Aktories; Joachim H. C. Orth. Salmonella Typhimurium effector SseI inhibits chemotaxis and increases host cell survival by deamidation of heterotrimeric Gi proteins. PLOS Pathogens 2018, 14, e1007248 .
AMA StyleThorsten Brink, Veronika Leiss, Peter Siegert, Doris Jehle, Julia K. Ebner, Carsten Schwan, Aliaksei Shymanets, Sebastian Wiese, Bernd Nürnberg, Michael Hensel, Klaus Aktories, Joachim H. C. Orth. Salmonella Typhimurium effector SseI inhibits chemotaxis and increases host cell survival by deamidation of heterotrimeric Gi proteins. PLOS Pathogens. 2018; 14 (8):e1007248.
Chicago/Turabian StyleThorsten Brink; Veronika Leiss; Peter Siegert; Doris Jehle; Julia K. Ebner; Carsten Schwan; Aliaksei Shymanets; Sebastian Wiese; Bernd Nürnberg; Michael Hensel; Klaus Aktories; Joachim H. C. Orth. 2018. "Salmonella Typhimurium effector SseI inhibits chemotaxis and increases host cell survival by deamidation of heterotrimeric Gi proteins." PLOS Pathogens 14, no. 8: e1007248.
Clostridium perfringens toxin TpeL belongs to the family of large clostridial glycosylating toxins. The toxin causes N-acetylglucosaminylation of Ras proteins at threonine35 thereby inactivating the small GTPases. Here, we show that all main types of oncogenic Ras proteins (H-Ras, K-Ras and N-Ras) are modified by the toxin in vitro and in vivo. Toxin-catalyzed modification of Ras was accompanied by inhibition of the MAP kinase pathway. Importantly, TpeL inhibited the paradoxical activation of the MAP kinase pathway induced by the BRAF inhibitor Vemurafenib in the human melanoma cell line SBCL2. The toxin also blocked Ras signaling in a zebrafish embryo model expressing oncogenic H-RasG12V, resulting in a reduction of melanocyte number. By using the binding and translocation component of anthrax toxin (protective antigen), the glucosyltransferase domain of TpeL was effectively introduced into target cells that were not sensitive to native TpeL toxin. To reach a higher specificity towards cancer cells, a chimeric TpeL toxin was engineered that possessed the knob region of adenovirus serotype 35 fiber, which interacts with CD46 of target cells frequently overexpressed in cancer cells. The chimeric TpeL fusion toxin efficiently inhibited Ras and MAP kinases in human pancreatic cancer Capan-2 cells, which were insensitive to the wild-type toxin. The data reveal that TpeL and TpeL-related immunotoxins provide a new toolset as Ras-inactivating agents.
Björn Schorch; Hannah Heni; Nour-Imene Zahaf; Tilman Brummer; Marina Mione; Gudula Schmidt; Panagiotis Papatheodorou; Klaus Aktories. Targeting oncogenic Ras by the Clostridium perfringens toxin TpeL. Oncotarget 2018, 9, 16489 -16500.
AMA StyleBjörn Schorch, Hannah Heni, Nour-Imene Zahaf, Tilman Brummer, Marina Mione, Gudula Schmidt, Panagiotis Papatheodorou, Klaus Aktories. Targeting oncogenic Ras by the Clostridium perfringens toxin TpeL. Oncotarget. 2018; 9 (23):16489-16500.
Chicago/Turabian StyleBjörn Schorch; Hannah Heni; Nour-Imene Zahaf; Tilman Brummer; Marina Mione; Gudula Schmidt; Panagiotis Papatheodorou; Klaus Aktories. 2018. "Targeting oncogenic Ras by the Clostridium perfringens toxin TpeL." Oncotarget 9, no. 23: 16489-16500.
// Kristine Østevold 1, 2 , Ana V. Meléndez 1 , Friederike Lehmann 1, 3, 4 , Gudula Schmidt 1 , Klaus Aktories 1, 5 and Carsten Schwan 1 1 Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, 79104 Freiburg, Germany 2 Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany 3 Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany 4 Faculty of Chemistry and Pharmacy, University of Freiburg, 79104 Freiburg, Germany 5 Centre for Biological Signalling Studies (BIOSS), University of Freiburg, 79104 Freiburg, Germany Correspondence to: Carsten Schwan, email: [email protected] Klaus Aktories, email: [email protected] Keywords: septin, microtentacles, microtubules, Clostridium difficile toxin, actin ADP-ribosylation Received: June 21, 2017 Accepted: August 17, 2017 Published: September 11, 2017 ABSTRACT Microtentacles are mostly microtubule-based cell protrusions that are formed by detached tumor cells. Here, we report that the formation of tumor cell microtentacles depends on the presence and dynamics of guanine nucleotide-binding proteins of the septin family, which are part of the cytoskeleton. In matrix-attached breast, lung, prostate and pancreas cancer cells, septins are associated with the cytosolic actin cytoskeleton. Detachment of cells causes redistribution of septins to the membrane, where microtentacle formation occurs. Forchlorfenuron, which inhibits septin functions, blocks microtentacle formation. The small GTPase Cdc42 and its effector proteins Borgs regulate septins and are essential for microtentacle formation. Dominant active and inactive Cdc42 inhibit microtentacle formation indicating that the free cycling of Cdc42 between its active and inactive state is essential for septin regulation and microtentacle formation. Cell attachment and aggregation models suggest that septins play an essential role in the metastatic behavior of tumor cells. Kristine Østevold1,2, Ana V. Meléndez1, Friederike Lehmann1,3,4, Gudula Schmidt1, Klaus Aktories1,5 and Carsten Schwan1 1Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, 79104 Freiburg, Germany 2Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany 3Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany 4Faculty of Chemistry and Pharmacy, University of Freiburg, 79104 Freiburg, Germany 5Centre for Biological Signalling Studies (BIOSS), University of Freiburg, 79104 Freiburg, Germany Correspondence to: Carsten Schwan, email: [email protected] Klaus Aktories, email: [email protected] Keywords: septin, microtentacles, microtubules, Clostridium difficile toxin, actin ADP-ribosylation Received: June 21, 2017 Accepted: August 17, 2017 Published: September 11, 2017 ABSTRACT Microtentacles are mostly microtubule-based cell protrusions that are formed by detached tumor cells. Here, we report that the formation of tumor cell microtentacles depends on the presence and dynamics of guanine nucleotide-binding proteins of the septin family, which are part of the cytoskeleton. In matrix-attached breast, lung, prostate and pancreas cancer cells, septins are associated with the cytosolic actin cytoskeleton. Detachment of cells causes redistribution of septins to the membrane, where microtentacle formation occurs. Forchlorfenuron, which inhibits septin functions, blocks microtentacle formation. The small GTPase Cdc42 and its effector proteins Borgs regulate septins and are essential for microtentacle formation. Dominant active and inactive Cdc42 inhibit microtentacle formation indicating that the free cycling of Cdc42 between its active and inactive state is essential for septin regulation and microtentacle formation. Cell attachment and aggregation models suggest that septins play an essential role in the metastatic behavior of tumor cells.
Kristine Østevold; Ana V. Meléndez; Friederike Lehmann; Gudula Schmidt; Klaus Aktories; Carsten Schwan. Septin remodeling is essential for the formation of cell membrane protrusions (microtentacles) in detached tumor cells. Oncotarget 2017, 8, 76686 -76698.
AMA StyleKristine Østevold, Ana V. Meléndez, Friederike Lehmann, Gudula Schmidt, Klaus Aktories, Carsten Schwan. Septin remodeling is essential for the formation of cell membrane protrusions (microtentacles) in detached tumor cells. Oncotarget. 2017; 8 (44):76686-76698.
Chicago/Turabian StyleKristine Østevold; Ana V. Meléndez; Friederike Lehmann; Gudula Schmidt; Klaus Aktories; Carsten Schwan. 2017. "Septin remodeling is essential for the formation of cell membrane protrusions (microtentacles) in detached tumor cells." Oncotarget 8, no. 44: 76686-76698.
Clostridium difficile is the cause of antibiotics-associated diarrhea and pseudomembranous colitis. The pathogen produces three protein toxins: C. difficile toxins A (TcdA) and B (TcdB), and C. difficile transferase toxin (CDT). The single-chain toxins TcdA and TcdB are the main virulence factors. They bind to cell membrane receptors and are internalized. The Nterminal glucosyltransferase and autoprotease domains of the toxins translocate from low-pH endosomes into the cytosol. After activation by inositol hexakisphosphate (InsP6), the autoprotease cleaves and releases the glucosyltransferase domain into the cytosol, where GTP-binding proteins of the Rho/Ras family are mono-O-glucosylated and, thereby, inactivated. Inactivation of Rho proteins disturbs the organization of the cytoskeleton and affects multiple Rho-dependent cellular processes, including loss of epithelial barrier functions, induction of apoptosis, and inflammation. CDT, the third C. difficile toxin, is a binary actin-ADP-ribosylating toxin that causes depolymerization of actin, thereby inducing formation of the microtubulebased protrusions. Recent progress in understanding of the toxins’ actions include insights into the toxin structures, their interaction with host cells, and functional consequences of their actions. Expected final online publication date for the Annual Review of Microbiology Volume 71 is September 8, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Klaus Aktories; Carsten Schwan; Thomas Jank. Clostridium difficileToxin Biology. Annual Review of Microbiology 2017, 71, 281 -307.
AMA StyleKlaus Aktories, Carsten Schwan, Thomas Jank. Clostridium difficileToxin Biology. Annual Review of Microbiology. 2017; 71 (1):281-307.
Chicago/Turabian StyleKlaus Aktories; Carsten Schwan; Thomas Jank. 2017. "Clostridium difficileToxin Biology." Annual Review of Microbiology 71, no. 1: 281-307.
Ribosomal translation factors are fundamental for protein synthesis and highly conserved in all kingdoms of life. The essential eukaryotic elongation factor 1A (eEF1A) delivers aminoacyl tRNAs to the A-site of the translating 80S ribosome. Several studies have revealed that eEF1A is posttranslationally modified. Using MS analysis, site-directed mutagenesis, and X-ray structural data analysis of Saccharomyces cerevisiae eEF1A, we identified a posttranslational modification in which the α amino group of mono-l-glutamine is covalently linked to the side chain of glutamate 45 in eEF1A. The MS analysis suggested that all eEF1A molecules are modified by this glutaminylation and that this posttranslational modification occurs at all stages of yeast growth. The mutational studies revealed that this glutaminylation is not essential for the normal functions of eEF1A in S. cerevisiae. However, eEF1A glutaminylation slightly reduced growth under antibiotic-induced translational stress conditions. Moreover, we identified the same posttranslational modification in eEF1A from Schizosaccharomyces pombe but not in various other eukaryotic organisms tested despite strict conservation of the Glu45 residue among these organisms. We therefore conclude that eEF1A glutaminylation is a yeast-specific posttranslational modification that appears to influence protein translation.
Thomas Jank; Yury Belyi; Christophe Wirth; Sabine Rospert; Zehan Hu; Joern Dengjel; Tina Tzivelekidis; Gregers Rom Andersen; Carola Hunte; Andreas Schlosser; Klaus Aktories. Protein glutaminylation is a yeast-specific posttranslational modification of elongation factor 1A. Journal of Biological Chemistry 2017, 292, 16014 -16023.
AMA StyleThomas Jank, Yury Belyi, Christophe Wirth, Sabine Rospert, Zehan Hu, Joern Dengjel, Tina Tzivelekidis, Gregers Rom Andersen, Carola Hunte, Andreas Schlosser, Klaus Aktories. Protein glutaminylation is a yeast-specific posttranslational modification of elongation factor 1A. Journal of Biological Chemistry. 2017; 292 (39):16014-16023.
Chicago/Turabian StyleThomas Jank; Yury Belyi; Christophe Wirth; Sabine Rospert; Zehan Hu; Joern Dengjel; Tina Tzivelekidis; Gregers Rom Andersen; Carola Hunte; Andreas Schlosser; Klaus Aktories. 2017. "Protein glutaminylation is a yeast-specific posttranslational modification of elongation factor 1A." Journal of Biological Chemistry 292, no. 39: 16014-16023.