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Cytoskeletoxins: Bacterial and Viral Effector Proteins Targeting the Cytoskeleton 2.0

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

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 17892

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Special Issue Editors

Dr. Dmitri S. Kudryashov

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Guest Editor

Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA
Interests: actin cytoskeleton; bacterial toxins; antimicrobial peptides
Special Issues, Collections and Topics in MDPI journals

Dr. Elena Kudryashova

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Guest Editor

Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA
Interests: actin cytoskeleton; bacterial toxins; antimicrobial peptides

Special Issue Information

Dear Colleagues,

The ability to disrupt, manipulate, or hijack the cytoskeleton is a common feature of numerous bacterial and viral pathogens. These abilities developed in response to several factors, one of which is the remarkable functional and structural versatility of the cytoskeleton. As an essential and multifaceted component of both innate and adaptive immunity, a compromised cytoskeleton implies a compromised defense, which opens a direct route to abundant resources—the bona fide goal of all pathogens. Furthermore, F-actin and microtubules are tracks for myosin and kinesin motors, respectively, but also potent motors on their own. As such, they are an attractive source of mechanical power for entry, locomotion, spread, and egress of pathogens. The third reason the cytoskeleton is a common and attractive target for bacterial pathogens is its exceptionally high level of evolutionary conservation of the key elements of the eukaryotic cytoskeleton that are not found in bacteria. These properties ensure that, once developed, the pathogenicity factors can be universally and specifically applied for targeting a vast number of eukaryotic hosts while remaining benign to the pathogens that produce them.

Several effector proteins/toxins produced by pathogenic bacteria and viruses are reasonably well understood and have become indispensable tools for revealing secrets of the cytoskeleton's organization and function. Many are understood superficially, while others remain to be discovered. In this Special Issue of IJMS, we invite research publications and review articles in a broad area at the interface between pathogens and the cytoskeleton that reveal novel details of the toxin pathogenicity, contribute to the understanding of the host, or summarize existing knowledge on either of the two topics.

The word “cytoskeletoxins” in the title of this Special Issue cannot be found in dictionaries. It is meant to intrigue and attract the attention of potential authors and readers but also to emphasize that the number of effector proteins targeting the cytoskeleton is so large and their role in the pathogenesis of various infectious diseases is so important that this group of effectors deserves to be given a very special name.

Dr. Dmitri S. Kudryashov
Dr. Elena Kudryashova
Guest Editors

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Keywords

toxin
effector
cytoskeleton
actin
tubulin
microtubules
actin-binding proteins
microtubule-binding proteins
pathogenesis
signaling
immunity

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Published Papers (6 papers)

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Research

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20 pages, 2679 KiB

Open AccessArticle

Clostridium novyi’s Alpha-Toxin Changes Proteome and Phosphoproteome of HEp-2 Cells

by Theresa Schweitzer, Harald Genth and Andreas Pich

Int. J. Mol. Sci. 2022, 23(17), 9939; https://doi.org/10.3390/ijms23179939 - 1 Sep 2022

Cited by 1 | Viewed by 1914

Abstract

C. novyi type A produces the alpha-toxin (TcnA) that belongs to the large clostridial glucosylating toxins (LCGTs) and is able to modify small GTPases by N-acetylglucosamination on conserved threonine residues. In contrast, other LCGTs including Clostridioides difficile toxin A and toxin B (TcdA; TcdB) modify small GTPases by mono-o-glucosylation. Both modifications inactivate the GTPases and cause strong effects on GTPase-dependent signal transduction pathways and the consequent reorganization of the actin cytoskeleton leading to cell rounding and finally cell death. However, the effect of TcnA on target cells is largely unexplored. Therefore, we performed a comprehensive screening approach of TcnA treated HEp-2 cells and analyzed their proteome and their phosphoproteome using LC-MS-based methods. With this data-dependent acquisition (DDA) approach, 5086 proteins and 9427 phosphosites could be identified and quantified. Of these, 35 proteins were found to be significantly altered after toxin treatment, and 1832 phosphosites were responsive to TcnA treatment. By analyzing the TcnA-induced proteomic effects of HEp-2 cells, 23 common signaling pathways were identified to be altered, including Actin Cytoskeleton Signaling, Epithelial Adherens Junction Signaling, and Signaling by Rho Family GTPases. All these pathways are also regulated after application of TcdA or TcdB of C. difficile. After TcnA treatment the regulation on phosphorylation level was much stronger compared to the proteome level, in terms of both strength of regulation and the number of regulated phosphosites. Interestingly, various signaling pathways such as Signaling by Rho Family GTPases or Integrin Signaling were activated on proteome level while being inhibited on phosphorylation level or vice versa as observed for the Role of BRCA1 in DNA Damage Response. ZIP kinase, as well as Calmodulin-dependent protein kinases IV & II, were observed as activated while Aurora-A kinase and CDK kinases tended to be inhibited in cells treated with TcnA based on their substrate regulation pattern. Full article

(This article belongs to the Special Issue Cytoskeletoxins: Bacterial and Viral Effector Proteins Targeting the Cytoskeleton 2.0)

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25 pages, 5646 KiB

Open AccessArticle

Photorhabdus luminescens TccC3 Toxin Targets the Dynamic Population of F-Actin and Impairs Cell Cortex Integrity

by Songyu Dong, Weili Zheng, Nicholas Pinkerton, Jacob Hansen, Svetlana B. Tikunova, Jonathan P. Davis, Sarah M. Heissler, Elena Kudryashova, Edward H. Egelman and Dmitri S. Kudryashov

Int. J. Mol. Sci. 2022, 23(13), 7026; https://doi.org/10.3390/ijms23137026 - 24 Jun 2022

Cited by 6 | Viewed by 2307

Abstract

Due to its essential role in cellular processes, actin is a common target for bacterial toxins. One such toxin, TccC3, is an effector domain of the ABC-toxin produced by entomopathogenic bacteria of Photorhabdus spp. Unlike other actin-targeting toxins, TccC3 uniquely ADP-ribosylates actin at Thr-148, resulting in the formation of actin aggregates and inhibition of phagocytosis. It has been shown that the fully modified F-actin is resistant to depolymerization by cofilin and gelsolin, but their effects on partially modified actin were not explored. We found that only F-actin unprotected by tropomyosin is the physiological TccC3 substrate. Yet, ADP-ribosylated G-actin can be produced upon cofilin-accelerated F-actin depolymerization, which was only mildly inhibited in partially modified actin. The affinity of TccC3-ADP-ribosylated G-actin for profilin and thymosin-β4 was weakened moderately but sufficiently to potentiate spontaneous polymerization in their presence. Interestingly, the Arp2/3-mediated nucleation was also potentiated by T148-ADP-ribosylation. Notably, even partially modified actin showed reduced bundling by plastins and α-actinin. In agreement with the role of these and other tandem calponin-homology domain actin organizers in the assembly of the cortical actin network, TccC3 induced intense membrane blebbing in cultured cells. Overall, our data suggest that TccC3 imposes a complex action on the cytoskeleton by affecting F-actin nucleation, recycling, and interaction with actin-binding proteins involved in the integration of actin filaments with each other and cellular elements. Full article

(This article belongs to the Special Issue Cytoskeletoxins: Bacterial and Viral Effector Proteins Targeting the Cytoskeleton 2.0)

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19 pages, 20162 KiB

Open AccessArticle

Human α-Defensin-6 Neutralizes Clostridioides difficile Toxins TcdA and TcdB by Direct Binding

by Lara Barthold, Sebastian Heber, Christoph Q. Schmidt, Marion Gradl, Gilbert Weidinger, Holger Barth and Stephan Fischer

Int. J. Mol. Sci. 2022, 23(9), 4509; https://doi.org/10.3390/ijms23094509 - 19 Apr 2022

Cited by 8 | Viewed by 2891

Abstract

Rising incidences and mortalities have drawn attention to Clostridioides difficile infections (CDIs) in recent years. The main virulence factors of this bacterium are the exotoxins TcdA and TcdB, which glucosylate Rho-GTPases and thereby inhibit Rho/actin-mediated processes in cells. This results in cell rounding, gut barrier disruption and characteristic clinical symptoms. So far, treatment of CDIs is limited and mainly restricted to some antibiotics, often leading to a vicious circle of antibiotic-induced disease recurrence. Here, we demonstrate the protective effect of the human antimicrobial peptide α-defensin-6 against TcdA, TcdB and the combination of both toxins in vitro and in vivo and unravel the underlying molecular mechanism. The defensin prevented toxin-mediated glucosylation of Rho-GTPases in cells and protected human cells, model epithelial barriers as well as zebrafish embryos from toxic effects. In vitro analyses revealed direct binding to TcdB in an SPR approach and the rapid formation of TcdB/α-defensin-6 complexes, as analyzed with fluorescent TcdB by time-lapse microscopy. In conclusion, the results imply that α-defensin-6 rapidly sequesters the toxin into complexes, which prevents its cytotoxic activity. These findings extend the understanding of how human peptides neutralize bacterial protein toxins and might be a starting point for the development of novel therapeutic options against CDIs. Full article

(This article belongs to the Special Issue Cytoskeletoxins: Bacterial and Viral Effector Proteins Targeting the Cytoskeleton 2.0)

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22 pages, 2218 KiB

Open AccessArticle

Effect of Clinically Used Microtubule Targeting Drugs on Viral Infection and Transport Function

by María Ángela Oliva, Carlota Tosat-Bitrián, Lucía Barrado-Gil, Francesca Bonato, Inmaculada Galindo, Urtzi Garaigorta, Beatriz Álvarez-Bernad, Rebeca París-Ogáyar, Daniel Lucena-Agell, Juan Francisco Giménez-Abián, Isabel García-Dorival, Jesús Urquiza, Pablo Gastaminza, José Fernando Díaz, Valle Palomo and Covadonga Alonso

Int. J. Mol. Sci. 2022, 23(7), 3448; https://doi.org/10.3390/ijms23073448 - 22 Mar 2022

Cited by 9 | Viewed by 4472

Abstract

Microtubule targeting agents (MTAs) have been exploited mainly as anti-cancer drugs because of their impact on cellular division and angiogenesis. Additionally, microtubules (MTs) are key structures for intracellular transport, which is frequently hijacked during viral infection. We have analyzed the antiviral activity of clinically used MTAs in the infection of DNA and RNA viruses, including SARS-CoV-2, to find that MT destabilizer agents show a higher impact than stabilizers in the viral infections tested, and FDA-approved anti-helminthic benzimidazoles were among the most active compounds. In order to understand the reasons for the observed antiviral activity, we studied the impact of these compounds in motor proteins-mediated intracellular transport. To do so, we used labeled peptide tools, finding that clinically available MTAs impaired the movement linked to MT motors in living cells. However, their effect on viral infection lacked a clear correlation to their effect in motor-mediated transport, denoting the complex use of the cytoskeleton by viruses. Finally, we further delved into the molecular mechanism of action of Mebendazole by combining biochemical and structural studies to obtain crystallographic high-resolution information of the Mebendazole-tubulin complex, which provided insights into the mechanisms of differential toxicity between helminths and mammalians. Full article

(This article belongs to the Special Issue Cytoskeletoxins: Bacterial and Viral Effector Proteins Targeting the Cytoskeleton 2.0)

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Review

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14 pages, 1494 KiB

Open AccessReview

Functional Mimicry of Eukaryotic Actin Assembly by Pathogen Effector Proteins

by Saif S. Alqassim

Int. J. Mol. Sci. 2022, 23(19), 11606; https://doi.org/10.3390/ijms231911606 - 1 Oct 2022

Cited by 3 | Viewed by 2419

Abstract

The actin cytoskeleton lies at the heart of many essential cellular processes. There are hundreds of proteins that cells use to control the size and shape of actin cytoskeletal networks. As such, various pathogens utilize different strategies to hijack the infected eukaryotic host actin dynamics for their benefit. These include the control of upstream signaling pathways that lead to actin assembly, control of eukaryotic actin assembly factors, encoding toxins that distort regular actin dynamics, or by encoding effectors that directly interact with and assemble actin filaments. The latter class of effectors is unique in that, quite often, they assemble actin in a straightforward manner using novel sequences, folds, and molecular mechanisms. The study of these mechanisms promises to provide major insights into the fundamental determinants of actin assembly, as well as a deeper understanding of host–pathogen interactions in general, and contribute to therapeutic development efforts targeting their respective pathogens. This review discusses mechanisms and highlights shared and unique features of actin assembly by pathogen effectors that directly bind and assemble actin, focusing on eukaryotic actin nucleator functional mimics Rickettsia Sca2 (formin mimic), Burkholderia BimA (Ena/VASP mimic), and Vibrio VopL (tandem WH2-motif mimic). Full article

(This article belongs to the Special Issue Cytoskeletoxins: Bacterial and Viral Effector Proteins Targeting the Cytoskeleton 2.0)

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33 pages, 4275 KiB

Open AccessReview

Bacterial Nucleotidyl Cyclases Activated by Calmodulin or Actin in Host Cells: Enzyme Specificities and Cytotoxicity Mechanisms Identified to Date

by Magda Teixeira-Nunes, Pascal Retailleau, Martine Comisso, Vincent Deruelle, Undine Mechold and Louis Renault

Int. J. Mol. Sci. 2022, 23(12), 6743; https://doi.org/10.3390/ijms23126743 - 16 Jun 2022

Cited by 3 | Viewed by 2788

Abstract

Many pathogens manipulate host cell cAMP signaling pathways to promote their survival and proliferation. Bacterial Exoenzyme Y (ExoY) toxins belong to a family of invasive, structurally-related bacterial nucleotidyl cyclases (NC). Inactive in bacteria, they use proteins that are uniquely and abundantly present in eukaryotic cells to become potent, unregulated NC enzymes in host cells. Other well-known members of the family include Bacillus anthracis Edema Factor (EF) and Bordetella pertussis CyaA. Once bound to their eukaryotic protein cofactor, they can catalyze supra-physiological levels of various cyclic nucleotide monophosphates in infected cells. Originally identified in Pseudomonas aeruginosa, ExoY-related NC toxins appear now to be more widely distributed among various γ- and β-proteobacteria. ExoY-like toxins represent atypical, poorly characterized members within the NC toxin family. While the NC catalytic domains of EF and CyaA toxins use both calmodulin as cofactor, their counterparts in ExoY-like members from pathogens of the genus Pseudomonas or Vibrio use actin as a potent cofactor, in either its monomeric or polymerized form. This is an original subversion of actin for cytoskeleton-targeting toxins. Here, we review recent advances on the different members of the NC toxin family to highlight their common and distinct functional characteristics at the molecular, cytotoxic and enzymatic levels, and important aspects that need further characterizations. Full article

(This article belongs to the Special Issue Cytoskeletoxins: Bacterial and Viral Effector Proteins Targeting the Cytoskeleton 2.0)

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