The DarT/DarG Toxin–Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies

Catara, Giuliana; Caggiano, Rocco; Palazzo, Luca

doi:10.3390/pathogens12020240

Cited by 3 publications

(1 citation statement)

References 207 publications

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“…To date, only a few TA systems have been tested and shown to contribute to host infection (Deep et al , 2018; Tiwari et al , 2015; Agarwal et al , 2018). The deleterious nature of many M. tuberculosis toxins has raised the possibility that new antibacterial properties demonstrated by toxins might be exploited to identify new drug targets or applied directly as antimicrobials, alone or in combination with standard antibacterial therapy (Freire et al , 2019; Kang et al , 2018; Catara et al , 2023).…”

Section: Introductionmentioning

confidence: 99%

Nucleotidyltransferase toxin MenT targets and extends the aminoacyl acceptor ends of serine tRNAs in vivo to control Mycobacterium tuberculosis growth

XU,

BARRIOT,

VOISIN

et al. 2024

Preprint

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Toxins of toxin-antitoxin systems use diverse mechanisms to control bacterial growth and represent attractive therapeutic targets to fight pathogens. In this study, we characterized the translation inhibitor toxin MenT3 of Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis in humans. We show that MenT3 is a robust cytidine specific tRNA nucleotidyltransferase in vitro, capable of modifying the aminoacyl acceptor ends of most tRNA but with a marked preference for tRNASer, to which long stretches of cytidines were added. Furthermore, transcriptomic-wide analysis of MenT3 targets in M. tuberculosis identified tRNASer as the sole target of MenT3 in vivo and revealed significant detoxification attempts by ribonuclease PH in response to MenT3 overexpression. Finally, under physiological conditions, only in the presence the native menAT3 operon, we found the unexpected presence of an active pool of endogenous MenT3 targeting tRNASer in M. tuberculosis, likely reflecting the importance of MenT3 during infection.

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Section: Introductionmentioning

confidence: 99%

Nucleotidyltransferase toxin MenT targets and extends the aminoacyl acceptor ends of serine tRNAs in vivo to control Mycobacterium tuberculosis growth

XU,

BARRIOT,

VOISIN

et al. 2024

Preprint

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MenT nucleotidyltransferase toxins extend tRNA acceptor stems and can be inhibited by asymmetrical antitoxin binding

Xu,

Usher,

Gutierrez

et al. 2023

Nat Commun

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Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis, has a genome encoding a remarkably high number of toxin-antitoxin systems of largely unknown function. We have recently shown that the M. tuberculosis genome encodes four of a widespread, MenAT family of nucleotidyltransferase toxin-antitoxin systems. In this study we characterize MenAT1, using tRNA sequencing to demonstrate MenT1 tRNA modification activity. MenT1 activity is blocked by MenA1, a short protein antitoxin unrelated to the MenA3 kinase. X-ray crystallographic analysis shows blockage of the conserved MenT fold by asymmetric binding of MenA1 across two MenT1 protomers, forming a heterotrimeric toxin-antitoxin complex. Finally, we also demonstrate tRNA modification by toxin MenT4, indicating conserved activity across the MenT family. Our study highlights variation in tRNA target preferences by MenT toxins, selective use of nucleotide substrates, and diverse modes of MenA antitoxin activity.

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Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

Spano,

Catara

2023

Cells

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Ubiquitination is a reversible post-translational modification based on the chemical addition of ubiquitin to proteins with regulatory effects on various signaling pathways. Ubiquitination can alter the molecular functions of tagged substrates with respect to protein turnover, biological activity, subcellular localization or protein–protein interaction. As a result, a wide variety of cellular processes are under ubiquitination-mediated control, contributing to the maintenance of cellular homeostasis. It follows that the dysregulation of ubiquitination reactions plays a relevant role in the pathogenic states of human diseases such as neurodegenerative diseases, immune-related pathologies and cancer. In recent decades, the enzymes of the ubiquitin–proteasome system (UPS), including E3 ubiquitin ligases and deubiquitinases (DUBs), have attracted attention as novel druggable targets for the development of new anticancer therapeutic approaches. This perspective article summarizes the peculiarities shared by the enzymes involved in the ubiquitination reaction which, when deregulated, can lead to tumorigenesis. Accordingly, an overview of the main pharmacological interventions based on targeting the UPS that are in clinical use or still in clinical trials is provided, also highlighting the limitations of the therapeutic efficacy of these approaches. Therefore, various attempts to circumvent drug resistance and side effects as well as UPS-related emerging technologies in anticancer therapeutics are discussed.

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The DarT/DarG Toxin–Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies

Cited by 3 publications

References 207 publications

Nucleotidyltransferase toxin MenT targets and extends the aminoacyl acceptor ends of serine tRNAs in vivo to control Mycobacterium tuberculosis growth

Nucleotidyltransferase toxin MenT targets and extends the aminoacyl acceptor ends of serine tRNAs in vivo to control Mycobacterium tuberculosis growth

MenT nucleotidyltransferase toxins extend tRNA acceptor stems and can be inhibited by asymmetrical antitoxin binding

Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

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