Mechanism of translation inhibition by type II GNAT toxins: AtaT, TacT, and ItaT
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ABSTRACT:
PROVIDER: PRJNA624163 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11521522.fastq.gz | Fastqsanger.gz | |||
| SRR11521523.fastq.gz | Fastqsanger.gz | |||
| SRR18036936.fastq.gz | Fastqsanger.gz | |||
| SRR18036937.fastq.gz | Fastqsanger.gz |
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Project description:Type II toxin-antitoxin (TA) systems are two-gene modules widely distributed among prokaryotes. GNAT toxins associated with the DUF1778 antitoxins represent a large family of type II TAs. GNAT toxins inhibit cell growth by disrupting translation via acetylation of aminoacyl-tRNAs. Using ribosome profiling, we investigated the in vivo substrate specificity of three GNAT toxins: AtaT2, TacT3, and ItaT.
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Project description:Type II Toxin-antitoxin (TA) systems are widely distributed in bacterial and archaeal genomes with diverse critical cellular functions such as defense against phages, biofilm formation, persistence and virulence. GCN5-related N -acetyltransferase (GNAT) toxin, with an acetyltransferase activity-dependent mechanism of translation inhibition, represents a relatively new and expanding family of type II TA toxins. Here, we describe a group of GNAT-Xre TA modules that are widely distributed among Pseudomonas species and even certain Gram-positive bacteria. We investigate one of its members PacTA (encoded by PA3270/PA3269) from Pseudomonas aeruginosa, and demonstrate that the toxin PacT positively regulates the iron acquisition in P. aeruginosa. Notably, other than arresting translation via acetylating aminoacyl-tRNAs, PacT could directly bind to Fur, a key ferric uptake regulator, to attenuate its DNA-binding affinity and thus permit expression of downstream iron-acquisition-related genes. We further show that expression of the pacTA locus is up-regulated in response to iron starvation and the absence of PacT causes biofilm formation defect and attenuated pathogenesis. Overall, these findings reveal a novel regulation mechanism of GNAT toxin that controls genes involved in iron uptake process and contributes to the bacterial virulence.
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Project description:Macrolides are clinically important antibiotics thought to inhibit bacterial growth by impeding the passage of newly synthesized polypeptides through the nascent peptide exit tunnel of the bacterial ribosome. Recent data challenged this view by showing that macrolide antibiotics can differentially affect synthesis of individual proteins. In order to understand the general mechanism of macrolide action, we used genome-wide ribosome profiling and analyzed the redistribution of ribosomes translating highly expressed genes in bacterial cells treated with high concentrations of macrolide antibiotics. The metagene analysis indicated that inhibition of early rounds of translation, which would be characteristic of the conventional view of macrolide action, occurs only at a limited number of genes. Translation of most genes proceeds past the 5' proximal codons and can be arrested at more distal codons when the ribosome encounters specific short sequence motifs. The sequence motifs enriched in the sites of arrest are confined to the nascent peptide residues in the peptidyl transferase center but not to the peptide segments that contact the antibiotic molecule in the exit tunnel. This led to the conclusion that the general mode of macrolide action involves selective inhibition of peptide bond formation between specific combinations of donor and acceptor substrates. Additional factors operating in the living cell but not during in vitro protein synthesis may modulate site-specific action of macrolide antibiotics. Comparing ribosome distribution in bacterial cells treated with macrolide antibiotics against the control cells.
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