AtaT blocks translation initiation by N-acetylation of the initiator tRNAfMet

Jurėnas, Dukas; Chatterjee, Sneha; Konijnenberg, Albert; Sobott, Frank; Droogmans, Louis; García-Pino, Abel; Melderen, Laurence Van

doi:10.1038/nchembio.2346

Cited by 71 publications

(109 citation statements)

References 52 publications

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“…The GNAT superfamily proteins are widely distributed in eukaryotes and prokaryotes, and have been shown to influence many physiological events by transferring the acetyl group from AcCoA to different substrates (Xie et al ., ). Three examples of GNAT toxins have been described, namely TacT of Salmonella enterica Typhimurium (Cheverton et al ., ), AtaT of enterohemorrhagic Escherichia coli O157:H7 (Jurėnas et al, ) and GmvT of Shigella flexneri pINV plasmids (McVicker and Tang, ). The toxicity of these GNAT toxins is abolished by the co‐expression of their cognate antitoxins that contain the ribbon‐helix‐helix (RHH) conserved domains and form the GNAT‐RHH family of type II TA systems.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of acetyltransferase‐type toxin‐antitoxin locus in Klebsiella pneumoniae

Qian

Yao

Tai

et al. 2018

Molecular Microbiology

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A type II toxin-antitoxin (TA) system, in which the toxin contains a Gcn5-related N-acetyltransferase (GNAT) domain, has been characterized recently. GNAT toxin acetylates aminoacyl-tRNA and blocks protein translation. It is abolished by the cognate antitoxin that contains the ribbon-helix-helix (RHH) domain. Here, we present an experimental demonstration of the interaction of the GNAT-RHH complex with TA promoter DNA. First, the GNAT-RHH TA locus kacAT was found in Klebsiella pneumoniae HS11286, a strain resistant to multiple antibiotics. Overexpression of KacT halted cell growth and resulted in persister cell formation. The crystal structure also indicated that KacT is a typical acetyltransferase toxin. Co-expression of KacA neutralized KacT toxicity. Expression of the bicistronic kacAT locus was up-regulated during antibiotic stress. Finally, KacT and KacA formed a heterohexamer that interacted with promoter DNA, resulting in negative autoregulation of kacAT transcription. The N-terminus region of KacA accounted for specific binding to the palindromic sequence on the operator DNA, whereas its C-terminus region was essential for the inactivation of the GNAT toxin. These results provide an important insight into the regulation of the GNAT-RHH family TA system.

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Section: Introductionmentioning

confidence: 99%

Identification and characterization of acetyltransferase‐type toxin‐antitoxin locus in Klebsiella pneumoniae

Qian

Yao

Tai

et al. 2018

Molecular Microbiology

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“…Toxins from Salmonella Typhimurium were shown to inhibit translation through acetylation of multiple elongator aminoacyl-tRNAs (12,13). Another translational inhibitor, the AtaT toxin from Escherichia coli O157:H7, was shown to specifically acetylate the amino group of initiator Met-tRNA fMet preventing its interaction with IF2·GTP (14,15). Toxicity of several other GNAT type II toxins has been demonstrated although their actual targets remain unknown (12,14,16–20).…”

Section: Introductionmentioning

confidence: 99%

Escherichia coli ItaT is a type II toxin that inhibits translation by acetylating isoleucyl-tRNAIle

Wilcox

Osterman

Serebryakova

et al. 2018

Nucleic Acids Research

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Prokaryotic toxin–antitoxin (TA) modules are highly abundant and are involved in stress response and drug tolerance. The most common type II TA modules consist of two interacting proteins. The type II toxins are diverse enzymes targeting various essential intracellular targets. The antitoxin binds to cognate toxin and inhibits its function. Recently, TA modules whose toxins are GNAT-family acetyltransferases were described. For two such systems, the target of acetylation was shown to be aminoacyl-tRNA: the TacT toxin targets aminoacylated elongator tRNAs, while AtaT targets the amino acid moiety of initiating tRNAMet. We show that the itaRT gene pair from Escherichia coli encodes a TA module with acetyltransferase toxin ItaT that specifically and exclusively acetylates Ile-tRNAIle thereby blocking translation and inhibiting cell growth. ItaT forms a tight complex with the ItaR antitoxin, which represses the transcription of itaRT operon. A comprehensive bioinformatics survey of GNAT acetyltransferases reveals that enzymes encoded by validated or putative TA modules are common and form a distinct branch of the GNAT family tree. We speculate that further functional analysis of such TA modules will result in identification of enzymes capable of specifically targeting many, perhaps all, aminoacyl tRNAs.

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“…Detailed molecular mechanism of action was reported for two of these GNAT‐toxins, AtaT from E. coli (Jurėnas et al ., a) and TacT from Salmonella enterica serovar Typhimurium (Cheverton et al ., ). An earlier report of another GNAT toxin, GmvT from a virulence plasmid of Shigella sonnei , only showed that it blocks mRNA translation in an acetyl‐CoA‐dependent manner (McVicker and Tang, ).…”

Section: Gnat Toxins: a Newly Discovered Member Of Type II Ta Toxins mentioning

confidence: 97%

“…Even though type II TA toxins were shown to have various molecular targets in the cell including DNA replication and peptidoglycan synthesis, the majority of them appear to affect translation with almost every step of the translation process a target (Table ) (Page and Peti, ; Van Melderen et al ., ). It was suggested that toxins targeting translation may be preferentially selected during evolution as inhibition of protein synthesis could be less harmful when compared to toxins that target DNA replication or peptidoglycan synthesis (Guglielmini and Van Melderen, ; Jurėnas et al ., b).…”

Section: A Multitude Of Type II Toxin–antitoxin (Ta) Systems In Prokamentioning

confidence: 98%

“…Novel type II TA systems were recently discovered in several bacterial species with the toxins exhibiting a GNAT‐fold (GCN5‐related N ‐acetyltransferases) and their cognate antitoxins having a ribbon‐helix‐helix (RHH) fold (Van Acker et al ., ; Iqbal et al ., ; Lobato‐Márquez et al ., ; Cheverton et al ., ; McVicker and Tang, ; Jurėnas et al ., a). GNAT represents a large family of enzymes in prokaryotes and eukaryotes that mainly utilizes acetyl‐CoA as the acetyl donor in acetylation reactions, with the term GNAT first derived from the yeast GCN5 (general control nonrepressible 5), which is a histone acetyltransferase (Favrot et al ., ; Ud‐Din et al ., ).…”

Section: Gnat Toxins: a Newly Discovered Member Of Type II Ta Toxins mentioning

confidence: 99%

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GNAT toxins of bacterial toxin–antitoxin systems: acetylation of charged tRNAs to inhibit translation

Yeo

2018

Molecular Microbiology

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GCN5-related N-acetyltransferase (GNAT) is a huge superfamily of proteins spanning the prokaryotic and eukaryotic domains of life. GNAT proteins usually transfer an acetyl group from acetyl-CoA to a wide variety of substrates ranging from aminoglycoside antibiotics to large macromolecules. Type II toxin-antitoxin (TA) modules are typically bicistronic and widespread in bacterial and archael genomes with diverse cellular functions. Recently, a novel family of type II TA toxins was described, which presents a GNAT-fold and functions by acetylating charged tRNA thereby precluding translation. These GNAT toxins are usually associated with a corresponding ribbon-helix-helix-fold (RHH) antitoxin. In this issue, Qian et al. describes a unique GNAT-RHH TA system, designated KacAT, from a multidrug resistant strain of the pathogen, Klebsiella pneumoniae. As most type II TA loci, kacAT is transcriptionally autoregulated with the KacAT complex binding to the operator site via the N-terminus region of KacA to repress kacAT transcription. The crystal structure of the KacT toxin is also presented giving a structural basis for KacT toxicity. These findings expand our knowledge on this newly discovered family of TA toxins and the potential role that they may play in antibiotic tolerance and persistence of bacterial pathogens.

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AtaT blocks translation initiation by N-acetylation of the initiator tRNAfMet

Abstract: This is a repository copy of AtaT blocks translation initiation by N-acetylation of the initiator tRNAfMet.

Cited by 71 publications

References 52 publications

Identification and characterization of acetyltransferase‐type toxin‐antitoxin locus in Klebsiella pneumoniae

Identification and characterization of acetyltransferase‐type toxin‐antitoxin locus in Klebsiella pneumoniae

Escherichia coli ItaT is a type II toxin that inhibits translation by acetylating isoleucyl-tRNAIle

GNAT toxins of bacterial toxin–antitoxin systems: acetylation of charged tRNAs to inhibit translation

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