Mechanism of translation inhibition by type II GNAT toxins: AtaT, TacT, and ItaT
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PROVIDER: PRJNA624163 | ENA |
REPOSITORIES: ENA
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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:In eukaryotic cells, protein synthesis typically begins with the binding of eIF4F to the 7-methylguanylate (m7G)cap found on the 5’ end of the majority of mRNAs. Surprisingly, overall translational output remains robust under eIF4F inhibition. The sustained protein synthesis has been largely attributed to cap-independent translation mediated by internal ribosome entry sites (IRES). However, the IRES-driven translation is substrate-specific and largely incompatible with the broad spectrum of eIF4F-resistant translatomes.Here, we report that N6-methyladenosine (m6A)-mediated translation prevails on capped mRNAs and is resistant to eIF4F inactivation.Depletion of the methyltransferase METTL3 selectively inhibits translation of mRNAs bearing 5’UTR methylation, but not mRNAs with 5’ terminal oligopyrimidine (TOP) elements. Mechanistically, we identify ABCF1 as a critical mediator of m6A-promoted translation under both stress and physiological conditions. Supporting the role of ABCF1 in m6A-mediated cap-independent translation, ABCF1-sensitive transcripts largely overlap with METTL3-responsible mRNA targets. By illustrating the scope and the mechanism of translation initiation that is neither cap- nor IRES-dependent, these findingsreshape our current perceptions of cellular translational pathways
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