A tRNA modifying enzyme as a tunable regulatory nexus for bacterial stress responses and virulence.

Fleming BA*, Blango MG*, Rousek AA*, Kincannon WM, Tran A, Lewis AJ, Russell CW, Zhou Q, Baird LM, Barber AE, Brannon JR, Beebout CJ, Bandarian V, Hadjifrangiskou M, Howard MT, Mulvey MA (2022) A tRNA modifying enzyme as a tunable regulatory nexus for bacterial stress responses and virulence. Nucleic Acids Res [Epub ahead of print]

*equal contribution

Abstract

Post-transcriptional modifications can impact the stability and functionality of many different classes of RNA molecules and are an especially important aspect of tRNA regulation. It is hypothesized that cells can orchestrate rapid responses to changing environmental conditions by adjusting the specific types and levels of tRNA modifications. We uncovered strong evidence in support of this tRNA global regulation hypothesis by examining effects of the well-conserved tRNA modifying enzyme MiaA in extraintestinal pathogenic Escherichia coli (ExPEC), a major cause of urinary tract and bloodstream infections. MiaA mediates the prenylation of adenosine-37 within tRNAs that decode UNN codons, and we found it to be crucial to the fitness and virulence of ExPEC. MiaA levels shifted in response to stress via a post-transcriptional mechanism, resulting in marked changes in the amounts of fully modified MiaA substrates. Both ablation and forced overproduction of MiaA stimulated translational frameshifting and profoundly altered the ExPEC proteome, with variable effects attributable to UNN content, changes in the catalytic activity of MiaA, or availability of metabolic precursors. Cumulatively, these data indicate that balanced input from MiaA is critical for optimizing cellular responses, with MiaA acting much like a rheostat that can be used to realign global protein expression patterns.

Leibniz-HKI-Autor*innen

Amelia Barber
Matthew Blango

Identifier

doi: 10.1093/nar/gkac116

PMID: 35212379