Toxin-mediated ribosome stalling reprograms the Mycobacterium tuberculosis proteome

Valdir C. Barth, Ju-Mei Zeng, Irina O. Vvedenskaya, Ming Ouyang, Robert N. Husson and Nancy A. Woychik ()
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Valdir C. Barth: Rutgers University, Robert Wood Johnson Medical School
Ju-Mei Zeng: Boston Children’s Hospital and Harvard Medical School
Irina O. Vvedenskaya: Rutgers University
Ming Ouyang: University of Massachusetts-Boston
Robert N. Husson: Boston Children’s Hospital and Harvard Medical School
Nancy A. Woychik: Rutgers University, Robert Wood Johnson Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract Mycobacterium tuberculosis readily adapts to survive a wide range of assaults by modifying its physiology and establishing a latent tuberculosis (TB) infection. Here we report a sophisticated mode of regulation by a tRNA-cleaving toxin that enlists highly selective ribosome stalling to recalibrate the transcriptome and remodel the proteome. This toxin, MazF-mt9, exclusively inactivates one isoacceptor tRNA, tRNALys43-UUU, through cleavage at a single site within its anticodon (UU↓U). Because wobble rules preclude compensation for loss of tRNALys43-UUU by the second M. tuberculosis lysine tRNA, tRNALys19-CUU, ribosome stalling occurs at in-frame cognate AAA Lys codons. Consequently, the transcripts harboring these stalled ribosomes are selectively cleaved by specific RNases, leading to their preferential deletion. This surgically altered transcriptome generates concomitant changes to the proteome, skewing synthesis of newly synthesized proteins away from those rich in AAA Lys codons toward those harboring few or no AAA codons. This toxin-mediated proteome reprogramming may work in tandem with other pathways to facilitate M. tuberculosis stress survival.

Date: 2019
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DOI: 10.1038/s41467-019-10869-8

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