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Nat Commun. 2019 Jul 10;10(1):3035. doi: 10.1038/s41467-019-10869-8.

Toxin-mediated ribosome stalling reprograms the Mycobacterium tuberculosis proteome.

Author information

1
Department of Biochemistry and Molecular Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.
2
Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
3
Waksman Institute, Rutgers University, Piscataway, NJ, 08854, USA.
4
Department of Genetics, Rutgers University, Piscataway, NJ, 08854, USA.
5
University of Massachusetts-Boston, 100 William T Morrissey Blvd, Boston, MA, 02125, USA.
6
Department of Biochemistry and Molecular Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA. nancy.woychik@rutgers.edu.
7
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. nancy.woychik@rutgers.edu.

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.

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