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.
Highlights
Mycobacterium tuberculosis readily adapts to survive a wide range of assaults by modifying its physiology and establishing a latent tuberculosis (TB) infection
We report the molecular mechanism of toxin MazF-mt[9], which demonstrates that tRNA-cleaving M. tuberculosis toxins do not necessarily act by inhibiting translation, it illuminates a sophisticated mode of transcriptome recalibration and proteome reprogramming through highly selective ribosome stalling
TRNA was identified as the primary target of MazFmt9—the first MazF toxin to exhibit a preference for tRNA—but we had not expressed this toxin in M. tuberculosis cells to identify the true target in vivo
Summary
Mycobacterium tuberculosis readily adapts to survive a wide range of assaults by modifying its physiology and establishing a latent tuberculosis (TB) infection. 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-mt[9], exclusively inactivates one isoacceptor tRNA, tRNALys43-UUU, through cleavage at a single site within its anticodon (UU↓U). 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. We report the molecular mechanism of toxin MazF-mt[9], which demonstrates that tRNA-cleaving M. tuberculosis toxins do not necessarily act by inhibiting translation, it illuminates a sophisticated mode of transcriptome recalibration and proteome reprogramming through highly selective ribosome stalling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
