A translational program that suppresses metabolism to shield the genome

Nathan C. Balukoff, J. J. David Ho, Phaedra R. Theodoridis, Miling Wang, Michael Bokros, Lis M. Llanio, Jonathan R. Krieger, Jonathan H. Schatz and Stephen Lee ()
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Nathan C. Balukoff: University of Miami
J. J. David Ho: University of Miami
Phaedra R. Theodoridis: University of Miami
Miling Wang: University of Miami
Michael Bokros: University of Miami
Lis M. Llanio: University of Miami
Jonathan R. Krieger: The Hospital for Sick Children
Jonathan H. Schatz: University of Miami
Stephen Lee: University of Miami

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Translatome reprogramming is a primary determinant of protein levels during stimuli adaptation. This raises the question: what are the translatome remodelers that reprogram protein output to activate biochemical adaptations. Here, we identify a translational pathway that represses metabolism to safeguard genome integrity. A system-wide MATRIX survey identified the ancient eIF5A as a pH-regulated translation factor that responds to fermentation-induced acidosis. TMT-pulse-SILAC analysis identified several pH-dependent proteins, including the mTORC1 suppressor Tsc2 and the longevity regulator Sirt1. Sirt1 operates as a pH-sensor that deacetylates nuclear eIF5A during anaerobiosis, enabling the cytoplasmic export of eIF5A/Tsc2 mRNA complexes for translational engagement. Tsc2 induction inhibits mTORC1 to suppress cellular metabolism and prevent acidosis-induced DNA damage. Depletion of eIF5A or Tsc2 leads to metabolic re-initiation and proliferation, but at the expense of incurring substantial DNA damage. We suggest that eIF5A operates as a translatome remodeler that suppresses metabolism to shield the genome.

Date: 2020
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DOI: 10.1038/s41467-020-19602-2

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