A translational program that suppresses metabolism to shield the genome.

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Balukoff NC,Ho JJD,Theodoridis PR,Wang M,Bokros M,Llanio LM,Krieger JR,Schatz JH,Lee S

doi

10.1038/s41467-020-19602-2

subject

Has Abstract

pub_date

2020-11-13 00:00:00

pages

5755

issue

1

issn

2041-1723

pii

10.1038/s41467-020-19602-2

journal_volume

11

pub_type

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