Systemic remodeling of translation efficiencies on oxygen stimulus.

Protein concentrations evolve under greater evolutionary constraint than mRNA levels. In addition, translation efficiency of mRNA populations represents the chief determinant of basal protein concentrations. This raises a fundamental question as to how mRNA and protein levels are actively coordinated in dynamic systems responding to acute physiological stimuli. This report examines the contributions of mRNA abundance and translation efficiency to protein output in cells responding to oxygen stimulus. We show that alternative translation efficiencies, not mRNA levels, represent the major adaptive mechanism that governs the cellular response to perturbations in [O2]. This phenomenon is coordinated by eIF4F under atmospheric [O2] and the previously uncharacterized hypoxic eIF4F (eIF4FH) under low [O2]. The oxygen-regulated remodeling of translation efficiency enables oxygenated and hypoxic cells to produce surprisingly divergent translatomes of similar complexity, with minimal dependence on mRNA levels. Changes in mRNA concentrations observed between normoxic and hypoxic cells are likely neutral, as they are during evolution. We propose that mRNAs contain hard-wired translation efficiency determinants for their triage by the translation apparatus on [O2] stimulus.