Rapid remodeling of NTP levels enables immediate translational adaptation to energy stress in yeast

Bexley, K., Ristová, M., Sharma, S., Spanos, C., Chabes, A., and Tollervey, D. 

By Maya Rowley, Marston/Deegan Labs

Cells exist in constantly changing biochemical environments, necessitating sophisticated mechanisms that confer physiological adaptability. Such adaptability demands rapid detection of and responses to external cues such as availability of carbon sources. 

Many yeasts preferentially metabolise glucose via glycolysis for fast ATP generation, even in the presence of oxygen. Termed aerobic glycolysis, this strategy is also employed by activated immune cells and cancer cells (the Warburg effect).

Glucose depletion in yeast triggers mRNA translation to halt within minutes to conserve energy and begin metabolic remodeling. The Tollervey lab has previously shown this is mediated by the remarkably rapid (<30 seconds) removal of translation initiation factors eIF4B, eIF4A, and Ded1 from the 5’ ends of mRNA. This inhibits the initial stages of protein synthesis. The mechanism by which the cell detects declining glucose levels and transmutes this information into initiation factor detachment at such short timescales was unknown.

Here, Bexley et al. discover a regulatory mechanism for global translation shutdown upon glucose withdrawal in budding yeast that is dependent on differential NTP affinities. They find that translation initiation factors eIF4A, eIF4B, and Ded1 bind ATP with relatively low affinities, causing rapid release of mRNA upon NTP decline during glucose depletion. In contrast, the GTPase translation elongation factors remain bound to mRNA, due to their 3000-fold higher binding affinity for GTP. Thus, the differential affinity of translation initiation and elongation factors for their respective energy currencies allows ribosomes already engaged in translation to complete protein synthesis even as translation initiation is blocked. 

These findings demonstrate that NTPase binding affinities are finely tuned as sensors for energy stress and help coordinate rapid and selective translation shutdown. More generally, it establishes differential enzymatic binding affinities as an effective and nuanced mechanism for remodeling cellular processes in response to changing nutrient conditions. 

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