A Chemical Screen Identifies a Link between Lipid Metabolism and mRNA Translation

Abstract

We here report our results on a chemical screen in which we evaluated how medically approved drugs, as well as drugs under development, influence translation. As expected, inhibitors of the mTOR signaling pathway were the most represented class among translation suppressors. In addition, we found that inhibitors of sphingosine kinases (SPHKs) also reduce translation levels independently of mTOR. Mechanistically this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum, which activates the integrated stress response (ISR). Interestingly, and despite the large number of molecules tested, our study failed to identify chemicals substantially increasing translation rates, raising doubts on to what extent translation can be supra-physiologically stimulated in mammalian cells. In summary, our study provides the first comprehensive characterization of the effect of known drugs on protein translation and has helped to unravel a new link between lipid metabolism and mRNA translation in human cells.

Keywords: Chemical Screen, Protein Translation, SKI-II, Sphingosine Kinases, Integrated Stress Response