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

40 Pages Posted: 30 Jun 2020 Publication Status: Review Complete

See all articles by Alba Corman

Alba Corman

Karolinska Institutet - Division of Genome Biology

Dimitris C. Kanellis

Karolinska Institutet - Division of Genome Biology

Maria Häggblad

Karolinska Institutet - Division of Genome Biology

Vanesa Lafarga

Spanish National Cancer Research Centre (CNIO) - Genomic Instability Group

Jiri Bartek

Karolinska Institutet - Division of Genome Biology

Jordi Carreras-Puigvert

Karolinska Institutet - Division of Genome Biology

Oscar Fernandez-Capetillo

Karolinska Institutet - Division of Genome Biology

More...

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

Suggested Citation

Corman, Alba and Kanellis, Dimitris C. and Häggblad, Maria and Lafarga, Vanesa and Bartek, Jiri and Carreras-Puigvert, Jordi and Fernandez-Capetillo, Oscar, A Chemical Screen Identifies a Link between Lipid Metabolism and mRNA Translation. Available at SSRN: https://ssrn.com/abstract=3624440 or http://dx.doi.org/10.2139/ssrn.3624440
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Alba Corman

Karolinska Institutet - Division of Genome Biology ( email )

Sweden

Dimitris C. Kanellis

Karolinska Institutet - Division of Genome Biology

Sweden

Maria Häggblad

Karolinska Institutet - Division of Genome Biology

Sweden

Vanesa Lafarga

Spanish National Cancer Research Centre (CNIO) - Genomic Instability Group

Madrid, 28029
Spain

Jiri Bartek

Karolinska Institutet - Division of Genome Biology

Sweden

Jordi Carreras-Puigvert

Karolinska Institutet - Division of Genome Biology

Sweden

Oscar Fernandez-Capetillo (Contact Author)

Karolinska Institutet - Division of Genome Biology ( email )

Sweden

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