RT Journal Article
SR Electronic
T1 Translational control through differential ribosome pausing during amino acid limitation in mammalian cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 321448
DO 10.1101/321448
A1 Alicia M. Darnell
A1 Arvind R. Subramaniam
A1 Erin K. O’Shea
YR 2018
UL http://biorxiv.org/content/early/2018/05/14/321448.abstract
AB Limitation for amino acids is thought to regulate translation in mammalian cells primarily by signaling through the kinases mTORC1 and GCN2. We find that limitation for the amino acid arginine causes a selective loss of tRNA charging, which regulates translation through ribosome pausing at two of six arginine codons. Surprisingly, limitation for leucine, an essential and abundant amino acid in protein, results in little or no ribosome pausing. Chemical and genetic perturbation of mTORC1 and GCN2 signaling revealed that their robust response to leucine limitation prevents ribosome pausing, while an insufficient response to arginine limitation led to loss of arginine tRNA charging and ribosome pausing. Codon-specific ribosome pausing decreased protein production and triggered premature ribosome termination without significantly reducing mRNA levels. Together, our results suggest that amino acids which are not optimally sensed by the mTORC1 and GCN2 pathways still regulate translation through an evolutionarily conserved mechanism based on codon-specific ribosome pausing.