In skeletal muscle, the essential amino acids play key roles in regulating protein synthesis. Furthermore, the branched-chain amino acids, and in particular leucine, have been shown to regulate protein synthesis through changes in translation initiation. In the present study, the mechanism through which leucine and histidine regulate initiation was examined using L6 myoblasts as a model system. It was found that both amino acids stimulated initiation. Furthermore, both amino acids stimulated the guanine nucleotide exchange activity of eukaryotic initiation factor eIF2B. The changes in etF2B activity could be in part, but not completely, accounted for by modulation of the phosphorylation state of the c-subunit of its substrate, eIF2. Leucine, but not histidine, additionally caused a redistribution of eIF4E from the inactive eIF4E/4E-BP1 complex to the active eIF4E/eIF4G complex. The redistribution was a result of increased phosphorylation of 4E-BP1 which was associated with activation of the p70S6k signal transduction pathway. Insulin prevented the leucine-induced changes in 4E-BP1 phosphorylation as well as the redistribution of eIF4E without affecting changes in protein synthesis. Overall, the results suggest that amino acids regulate global protein synthesis through changes in the activity of eIF2B and that: the alterations in eIF4E availability caused by leucine may be involved in regulating the translation of specific mRNAs. Supported by NIH Grants DK13499 and I)K15658.
|Published - Dec 1 1998
All Science Journal Classification (ASJC) codes
- Molecular Biology