Mechanisms of translational control in liver and skeletal muscle

The initiation of peptide chains on ribosomes represents the first step in translation and is a dominant control point for regulation of protein synthesis in mammalian cells. An inhibition of peptide-chain initiation occurs in both rat liver treated with calcium-mobilizing hormones and in rat skeletal muscle in response to the isulin deprivation associated with diabetes mellitus or fasting. The inhibition of peptide-chain initiation in both tissues is accompanied by a shift in polysomal aggregation toward an accumulation of free ribosomal particles and a reduction in formation of 43S preinitiation complexes. Furthermore, in both tissues, the inhibition involves a reduction in the activity of a protein termed eukaryotic initiation factor (eIF)-2B. However, the mechanisms involved in the reduction in eIF-2B activity, and thus protein synthesis, in the two tissues under these conditions appear to be distinct. In liver treated with calcium-mobilizing hormones, the reduction in eIF-2B activity is the result of an increase in the phosphorylation state of the α-subunit of a second initiation factor, eIF-2. In contrast, the inhibition of initiation that occurs in skeletal muscle deprived of insulin is not due to a change in the phosphorylation state of eIF-2α. Instead, the activity of eIF-2B may be directly modulated in response to insulin. Studies by others have shown that the ε-subunit of eIF-2B is a substrate for at least three different protein kinases and that phosphorylation by at least one of these kinases stimulates the activity of the factor in in vitro assays. Recent studies in our laboratory have shown that eIF-2Bε kinase activity in extracts of skeletal muscle is elevated during diabetes and is reduced to below control values within 2 h of insulin treatment of diabetic rats. Furthermore, at least two different eIF-2Bε kinases are present in muscle extracts and the two kinases are differentially regulated by insulin. Thus, one kinase exhibits reduced activity following insulin treatment of diabetic rats and the other is stimulated. Current efforts are aimed at purifying and characterizing the two eIF-2Bε kinases.