13 The Double-stranded RNA-activated Protein Kinase PKR

Abstract

Cells respond to environmental stress by immediate changes in their capacity and specificity to select mRNAs for translation. Most translational control occurs at the level of initiation. The rate of translation initiation depends on mRNA abundance, the number of ribosomes, the availability of initiator tRNA_i^Met, and the amount and activity of eukaryotic translation initiation factors (eIFs). Reversible covalent modification of these eIFs is a fundamental mechanism that determines the rate of initiation. One modification used for translational control in response to environmental stress is the reversible phosphorylation of eIF2. Phosphorylation of heterotrimeric eIF2 on the α subunit (eIF2α) rapidly reduces the level of functional eIF2 and limits initiation events on all cellular mRNAs within the cell. In higher eukaryotes, it is not known whether some mRNAs are selectively translated when eIF2 is inactivated by phosphorylation, as demonstrated for the Saccharomyces cerevisiae mRNA encoding GCN4 (see Chapter 5). Reversible phosphorylation of eIF2α provides the cell with an efficient, rapid, and reversible means to respond to a variety of different stimuli.

Initiation of polypeptide chain synthesis requires the recycling of eIF2 between GTP- and GDP-bound states in a reaction catalyzed by the guanine nucleotide exchange factor, eIF2B (for review, see Pain 1996; Chapters 2 and 5). Phosphorylation of eIF2α at residue Ser-51 stabilizes the eIF2/GDP/eIF2B complex and prevents the GDP–GTP exchange reaction. Because the cellular levels of eIF2B are lower than the levels of eIF2 (Oldfield et al. 1994), the exchange process is inhibited when only a fraction (i.e., 20–30%)...