Protein Synthesis and Degradation
An RNA stem-loop functions in conjunction with an upstream open reading frame to direct preferential translation in the integrated stress response
In response to environmental stresses, cells invoke translational control to conserve resources and rapidly reprogram gene expression for optimal adaptation. A central mechanism for translational control involves phosphorylation of the α subunit of eIF2 (p-eIF2α), which reduces delivery of initiator tRNA to ribosomes. Because p-eIF2α is invoked by multiple protein kinases, each responding to distinct stresses, this pathway is named the integrated stress response (ISR). While p-eIF2α lowers bulk translation initiation, many stress-related mRNAs are preferentially translated.Translation Regulation of the Glutamyl-prolyl-tRNA Synthetase Gene EPRS through Bypass of Upstream Open Reading Frames with Noncanonical Initiation Codons
In the integrated stress response, phosphorylation of eIF2α (eIF2α-P) reduces protein synthesis while concomitantly promoting preferential translation of specific transcripts associated with stress adaptation. Translation of the glutamyl-prolyl-tRNA synthetase gene EPRS is enhanced in response to eIF2α-P. To identify the underlying mechanism of translation control, we employed biochemical approaches to determine the regulatory features by which upstream ORFs (uORFs) direct downstream translation control and expression of the EPRS coding region.Ribosome Reinitiation Directs Gene-specific Translation and Regulates the Integrated Stress Response
Background: eIF2α-P induced GADD34 and constitutively expressed CReP target PP1c to dephosphorylate eIF2α-P to dictate translation control of the ISR.Results: Differential expression of GADD34 and CReP is regulated by upstream ORF (uORF)-mediated ribosome reinitiation.Conclusion: uORFs regulate differential expression of GADD34 and CReP and are important for cell adaptation to stress.Significance: Regulation of eIF2α-P is central for protein homeostasis and cell viability.
