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Translational reprogramming in cellular stress response

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Cell survival in changing environments requires appropriate regulation of gene expression, including translational control. Multiple stress signaling pathways converge on several key translation factors, such as eIF4F and eIF2, and rapidly modulate messenger RNA (mRNA) translation at both the initiation and the elongation stages. Repression of global protein synthesis is often accompanied with selective translation of mRNAs encoding proteins that are vital for cell survival and stress recovery. The past decade has seen significant progress in our understanding of translational reprogramming in part due to the development of technologies that allow the dissection of the interplay between mRNA elements and corresponding binding proteins. Recent genome‐wide studies using ribosome profiling have revealed unprecedented proteome complexity and flexibility through alternative translation, raising intriguing questions about stress‐induced translational reprogramming. Many surprises emerged from these studies, including wide‐spread alternative translation initiation, ribosome pausing during elongation, and reversible modification of mRNAs. Elucidation of the regulatory mechanisms underlying translational reprogramming will ultimately lead to the development of novel therapeutic strategies for human diseases. This article is categorized under: Translation > Translation Mechanisms Translation > Translation Regulation

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Multiple stress signals converge on initiation factors and inhibit global protein synthesis. Cap‐dependent translation initiation requires cap binding, eIF4F complex assembly (light grey square), and ternary complex formation (light yellow square). Nutrient signaling mTORC1 controls eIF4F complex formation by phosphorylating 4EBP, which releases eIF4E for cap binding. Nutrient starvation not only inhibits the mTORC1 signaling pathway, but also triggers GCN2 kinase activity. GCN2 phosphorylates eIF2α that inhibits ternary complex formation. In addition to the GCN2 kinase, other kinases integrate many stress conditions by phosphorylating eIF2α, forming an integrated stress response targeting translation initiation.
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Types of cis‐sequence elements that contribute to translational regulation. mRNA contains multiple start codons (green triangle) and stop codons (black triangle), generating ORFs in‐frame (blue box) or out‐of‐frame (cyan box). Secondary structures are present in 5′UTR and/or 3′UTR, with or without interacting proteins. Reversible mRNA modification could also regulate translational reprogramming in response to stress conditions.
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Translational regulation by tRNA modification. tRNA contains many modified nucleobases. Anticodon modification influences decoding processes and the overall translation capacity. Oxidative stress has multiple effects on tRNA metabolism, including m5C at the wobble position, tRNA misacylation, and tRNA cleavage. In addition, metabolic homeostasis such as sulfur amino acid levels regulates tRNA thiolation at the wobble position. These tRNA modifications trigger translational reprogramming in response to stress conditions.
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Translational regulation at the elongation stage. Nutrient starvation inhibits mTORC1 and activates eEF2K, which inhibits translation elongation by blocking the function of eEF2. Starvation also activates AMPK that promotes the activation of eEF2K, resulting in elongation inhibition. Many stressors could affect the activity of eEF1, although the underlying mechanism is not completely understood. In addition, ribosome‐associated chaperones regulate translation elongation, enabling cells to modulate translational capacity in response to proteotoxic stress.
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