Translation initiation: variations in the mechanism can be anticipated

Malys, Naglis; McCarthy, John E.G.

doi:10.1007/s00018-010-0588-z

Cited by 88 publications

(80 citation statements)

References 137 publications

(197 reference statements)

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“…The mechanisms responsible for selective mRNA translation are not well understood but are under intense study. Recent work suggests that translation of 10 -15% of all mRNAs can occur via cap-independent mechanisms that utilize specialized mRNA structural elements such as internal ribosome entry sites (31,41). Transcript length may also play an important role in selective mRNA translation under conditions that inhibit protein synthesis (35).…”

Section: Discussionmentioning

confidence: 99%

GCN-2 dependent inhibition of protein synthesis activates osmosensitive gene transcription via WNK and Ste20 kinase signaling

Lee

Strange

2012

American Journal of Physiology-Cell Physiology

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Lee EC, Strange K. GCN-2 dependent inhibition of protein synthesis activates osmosensitive gene transcription via WNK and Ste20 kinase signaling. Am J Physiol Cell Physiol 303: C1269 -C1277, 2012. First published October 17, 2012; doi:10.1152/ajpcell.00294.2012.-Increased gpdh-1 transcription is required for accumulation of the organic osmolyte glycerol and survival of Caenorhabditis elegans during hypertonic stress. Our previous work has shown that regulators of gpdh-1 (rgpd) gene knockdown constitutively activates gpdh-1 expression. Fifty-five rgpd genes play essential roles in translation suggesting that inhibition of protein synthesis is an important signal for regulating osmoprotective gene transcription. We demonstrate here that translation is reduced dramatically by hypertonic stress or knockdown of rgpd genes encoding aminoacyl-tRNA synthetases and eukaryotic translation initiation factors (eIFs). Toxin-induced inhibition of translation also activates gpdh-1 expression. Hypertonicityinduced translation inhibition is mediated by general control nonderepressible (GCN)-2 kinase signaling and eIF-2␣ phosphoryation. Loss of gcn-1 or gcn-2 function prevents eIF-2␣ phosphorylation, completely blocks reductions in translation, and inhibits gpdh-1 transcription. gpdh-1 expression is regulated by the highly conserved with-no-lysine kinase (WNK) and Ste20 kinases WNK-1 and GCK-3, which function in the GCN-2 signaling pathway downstream from eIF-2␣ phosphorylation. Our previous work has shown that hypertonic stress causes rapid and dramatic protein damage in C. elegans and that inhibition of translation reduces this damage. The current studies demonstrate that reduced translation also serves as an essential signal for activation of WNK-1/GCK-3 kinase signaling and subsequent transcription of gpdh-1 and possibly other osmoprotective genes.C. elegans; organic osmolytes; hypertonic stress; osmoregulation MAINTENANCE OF CELLULAR AND extracellular water balance is essential for life. All cells are exposed to osmotic stress from changes in intracellular solute levels that occur during normal fluctuations in metabolism and membrane solute flux. Countless diverse organisms live in osmotically unstable environments and are exposed to extreme changes in extracellular osmolality. Mammalian cells are largely protected from extracellular osmotic perturbations by the kidney, which tightly regulates blood ionic and osmotic concentrations. However, cells in the renal medulla and gut are subjected normally to large osmotic challenges due to the renal concentrating mechanism and changes in fluid and food intake. In addition, several disorders, such as renal failure, diabetes, syndrome of inappropriate antidiuretic hormone secretion, and hypernatremia, disrupt plasma osmolality, and hypertonic solutions are used widely to treat diverse clinical problems such as intracranial hypertension and hemorrhagic shock. Cellular osmotic homeostasis requires the regulated gain or loss of solutes and activation of mechanisms that repair or remove ...

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Section: Discussionmentioning

confidence: 99%

GCN-2 dependent inhibition of protein synthesis activates osmosensitive gene transcription via WNK and Ste20 kinase signaling

Lee

Strange

2012

American Journal of Physiology-Cell Physiology

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“…Additionally, ribosome contacts that identify the start codon for LL mRNA may also be important for SDL mRNAs, but their importance has been overshadowed by the SD-ASD interaction. Leaderless mRNA studies are likely to be relevant to all translation systems, since all domains (Bacteria, Eukarya, and Archaea) contain and are able to express leaderless mRNAs (Janssen 1993;Malys and McCarthy 2010). Additional analysis of the mechanisms by which leaderless mRNAs recognize and bind ribosomes will contribute to our understanding of mRNA-ribosome interactions, ribosome structure-function, and possibly reveal novel mechanisms of translational control.…”

Section: Final Remarksmentioning

confidence: 99%

A 5′-terminal phosphate is required for stable ternary complex formation and translation of leaderless mRNA in Escherichia coli

Giliberti¹,

O’Donnell²,

Etten³

et al. 2012

RNA

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The bacteriophage l's cI mRNA was utilized to examine the importance of the 59-terminal phosphate on expression of leadered and leaderless mRNA in Escherichia coli. A hammerhead ribozyme was used to produce leadered and leaderless mRNAs, in vivo and in vitro, that contain a 59-hydroxyl. Although these mRNAs may not occur naturally in the bacterial cell, they allow for the study of the importance of the 59-phosphorylation state in ribosome binding and translation of leadered and leaderless mRNAs. Analyses with mRNAs containing either a 59-phosphate or a 59-hydroxyl indicate that leaderless cI mRNA requires a 59-phosphate for stable ribosome binding in vitro as well as expression in vivo. Ribosome-binding assays show that 30S subunits and 70S ribosomes do not bind as strongly to 59-hydroxyl as they do to 59-phosphate containing leaderless mRNA and the tRNAdependent ternary complex is less stable. Additionally, filter-binding assays revealed that the 70S ternary complex formed with a leaderless mRNA containing a 59-hydroxyl has a dissociation rate (k off ) that is 4.5-fold higher compared with the complex formed with a 59-phosphate leaderless mRNA. Fusion to a lacZ reporter gene revealed that leaderless cI mRNA expression with a 59-hydroxyl was >100-fold lower than the equivalent mRNA with a 59-phosphate. These data indicate that a 59-phosphate is an important feature of leaderless mRNA for stable ribosome binding and expression.

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“…ribosomes), and consequently, the entire process is under tight control (Acker & Lorsch 2008;Malys & McCarthy 2011). mTOR, primarily mTORC1, is involved in different aspects of protein synthesis (Ma & Blenis 2009;Sonenberg & Hinnebusch 2009).…”

Section: Protein Synthesis and Maturationmentioning

confidence: 99%