scholarly journals Evolutionarily divergent mTOR remodels the translatome to drive rapid wound closure and regeneration

2021 ◽  
Author(s):  
Olena Zhulyn ◽  
Hannah Dorothy Rosenblatt ◽  
Leila Shokat ◽  
Shizhong A Dai ◽  
Duygu Kuzuoglu-Öztürk ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Sequence ◽  
Wound Closure ◽  
Limb Regeneration ◽  
Nutrient Sensing ◽  
Evolutionarily Conserved ◽  
Mtorc1 Pathway ◽  
Mtor Protein ◽  
Rapid Activation ◽  
Labile State

An outstanding mystery in biology is why some species, such as the axolotl, can scarlessly heal and regenerate tissues while most mammals cannot. Here, we demonstrate that rapid activation of protein synthesis is a unique, and previously uncharacterized, feature of the injury response critical for limb regeneration in the axolotl (A. mexicanum). By applying polysome sequencing, we identify hundreds of transcripts, including antioxidants and ribosome components, which do not change in their overall mRNA abundance but are selectively activated at the level of translation from pre-existing mRNAs in response to injury. In contrast, we show that protein synthesis is not activated in response to digit amputation in the non-regenerative mouse. We further identify the mTORC1 pathway as a key upstream signal that mediates this regenerative translation response in the axolotl. Inhibition of this pathway is sufficient to suppress translation and axolotl regeneration. Surprisingly, although mTOR is highly evolutionarily conserved, we discover unappreciated expansions in mTOR protein sequence among urodele amphibians. By engineering an axolotl mTOR in human cells, we demonstrate that this change creates a hypersensitive kinase that may allow axolotls to maintain this pathway in a highly labile state primed for rapid activation. This may underlie metabolic differences and nutrient sensing between regenerative and non-regenerative species that are key to regeneration. Together, these findings highlight the unanticipated impact of the translatome on orchestrating the early steps of wound healing in highly regenerative species and provide a missing link in our understanding of vertebrate regenerative potential.

The rapid activation of protein synthesis by growth hormone requires signaling through mTOR

2007 ◽  
Vol 292 (6) ◽  
pp. E1647-E1655 ◽  
Author(s):  
Amanda A. Hayashi ◽  
Christopher G. Proud
Keyword(s):  
Growth Hormone ◽  
Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Elongation Factor ◽  
Tissue Growth ◽  
Mtor Signaling ◽  
Gh Treatment ◽  
Translational Machinery ◽  
Upstream Regulator ◽  
Rapid Activation

An important function of growth hormone (GH) is to promote cell and tissue growth, and a key component of these effects is the stimulation of protein synthesis. In this study, we demonstrate that, in H4IIE hepatoma cells, GH acutely activated protein synthesis through signaling via the mammalian target of rapamycin (mTOR) and specifically through the rapamycin-sensitive mTOR complex 1 (mTORC1). GH treatment enhanced the phosphorylation of two targets of mTOR signaling, 4E-BP1 and ribosomal protein S6. Phosphorylation of S6 and 4E-BP1 was maximal at 30–45 min and 10–20 min after GH stimulation, respectively. Both proteins modulate components of the translational machinery. The GH-induced phosphorylation of 4E-BP1 led to its dissociation from eIF4E and increased binding of eIF4E to eIF4G to form (active) eIF4F complexes. The ability of GH to stimulate the phosphorylation of S6 and 4E-BP1 was blocked by rapamycin. GH also led to the dephosphorylation of a third translational component linked to mTORC1, the elongation factor eEF2. Its regulation followed complex biphasic kinetics, both phases of which required mTOR signaling. GH rapidly activated both the MAP kinase (ERK) and PI 3-kinase pathways. Signaling through PI 3-kinase alone was, however, sufficient to activate the downstream mTORC1 pathway. Consistent with this, GH increased the phosphorylation of TSC2, an upstream regulator of mTORC1, at sites that are targets for Akt/PKB. Finally, the activation of overall protein synthesis by GH in H4IIE cells was essentially completely inhibited by wortmannin or rapamycin. These results demonstrate for the first time that mTORC1 plays a major role in the rapid activation of protein synthesis by GH.

scholarly journals Anabolic Function Downstream of TOR Controls Trade-offs Between Longevity and Reproduction at the Level of Specific Tissues in C. elegans

2021 ◽  
Vol 2 ◽  
Author(s):  
Amber C. Howard ◽  
Dilawar Mir ◽  
Santina Snow ◽  
Jordan Horrocks ◽  
Hussein Sayed ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Energy Expenditure ◽  
Dietary Restriction ◽  
Nutrient Sensing ◽  
Whole Body ◽  
C Elegans ◽  
Positive Effects ◽  
Body Muscle ◽  
Trade Offs ◽  
Different Tissues

As the most energetically expensive cellular process, translation must be finely tuned to environmental conditions. Dietary restriction attenuates signaling through the nutrient sensing mTOR pathway, which reduces translation and redirects resources to preserve the soma. These responses are associated with increased lifespan but also anabolic impairment, phenotypes also observed when translation is genetically suppressed. Here, we restricted translation downstream of mTOR separately in major tissues in C. elegans to better understand their roles in systemic adaptation and whether consequences to anabolic impairment were separable from positive effects on lifespan. Lowering translation in neurons, hypodermis, or germline tissue led to increased lifespan under well-fed conditions and improved survival upon withdrawal of food, indicating that these are key tissues coordinating enhanced survival when protein synthesis is reduced. Surprisingly, lowering translation in body muscle during development shortened lifespan while accelerating and increasing reproduction, a reversal of phenotypic trade-offs associated with systemic translation suppression. Suppressing mTORC1 selectively in body muscle also increased reproduction while slowing motility during development. In nature, this may be indicative of reduced energy expenditure related to foraging, acting as a “GO!” signal for reproduction. Together, results indicate that low translation in different tissues helps direct distinct systemic adaptations and suggest that unknown endocrine signals mediate these responses. Furthermore, mTOR or translation inhibitory therapeutics that target specific tissues may achieve desired interventions to aging without loss of whole-body anabolism.

Nutrient sensing systems for rapid activation of the protein kinase A pathway in yeast

2005 ◽  
Vol 33 (1) ◽  
pp. 253-256 ◽  
Author(s):  
J.M. Thevelein ◽  
R. Geladé ◽  
I. Holsbeeks ◽  
O. Lagatie ◽  
Y. Popova ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Point Mutations ◽  
Nutrient Sensing ◽  
Amino Acid Permease ◽  
Yeast Saccharomyces Cerevisiae ◽  
Receptor System ◽  
Pka Pathway ◽  
Rapid Activation ◽  
Kinase A

The cAMP-protein kinase A (PKA) pathway in the yeast Saccharomyces cerevisiae controls a variety of properties that depend on the nutrient composition of the medium. High activity of the pathway occurs in the presence of rapidly fermented sugars like glucose or sucrose, but only as long as growth is maintained. Growth arrest of fermenting cells or growth on a respirative carbon source, like glycerol or ethanol, is associated with low activity of the PKA pathway. We have studied how different nutrients trigger rapid activation of the pathway. Glucose and sucrose activate cAMP synthesis through a G-protein-coupled receptor system, consisting of the GPCR Gpr1, the Gα protein Gpa2 and its RGS protein Rgs2. Glucose is also sensed intracellularly through its phosphorylation. Specific mutations in Gpr1 abolish glucose but not sucrose signalling. Activation of the PKA pathway by addition of a nitrogen source or phosphate to nitrogen- or phosphate-starved cells, respectively, is not mediated by an increase in cAMP. Activation by amino acids is triggered by the general amino acid permease Gap1, which functions as a transporter/receptor. Short truncation of the C-terminus results in constitutively activating alleles. Activation by ammonium uses the ammonium permeases Mep1 and Mep2 as receptor. Specific point mutations in Mep2 uncouple signalling from transport. Activation by phosphate is triggered a.o. by the Pho84 phosphate permease. Several mutations in Pho84 separating transport and signalling or triggering constitutive activation have been obtained.

scholarly journals The general mRNA exporters Mex67 and Mtr2 play distinct roles in nuclear export of tRNAs in Trypanosoma brucei

2019 ◽  
Vol 47 (16) ◽  
pp. 8620-8631
Author(s):  
Eva Hegedűsová ◽  
Sneha Kulkarni ◽  
Brandon Burgman ◽  
Juan D Alfonzo ◽  
Zdeněk Paris
Keyword(s):  
Protein Synthesis ◽  
Trypanosoma Brucei ◽  
Nuclear Export ◽  
Nuclear Accumulation ◽  
Down Regulation ◽  
Regulation Of Expression ◽  
Alternative Pathways ◽  
Transport Receptors ◽  
Evolutionarily Conserved ◽  
Family Based

Abstract Transfer RNAs (tRNAs) are central players in protein synthesis, which in Eukarya need to be delivered from the nucleus to the cytoplasm by specific transport receptors, most of which belong to the evolutionarily conserved beta-importin family. Based on the available literature, we identified two candidates, Xpo-t and Xpo-5 for tRNA export in Trypanosoma brucei. However, down-regulation of expression of these genes did not disrupt the export of tRNAs to the cytoplasm. In search of alternative pathways, we tested the mRNA export complex Mex67-Mtr2, for a role in tRNA nuclear export, as described previously in yeast. Down-regulation of either exporter affected the subcellular distribution of tRNAs. However, contrary to yeast, TbMex67 and TbMtr2 accumulated different subsets of tRNAs in the nucleus. While TbMtr2 perturbed the export of all the tRNAs tested, silencing of TbMex67, led to the nuclear accumulation of tRNAs that are typically modified with queuosine. In turn, inhibition of tRNA nuclear export also affected the levels of queuosine modification in tRNAs. Taken together, the results presented demonstrate the dynamic nature of tRNA trafficking in T. brucei and its potential impact not only on the availability of tRNAs for protein synthesis but also on their modification status.

scholarly journals Targeting influenza at the Topologically conserved substructures

2021 ◽  
pp. 121-129
Author(s):  
Zubair Ahamed ◽  
Vandana Kamjula ◽  
Bhuvaneswari Kakunuri
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Protein Sequence ◽  
Asian Countries ◽  
Topological Map ◽  
H9n2 Avian Influenza Virus ◽  
Evolutionarily Conserved ◽  
Potent Drug ◽  
Endemic Strain

H9N2 avian influenza virus is a low pathogenic endemic strain in the domestic poultry of most of the Asian countries. Attempts have extensively failed in eradicating its diverse strains. To find the drug against the evolutionarily conserved substructures, the target protein sequence is analyzed through sequence and modelled structure for mapping the structurally conserved topology. The available drugs are screened against the deciphered topological map through the predicted ADMET and drug-likelihood scores. This study helps to build a theoretical framework to make the foremost potent drug.

scholarly journals A conserved strategy for inducing appendage regeneration in moon jellyfish, Drosophila, and mice

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Michael J Abrams ◽  
Fayth Hui Tan ◽  
Yutian Li ◽  
Ty Basinger ◽  
Martin L Heithe ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Amino Acid ◽  
Limb Regeneration ◽  
Testable Hypothesis ◽  
The Moon ◽  
Moon Jellyfish ◽  
Nutrient Supplementation ◽  
Adult Mice ◽  
Evolutionarily Conserved ◽  
Animal Phylogeny

Can limb regeneration be induced? Few have pursued this question, and an evolutionarily conserved strategy has yet to emerge. This study reports a strategy for inducing regenerative response in appendages, which works across three species that span the animal phylogeny. In Cnidaria, the frequency of appendage regeneration in the moon jellyfish Aurelia was increased by feeding with the amino acid L-leucine and the growth hormone insulin. In insects, the same strategy induced tibia regeneration in adult Drosophila. Finally, in mammals, L-leucine and sucrose administration induced digit regeneration in adult mice, including dramatically from mid-phalangeal amputation. The conserved effect of L-leucine and insulin/sugar suggests a key role for energetic parameters in regeneration induction. The simplicity by which nutrient supplementation can induce appendage regeneration provides a testable hypothesis across animals.

scholarly journals A lipid-mTORC1 nutrient-sensing pathway regulates animal development by peroxisome-derived hormones

2021 ◽  
Author(s):  
Na Li ◽  
Beilei Hua ◽  
qing chen ◽  
Meiyu Ruan ◽  
Mengnan ZHU ◽  
...  
Keyword(s):  
Large Scale ◽  
Amino Acid Level ◽  
Nutrient Sensing ◽  
Whole Body ◽  
Apical Region ◽  
Beta Oxidation ◽  
Dependent Development ◽  
Animal Development ◽  
Signaling Mechanisms ◽  
Mtorc1 Pathway

Animals have developed many signaling mechanisms that alter cellular and developmental programs in response to changes in nutrients and their derived metabolites, many of which remain to be understood. We recently uncovered that glucosylceramides, a core sphingolipid, act as a critical nutrient signal for overall amino-acid level to promote development by activating the intestinal mTORC1 pathway. However, how the intestinal GlcCer-mTORC1 activity regulates development throughout the whole body is unknown. Through a large-scale genetic screen, we found that the peroxisomes are critical for antagonizing the GlcCer-mTORC1-mediated nutrient signal. Mechanistically, deficiency of glucosylceramide, inactivation of the downstream mTORC1 activity, or prolonged starvation relocated peroxisomes closer to the intestinal apical region to release peroxisomal-beta-oxidation derived hormones that targeting chemosensory neurons to arrest the animal development. Our data illustrated a new gut-brain axis for orchestrating nutrient-sensing dependent development in Caenorhabditis elegans, which may also explain why glucosylceramide and peroxisome become essential in metazoans.

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