scholarly journals UV damage induces G3BP1-dependent stress granule formation that is not driven by mTOR inhibition-mediated translation arrest

2020 ◽  
Vol 133 (20) ◽  
pp. jcs248310
Author(s):  
Shan Ying ◽  
Denys A. Khaperskyy
Keyword(s):  
Translation Initiation Factor ◽  
Cellular Stress Response ◽  
Initiation Factor ◽  
Major Type ◽  
Uv Damage ◽  
Mtor Inhibition ◽  
Granule Formation ◽  
Translation Arrest ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

ABSTRACTTranslation arrest is a part of the cellular stress response that decreases energy consumption and enables rapid reprioritisation of gene expression. Often translation arrest leads to condensation of untranslated messenger ribonucleoproteins (mRNPs) into stress granules (SGs). Studies into mechanisms of SG formation and functions are complicated because various types of stress cause formation of SGs with different properties and composition. In this work, we focused on the mechanism of SG formation triggered by UV damage. We demonstrate that UV-induced inhibition of translation does not involve inhibition of the mechanistic target of rapamycin (mTOR) signaling or dissociation of the 48S preinitiation complexes. The general control non-derepressible 2 (GCN2; also known as EIF2AK4) kinase contributes to UV-induced SG formation, which is independent of the phosphorylation of the eukaryotic translation initiation factor 2α. Like many other types of SGs, condensation of UV-induced granules requires the Ras-GTPase-activating protein SH3-domain-binding protein 1 (G3BP1). Our work reveals that, in UV-treated cells, the mechanisms of translation arrest and SG formation may be unlinked, resulting in SGs that do not contain the major type of polysome-free preinitiation complexes that accumulate in the cytoplasm.This article has an associated First Person interview with the first author of the paper.

scholarly journals UV damage induces G3BP1-dependent stress granule formation that is not driven by translation arrest via mTOR inhibition

2020 ◽  
Author(s):  
Shan Ying ◽  
Denys A. Khaperskyy
Keyword(s):  
Translation Initiation Factor ◽  
Cellular Stress Response ◽  
Initiation Factor ◽  
Major Type ◽  
Uv Damage ◽  
Mtor Inhibition ◽  
Granule Formation ◽  
Translation Arrest ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

ABSTRACTTranslation arrest is a part of the cellular stress response that decreases energy consumption and enables rapid reprioritisation of gene expression. Often translation arrest leads to condensation of untranslated messenger ribonucleoproteins (mRNPs) into stress granules (SGs). Studies into mechanisms of SG formation and functions are complicated because various types of stress cause formation of SGs with different properties and composition. In this work we focused on the mechanism of SG formation triggered by UV damage. We demonstrate that UV-induced inhibition of translation does not cause dissociation of the 48S preinitiation complexes. The catalytic activity of the general control non-derepressible 2 (GCN2) kinase contributes to UV-induced SG formation, which is independent of the GCN2-mediated phosphorylation of the eukaryotic translation initiation factor 2α. Like many other types of SGs, condensation of UV-induced granules specifically requires the Ras-GTPase-Activating Protein SH3-Domain-Binding Protein 1 (G3BP1). Our work reveals that in UV-treated cells the mechanisms of translation arrest and SG formation may be unlinked, resulting in condensation of ribonucleoproteins that do not represent the major type of polysome-free preinitiation complexes that accumulate in the cytoplasm.

scholarly journals Inhibition of Eukaryotic Translation Initiation Factor 5A (eIF5A) Hypusination Suppress p53 Translation and Alters the Association of eIF5A to the Ribosomes

2020 ◽  
Vol 21 (13) ◽  
pp. 4583 ◽  
Author(s):  
Marianna Martella ◽  
Caterina Catalanotto ◽  
Claudio Talora ◽  
Anna La Teana ◽  
Paola Londei ◽  
...  
Keyword(s):  
Translation Initiation ◽  
De Novo ◽  
P53 Protein ◽  
Translation Initiation Factor ◽  
Cellular Stress Response ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
P53 Expression ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

The eukaryotic translation initiation factor 5A (eIF5A) is an essential protein for the viability of the cells whose proposed function is to prevent the stalling of the ribosomes during translation elongation. eIF5A activity requires a unique and functionally essential post-translational modification, the change of a lysine to hypusine. eIF5A is recognized as a promoter of cell proliferation, but it has also been suggested to induce apoptosis. To date, the precise molecular mechanism through which eIF5A affects these processes remains elusive. In the present study, we explored whether eIF5A is involved in controlling the stress-induced expression of the key cellular regulator p53. Our results show that treatment of HCT-116 colon cancer cells with the deoxyhypusine (DHS) inhibitor N1-guanyl-1,7-diamineheptane (GC7) caused both inhibition of eIF5A hypusination and a significant reduction of p53 expression in UV-treated cells, and that eIF5A controls p53 expression at the level of protein synthesis. Furthermore, we show that treatment with GC7 followed by UV-induced stress counteracts the pro-apoptotic process triggered by p53 up-regulation. More in general, the importance of eIF5A in the cellular stress response is illustrated by the finding that exposure to UV light promotes the binding of eIF5A to the ribosomes, whereas UV treatment complemented by the presence of GC7 inhibits such binding, allowing a decrease of de novo synthesis of p53 protein.

scholarly journals Inhibition of Mammalian Target of Rapamycin Induces Phosphatidylinositol 3-Kinase-Dependent and Mnk-Mediated Eukaryotic Translation Initiation Factor 4E Phosphorylation

2007 ◽  
Vol 27 (21) ◽  
pp. 7405-7413 ◽  
Author(s):  
Xuerong Wang ◽  
Ping Yue ◽  
Chi-Bun Chan ◽  
Keqiang Ye ◽  
Takeshi Ueda ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mtor Signaling ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Mtor Inhibition ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

ABSTRACT The initiation factor eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in initiating translation of mRNAs, including those encoding oncogenic proteins. Therefore, eIF4E is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eIF4E (usually at Ser209) increases its binding affinity for the cap of mRNA and may also favor its entry into initiation complexes. Mammalian target of rapamycin (mTOR) inhibitors suppress cap-dependent translation through inhibition of the phosphorylation of eIF4E-binding protein 1. Paradoxically, we have shown that inhibition of mTOR signaling increases eIF4E phosphorylation in human cancer cells. In this study, we focused on revealing the mechanism by which mTOR inhibition increases eIF4E phosphorylation. Silencing of either mTOR or raptor could mimic mTOR inhibitors’ effects to increase eIF4E phosphorylation. Moreover, knockdown of mTOR, but not rictor or p70S6K, abrogated rapamycin's ability to increase eIF4E phosphorylation. These results indicate that mTOR inhibitor-induced eIF4E phosphorylation is secondary to mTOR/raptor inhibition and independent of p70S6K. Importantly, mTOR inhibitors lost their ability to increase eIF4E phosphorylation only in cells where both Mnk1 and Mnk2 were knocked out, indicating that mTOR inhibitors increase eIF4E phosphorylation through a Mnk-dependent mechanism. Given that mTOR inhibitors failed to increase Mnk and eIF4E phosphorylation in phosphatidylinositol 3-kinase (PI3K)-deficient cells, we conclude that mTOR inhibition increases eIF4E phosphorylation through a PI3K-dependent and Mnk-mediated mechanism. In addition, we also suggest an effective therapeutic strategy for enhancing mTOR-targeted cancer therapy by cotargeting mTOR signaling and Mnk/eIF4E phosphorylation.

scholarly journals PRMT7 methylates eukaryotic translation initiation factor 2α and regulates its role in stress granule formation

2019 ◽  
Vol 30 (6) ◽  
pp. 778-793 ◽  
Author(s):  
Nasim Haghandish ◽  
R. Mitchell Baldwin ◽  
Alan Morettin ◽  
Haben Tesfu Dawit ◽  
Hemanta Adhikary ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Stress Granule ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Single Type ◽  
Granule Formation ◽  
Eukaryotic Translation Initiation Factor ◽  
Eukaryotic Translation ◽  
Arginine Residues ◽  
Eukaryotic Translation Initiation

Protein arginine methyltransferases (PRMTs) are a family of enzymes that modify proteins by methylating the guanidino nitrogen atoms of arginine residues to regulate cellular processes such as chromatin remodeling, pre-mRNA splicing, and signal transduction. PRMT7 is the single type III PRMT solely capable of arginine monomethylation. To date, other than histone proteins, there are very few identified substrates of PRMT7. We therefore performed quantitative mass spectrometry experiments to identify PRMT7’s interactome and potential substrates to better characterize the enzyme’s biological function(s) in cells. These experiments revealed that PRMT7 interacts with and can methylate eukaryotic translation initiation factor 2 alpha (eIF2α), in vitro and in breast cancer cells. Furthermore, we uncovered a potential regulatory interplay between eIF2α arginine methylation by PRMT7 and stress-induced phosphorylation status of eIF2α at serine 51. Finally, we demonstrated that PRMT7 is required for eIF2α-dependent stress granule formation in the face of various cellular stresses. Altogether, our findings implicate PRMT7 as a novel mediator of eIF2α-dependent cellular stress response pathways.

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