scholarly journals Phosphorylation of eIF2α at Serine 51 Is an Important Determinant of Cell Survival and Adaptation to Glucose Deficiency

2010 ◽  
Vol 21 (18) ◽  
pp. 3220-3231 ◽  
Author(s):  
Hala Muaddi ◽  
Mithu Majumder ◽  
Philippos Peidis ◽  
Andreas I. Papadakis ◽  
Martin Holcik ◽  
...  
Keyword(s):  
Cell Survival ◽  
Biological Response ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Α Subunit ◽  
Eukaryotic Translation ◽  
Life And Death ◽  
Eif2α Phosphorylation ◽  
Apoptosis Protein ◽  
Eukaryotic Translation Initiation

Various forms of stress induce pathways that converge on the phosphorylation of the alpha (α) subunit of eukaryotic translation initiation factor eIF2 at serine 51 (S51), a modification that results in a global inhibition of protein synthesis. In many cases eIF2α phosphorylation is a biological response that facilitates cells to cope with stressful environments. Glucose deficiency, an important form of stress, is associated with an induction of apoptosis. Herein, we demonstrate that eIF2α phosphorylation is a key step in maintaining a balance between the life and death of a glucose-deficient cell. That is, eIF2α phosphorylation acts as a molecular switch that shifts cells from a proapoptotic to a cytoprotective state in response to prolonged glucose deficiency. This adaptation process is associated with the timely expression of proteins and activation of pathways with significant contributions to cell survival and adaptation including the X-linked inhibitor of apoptosis protein (XIAP). We also show that among the eIF2α kinases GCN2 plays a proapoptotic role whereas PERK and PKR play a cytoprotective one in response to glucose deficiency. Our data demonstrate that eIF2α phosphorylation is a significant determinant of survival and adaptation of glucose-deficient cells with possible important implications in biological processes that interfere with glucose metabolism.

scholarly journals Snf1 Promotes Phosphorylation of the α Subunit of Eukaryotic Translation Initiation Factor 2 by Activating Gcn2 and Inhibiting Phosphatases Glc7 and Sit4

2010 ◽  
Vol 30 (12) ◽  
pp. 2862-2873 ◽  
Author(s):  
Vera Cherkasova ◽  
Hongfang Qiu ◽  
Alan G. Hinnebusch
Keyword(s):  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Activation Loop ◽  
Α Subunit ◽  
Eukaryotic Translation ◽  
Eif2α Phosphorylation ◽  
Initiation Factor 2 ◽  
Eukaryotic Translation Initiation ◽  
Translation Initiation Factor 2

ABSTRACT Snf1 is the ortholog of mammalian AMP-activated kinase and is responsible for activation of glucose-repressed genes at low glucose levels in budding yeast. We show that Snf1 promotes the formation of phosphorylated α subunit of eukaryotic translation initiation factor 2 (eIF2α-P), a regulator of general and gene-specific translation, by stimulating the function of eIF2α kinase Gcn2 during histidine starvation of glucose-grown cells. Thus, eliminating Snf1 or mutating its activation loop lowers Gcn2 kinase activity, reducing the autophosphorylation of Thr-882 in the Gcn2 activation loop, and decreases eIF2α-P levels in starved cells. Consistently, eliminating Reg1, a negative regulator of Snf1, provokes Snf1-dependent hyperphosphorylation of both Thr-882 and eIF2α. Interestingly, Snf1 also promotes eIF2α phosphorylation in the nonpreferred carbon source galactose, but this occurs by inhibition of protein phosphatase 1α (PP1α; Glc7) and the PP2A-like enzyme Sit4, rather than activation of Gcn2. Both Glc7 and Sit4 physically interact with eIF2α in cell extracts, supporting their direct roles as eIF2α phosphatases. Our results show that Snf1 modulates the level of eIF2α phosphorylation by different mechanisms, depending on the kind of nutrient deprivation existing in cells.

scholarly journals Control of α Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2α) Phosphorylation by the Human Papillomavirus Type 18 E6 Oncoprotein: Implications for eIF2α-Dependent Gene Expression and Cell Death

2004 ◽  
Vol 24 (8) ◽  
pp. 3415-3429 ◽  
Author(s):  
Shirin Kazemi ◽  
Stavroula Papadopoulou ◽  
Suiyang Li ◽  
Qiaozhu Su ◽  
Shuo Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Α Subunit ◽  
Eukaryotic Translation ◽  
Eif2α Phosphorylation ◽  
E6 Oncoprotein ◽  
Initiation Factor 2 ◽  
Eukaryotic Translation Initiation ◽  
Translation Initiation Factor 2

ABSTRACT Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at serine 51 inhibits protein synthesis in cells subjected to various forms of stress including virus infection. The human papillomavirus (HPV) E6 oncoprotein contributes to virus-induced pathogenicity through multiple mechanisms including the inhibition of apoptosis and the blockade of interferon (IFN) action. We have investigated a possible functional relationship between the E6 oncoprotein and eIF2α phosphorylation by an inducible-dimerization form of the IFN-inducible protein kinase PKR. Herein, we demonstrate that HPV type 18 E6 protein synthesis is rapidly repressed upon eIF2α phosphorylation caused by the conditional activation of the kinase. The remainder of E6, however, can rescue cells from PKR-mediated inhibition of protein synthesis and induction of apoptosis. E6 physically associates with GADD34/PP1 holophosphatase complex, which mediates translational recovery, and facilitates eIF2α dephosphorylation. Inhibition of eIF2α phosphorylation by E6 mitigates eIF2α-dependent responses to transcription and translation of proapoptotic genes. These findings demonstrate, for the first time, a role of the oncogenic E6 in apoptotic signaling induced by PKR and eIF2α phosphorylation. The functional interaction between E6 and the eIF2α phosphorylation pathway may have important implications for HPV infection and associated pathogenesis.

scholarly journals Caspase-mediated cleavage of eukaryotic translation initiation factor subunit 2α

1999 ◽  
Vol 342 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Shinya SATOH ◽  
Makoto HIJIKATA ◽  
Hiroshi HANDA ◽  
Kunitada SHIMOTOHNO
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Caspase 3 ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation Initiation Factor ◽  
Α Subunit ◽  
Eukaryotic Translation ◽  
Initiation Of Translation ◽  
Eukaryotic Translation Initiation

Eukaryotic translation initiation factor 2α (eIF-2α), a target molecule of the interferon-inducible double-stranded-RNA-dependent protein kinase (PKR), was cleaved in apoptotic Saos-2 cells on treatment with poly(I)˙poly(C) or tumour necrosis factor α. This cleavage occurred with a time course similar to that of poly(ADP-ribose) polymerase, a well-known caspase substrate. In addition, eIF-2α was cleaved by recombinant active caspase-3 in vitro. By site-directed mutagenesis, the cleavage site was mapped to an Ala-Glu-Val-Asp300 ↓ Gly301 sequence located in the C-terminal portion of eIF-2α. PKR phosphorylates eIF-2α on Ser51, resulting in the suppression of protein synthesis. PKR-mediated translational suppression was repressed when the C-terminally cleaved product of eIF-2α was overexpressed in Saos-2 cells, even though PKR can phosphorylate this cleaved product. These results suggest that caspase-3 or related protease(s) can modulate the efficiency of protein synthesis by cleaving the α subunit of eIF-2, a key component in the initiation of translation.

scholarly journals Regulation of eIF2α Phosphorylation by MAPKs Influences Polysome Stability and Protein Translation

2021 ◽  
Author(s):  
Sana Parveen ◽  
Haripriya Parthasarathy ◽  
Dhiviya Vedagiri ◽  
Divya Gupta ◽  
Hitha Gopalan Nair ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Translation Regulation ◽  
Eukaryotic Translation ◽  
Eif2α Phosphorylation ◽  
Mitogen Activated Protein ◽  
Eukaryotic Translation Initiation ◽  
Polysome Stability

Regulation of protein translation occurs primarily at the level of initiation and is mediated by multiple signaling pathways, majorly mechanistic target of rapamycin complex 1 (mTORC1), mitogen-activated protein kinases (MAPKs), and the eukaryotic translation initiation factor eIF2. While mTORC1 and eIF2α influence the polysome stability, MAPKs influence the phosphorylation of the cap-binding protein eIF4E and are known to influence translation of only a small set of mRNAs. Here, we demonstrate that p38 MAPK and ERK1/2 regulate translation through integrated stress response (ISR) pathways. Dual inhibition (dual-Mi) of p38 MAPK and ERK1/2 caused substantial phosphorylation of eIF2α in a synergistic manner, resulting in near-absolute collapse of polysomes. This regulation was independent of Mnk1/2, a well-studied mediator of translation regulation by the MAPKs. Dual-Mi-induced polysome dissociation was far more striking than that caused by sodium arsenite, a strong inducer of ISR. Interestingly, induction of ISR caused increased p38 phosphorylation, and its inhibition resulted in stronger polysome dissociation, indicating the importance of p38 in the translation activities. Thus, our studies demonstrate a major, unidentified role for ERK1/2 and more particularly p38 MAPK in the maintenance of homeostasis of polysome association and translation activities.

scholarly journals Light dependent activation of the GCN2 kinase under cold and salt stress is mediated by the photosynthetic status of the chloroplast

2019 ◽  
Author(s):  
Ansul Lokdarshi ◽  
Philip W. Morgan ◽  
Michelle Franks ◽  
Zoe Emert ◽  
Catherine Emanuel ◽  
...  
Keyword(s):  
Salt Stress ◽  
Reactive Oxygen ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Dependent Manner ◽  
Α Subunit ◽  
Eukaryotic Translation ◽  
The Status ◽  
Eukaryotic Translation Initiation

ABSTRACTRegulation of cytosolic mRNA translation is a key node for rapid adaptation to environmental stress conditions. In yeast and animals, phosphorylation of the α-subunit of eukaryotic translation initiation factor eIF2 is the most thoroughly characterized event in regulating global translation under stress. In plants, the GCN2 kinase (General Control Non-derepressible-2) is the only known kinase for eIF2α. GCN2 is activated under a variety of stresses including reactive oxygen species. Here we provide new evidence that the GCN2 kinase in Arabidopsis is also activated rapidly and in a light dependent manner by cold and salt treatments. These treatments alone did not repress global mRNA ribosome loading in a major way. The activation of GCN2 was attenuated by inhibitors of photosynthesis and antioxidants, suggesting that it is gated by the redox poise or the reactive oxygen status of the chloroplast. In keeping with these results, gcn2 mutant seedlings were more sensitive than wild type to both cold and salt in a root elongation assay. These data suggest that cold and salt stress may both affect the status of the cytosolic translation apparatus via the conserved GCN2-eIF2α module. The potential role of the GCN2 kinase pathway in the global repression of translation under abiotic stress will be discussed.

scholarly journals A Subunit of Eukaryotic Translation Initiation Factor 2α-Phosphatase (CreP/PPP1R15B) Regulates Membrane Traffic

2012 ◽  
Vol 287 (42) ◽  
pp. 35299-35317 ◽  
Author(s):  
Nicole Kloft ◽  
Claudia Neukirch ◽  
Gisela von Hoven ◽  
Wiesia Bobkiewicz ◽  
Silvia Weis ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Membrane Traffic ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Interaction Domain ◽  
Eukaryotic Translation ◽  
Eif2α Phosphorylation ◽  
Early Endosomes ◽  
Eukaryotic Translation Initiation ◽  
Α Helix

The constitutive reverter of eIF2α phosphorylation (CReP)/PPP1r15B targets the catalytic subunit of protein phosphatase 1 (PP1c) to phosphorylated eIF2α (p-eIF2α) to promote its dephosphorylation and translation initiation. Here, we report a novel role and mode of action of CReP. We found that CReP regulates uptake of the pore-forming Staphylococcus aureus α-toxin by epithelial cells. This function was independent of PP1c and translation, although p-eIF2α was involved. The latter accumulated at sites of toxin attack and appeared conjointly with α-toxin in early endosomes. CReP localized to membranes, interacted with phosphomimetic eIF2α, and, upon overexpression, induced and decorated a population of intracellular vesicles, characterized by accumulation of N-(lissamine rhodamine B sulfonyl)phosphatidylethanolamine (N-Rh-PE), a lipid marker of exosomes and intralumenal vesicles of multivesicular bodies. By truncation analysis, we delineated the CReP vesicle induction/association region, which comprises an amphipathic α-helix and is distinct from the PP1c interaction domain. CReP was also required for exocytosis from erythroleukemia cells and thus appears to play a broader role in membrane traffic. In summary, the mammalian traffic machinery co-opts p-eIF2α and CReP, regulators of translation initiation.

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