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 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.

The role of Eif2s3y in mouse spermatogenesis

2021 ◽  
Vol 16 ◽  
Author(s):  
Wenqing Liu ◽  
Na Li ◽  
Mengfei Zhang ◽  
Ahmed H. Arisha ◽  
Jinlian Hua
Keyword(s):  
Translation Initiation ◽  
Mrna Translation ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Gene Encoding ◽  
Eukaryotic Translation ◽  
Initiation Factor 2 ◽  
Eukaryotic Translation Initiation

: Eukaryotic translation initiation factor 2 subunit 3 and structural gene Y-linked (Eif2s3y) gene, the gene encoding eIF2γ protein, is located on the mouse Y chromosome short arm. The Eif2s3y gene is globally expressed in all tissues and plays an important role in regulating global and gene-specific mRNA translation initiation. During the process of protein translation initiation, Eif2s3x(its homolog) and Eif2s3y encoded eIF2γ perform similar functions. However, it has been noticed that Eif2s3y plays a crucial role in spermatogenesis, including spermatogonia mitosis, meiosis, and spermiogenesis of spermatids, which may account for infertility. In the period of spermatogenesis, the role of Eif2s3x and Eif2s3y are not equivalent. Importance of Eif2s3y has been observed in ESC and implicated in several aspects, including the pluripotency state and the proliferation rate. Here, we discuss the functional significance of Eif2s3y in mouse spermatogenesis and self-renewal of ESCs.

scholarly journals Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer

2020 ◽  
Vol 21 (4) ◽  
pp. 1199 ◽  
Author(s):  
Savitha Sridharan ◽  
Alakananda Basu
Keyword(s):  
Breast Cancer ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
And Function ◽  
Cell Growth And Proliferation ◽  
High Degree ◽  
Mtor Complex 1

The mechanistic target of rapamycin (mTOR) is a master regulator of protein translation, metabolism, cell growth and proliferation. It forms two complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is frequently deregulated in many cancers, including breast cancer, and is an important target for cancer therapy. The immunosuppressant drug rapamycin and its analogs that inhibit mTOR are currently being evaluated for their potential as anti-cancer agents, albeit with limited efficacy. mTORC1 mediates its function via its downstream targets 40S ribosomal S6 kinases (S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). There are two homologs of S6K: S6K1 and S6K2. Most of the earlier studies focused on S6K1 rather than S6K2. Because of their high degree of structural homology, it was generally believed that they behave similarly. Recent studies suggest that while they may share some functions, they may also exhibit distinct or even opposite functions. Both homologs have been implicated in breast cancer, although how they contribute to breast cancer may differ. The purpose of this review article is to compare and contrast the expression, structure, regulation and function of these two S6K homologs in breast cancer.

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 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.

scholarly journals A novel inhibitor stabilizes the inactive conformation of MAPK-interacting kinase 1

2018 ◽  
Vol 74 (3) ◽  
pp. 156-160 ◽  
Author(s):  
Yumi Matsui ◽  
Isao Yasumatsu ◽  
Ken-ichi Yoshida ◽  
Shin Iimura ◽  
Yutaka Ikeno ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Translation Initiation ◽  
Kinase Activity ◽  
Translation Initiation Factor ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Structural Basis ◽  
Eukaryotic Translation ◽  
Mitogen Activated Protein ◽  
Eukaryotic Translation Initiation

Mitogen-activated protein kinase (MAPK)-interacting kinases 1 (Mnk1) and 2 (Mnk2) modulate translation initiation through the phosphorylation of eukaryotic translation initiation factor 4E, which promotes tumorigenesis. However, Mnk1 and Mnk2 are dispensable in normal cells, suggesting that the inhibition of Mnk1 and Mnk2 could be effective in cancer therapy. To provide a structural basis for Mnk1 inhibition, a novel Mnk1 inhibitor was discovered and the crystal structure of Mnk1 in complex with this inhibitor was determined. The crystal structure revealed that the inhibitor binds to the autoinhibited state of Mnk1, stabilizing the Mnk-specific DFD motif in the DFD-out conformation, thus preventing Mnk1 from switching to the active conformation and thereby inhibiting the kinase activity. These results provide a valuable platform for the structure-guided design of Mnk1 inhibitors.

scholarly journals The 4E-BP growth pathway regulates the effect of ambient temperature onDrosophilametabolism and lifespan

2017 ◽  
Vol 114 (36) ◽  
pp. 9737-9742 ◽  
Author(s):  
Gil B. Carvalho ◽  
Ilaria Drago ◽  
Sany Hoxha ◽  
Ryuichi Yamada ◽  
Olena Mahneva ◽  
...  
Keyword(s):  
Ambient Temperature ◽  
Mitochondrial Protein ◽  
Model Organism ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Metabolic Switch ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
Underlying Mechanisms

Changes in body temperature can profoundly affect survival. The dramatic longevity-enhancing effect of cold has long been known in organisms ranging from invertebrates to mammals, yet the underlying mechanisms have only recently begun to be uncovered. In the nematodeCaenorhabditis elegans, this process is regulated by a thermosensitive membrane TRP channel and the DAF-16/FOXO transcription factor, but in more complex organisms the underpinnings of cold-induced longevity remain largely mysterious. We report that, inDrosophila melanogaster, variation in ambient temperature triggers metabolic changes in protein translation, mitochondrial protein synthesis, and posttranslational regulation of the translation repressor, 4E-BP (eukaryotic translation initiation factor 4E-binding protein). We show that 4E-BP determinesDrosophilalifespan in the context of temperature changes, revealing a genetic mechanism for cold-induced longevity in this model organism. Our results suggest that the 4E-BP pathway, chiefly thought of as a nutrient sensor, may represent a master metabolic switch responding to diverse environmental factors.

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