scholarly journals MARK2 phosphorylates eIF2α in response to proteotoxic stress

PLoS Biology ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. e3001096
Author(s):  
Yu-Ning Lu ◽  
Sarah Kavianpour ◽  
Tao Zhang ◽  
Xumei Zhang ◽  
Dao Nguyen ◽  
...  
Keyword(s):  
Stress Responses ◽  
Protein Misfolding ◽  
Critical Role ◽  
Heat Shock Protein 90 ◽  
Human Diseases ◽  
Initiation Factor ◽  
Translation Regulation ◽  
Proteotoxic Stress ◽  
Initiation Factor 2 ◽  
Lateral Sclerosis

The regulation of protein synthesis is essential for maintaining cellular homeostasis, especially during stress responses, and its dysregulation could underlie the development of human diseases. The critical step during translation regulation is the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). Here we report the identification of a direct kinase of eIF2α, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2α in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2α kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKCδ), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKCδ are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKCδ-MARK2-eIF2α cascade that may play a critical role in cellular proteotoxic stress responses and human diseases.

scholarly journals Choice of PP1 catalytic subunit affects neither requirement for G-actin nor insensitivity to Sephin1 of PPP1R15A-regulated eIF2αP dephosphorylation

2017 ◽  
Author(s):  
Ana Crespillo-Casado ◽  
Zander Claes ◽  
Meng S. Choy ◽  
Wolfgang Peti ◽  
Mathieu Bollen ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Catalytic Subunit ◽  
Translation Initiation Factor ◽  
Terminal Repeat ◽  
Initiation Factor ◽  
Regulatory Subunit ◽  
Rabbit Muscle ◽  
Α Subunit ◽  
Regulatory Subunits ◽  
Initiation Factor 2

ABSTRACTThe integrated stress response (ISR) is regulated by kinases that phosphorylate the α subunit of translation initiation factor 2 and phosphatases that dephosphorylate it. Genetic and biochemical observations indicate that the eIF2αP-directed holophosphatase - a therapeutic target in diseases of protein misfolding - is comprised of a regulatory, PPP1R15, and a catalytic, Protein Phosphatase 1 (PP1) subunit. In mammals, there are two isoforms of the regulatory subunit, PPP1R15A and PPP1R15B, with overlapping roles in promoting the essential function of eIF2αP dephosphorylation. However, conflicting reports have appeared regarding the requirement for an additional co-factor, G-actin, in enabling substrate-specific de-phosphorylation by PPP1R15-containing PP1 holoenzymes. An additional concern relates to the sensitivity of the PPP1R15A-containing PP1 holoenzyme to the [(ochlorobenzylidene)amino]guanidines (Sephin1 or Guanabenz), small molecule proteostasis modulators. It has been suggested that the source and method of purification of the PP1 catalytic subunit and the presence or absence of an N-terminal repeat-containing region in the PPP1R15A regulatory subunit might influence both the requirement for G-actin by the eIF2αP-directed holophosphatase and its sensitivity to inhibitors. Here we report that in the absence of G-actin, PPP1R15A regulatory subunits were unable to accelerate eIF2αP dephosphorylation beyond that affected by a catalytic subunit alone, whether PPP1R15A regulatory subunit had or lacked the N-terminal repeat-containing region and whether paired with native PP1 purified from rabbit muscle, or recombinant PP1 expressed in and purified from bacteria. Furthermore, none of the PPP1R15A-containing PP1c holophosphatases were inhibited by Sephin1 or Guanabenz.

scholarly journals Gadd34 Requirement for Normal Hemoglobin Synthesis

2006 ◽  
Vol 26 (5) ◽  
pp. 1644-1653 ◽  
Author(s):  
Andrew D. Patterson ◽  
M. Christine Hollander ◽  
Georgina F. Miller ◽  
Albert J. Fornace
Keyword(s):  
Stress Responses ◽  
Protein Phosphatase ◽  
Biochemical Analysis ◽  
Growth Arrest ◽  
Protein Phosphatase 1 ◽  
Initiation Factor ◽  
Hemoglobin Content ◽  
Α Subunit ◽  
Hemoglobin Synthesis ◽  
Initiation Factor 2

ABSTRACT The protein encoded by growth arrest and DNA damage-inducible transcript 34 (Gadd34) is associated with translation initiation regulation following certain stress responses. Through interaction with the protein phosphatase 1 catalytic subunit (PP1c), Gadd34 recruits PP1c for the removal of an inhibitory phosphate group on the α subunit of elongation initiation factor 2, thereby reversing the shutoff of protein synthesis initiated by stress-inducible kinases. In the absence of stress, the physiologic consequences of Gadd34 function are not known. Initial analysis of Gadd34-null mice revealed several significant findings, including hypersplenism, decreased erythrocyte volume, increased numbers of circulating erythrocytes, and decreased hemoglobin content, resembling some thalassemia syndromes. Biochemical analysis of the hemoglobin-producing reticulocyte (an erythrocyte precursor) revealed that the decreased hemoglobin content in the Gadd34-null erythrocyte is due to the reduced initiation of the globin translation machinery. We propose that an equilibrium state exists between Gadd34/PP1c and the opposing heme-regulated inhibitor kinase during hemoglobin synthesis in the reticulocyte.

scholarly journals Phospholipase Lpl1 links lipid droplet function with quality control protein degradation

2017 ◽  
Vol 28 (6) ◽  
pp. 716-725 ◽  
Author(s):  
Nina Weisshaar ◽  
Hendrik Welsch ◽  
Angel Guerra-Moreno ◽  
John Hanna
Keyword(s):  
Protein Degradation ◽  
Lipid Droplet ◽  
Stress Responses ◽  
Protein Misfolding ◽  
Lipid Droplets ◽  
Genetic Interaction ◽  
Phospholipid Metabolism ◽  
Dynamic Regulation ◽  
Proteotoxic Stress ◽  
The Unfolded Protein Response

Protein misfolding is toxic to cells and is believed to underlie many human diseases, including many neurodegenerative diseases. Accordingly, cells have developed stress responses to deal with misfolded proteins. The transcription factor Rpn4 mediates one such response and is best known for regulating the abundance of the proteasome, the complex multisubunit protease that destroys proteins. Here we identify Lpl1 as an unexpected target of the Rpn4 response. Lpl1 is a phospholipase and a component of the lipid droplet. Lpl1 has dual functions: it is required for both efficient proteasome-mediated protein degradation and the dynamic regulation of lipid droplets. Lpl1 shows a synthetic genetic interaction with Hac1, the master regulator of a second proteotoxic stress response, the unfolded protein response (UPR). The UPR has long been known to regulate phospholipid metabolism, and Lpl1's relationship with Hac1 appears to reflect Hac1's role in stimulating phospholipid synthesis under stress. Thus two distinct proteotoxic stress responses control phospholipid metabolism. Furthermore, these results provide a direct link between the lipid droplet and proteasomal protein degradation and suggest that dynamic regulation of lipid droplets is a key aspect of some proteotoxic stress responses.

scholarly journals Translation Regulation by Eukaryotic Initiation Factor-2 Kinases in the Development of Latent Cysts inToxoplasma gondii

2008 ◽  
Vol 283 (24) ◽  
pp. 16591-16601 ◽  
Author(s):  
Jana Narasimhan ◽  
Bradley R. Joyce ◽  
Arunasalam Naguleswaran ◽  
Aaron T. Smith ◽  
Meredith R. Livingston ◽  
...  
Keyword(s):  
Initiation Factor ◽  
Translation Regulation ◽  
Eukaryotic Initiation Factor ◽  
Eukaryotic Initiation Factor 2 ◽  
Initiation Factor 2

scholarly journals PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ana Crespillo-Casado ◽  
Joseph E Chambers ◽  
Peter M Fischer ◽  
Stefan J Marciniak ◽  
David Ron
Keyword(s):  
Protein Misfolding ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protective Effects ◽  
Unfolded Protein ◽  
Promising Target ◽  
Initiation Factor 2 ◽  
Misfolding Diseases ◽  
Protein Response

Dephosphorylation of translation initiation factor 2 (eIF2α) terminates signalling in the mammalian integrated stress response (ISR) and has emerged as a promising target for modifying the course of protein misfolding diseases. The [(o-chlorobenzylidene)amino]guanidines (Guanabenz and Sephin1) have been proposed to exert protective effects against misfolding by interfering with eIF2α-P dephosphorylation through selective disruption of a PP1-PPP1R15A holophosphatase complex. Surprisingly, they proved inert in vitro affecting neither stability of the PP1-PPP1R15A complex nor substrate-specific dephosphorylation. Furthermore, eIF2α-P dephosphorylation, assessed by a kinase shut-off experiment, progressed normally in Sephin1-treated cells. Consistent with its role in defending proteostasis, Sephin1 attenuated the IRE1 branch of the endoplasmic reticulum unfolded protein response. However, repression was noted in both wildtype and Ppp1r15a deleted cells and in cells rendered ISR-deficient by CRISPR editing of the Eif2s1 locus to encode a non-phosphorylatable eIF2α (eIF2αS51A). These findings challenge the view that [(o-chlorobenzylidene)amino]guanidines restore proteostasis by interfering with eIF2α-P dephosphorylation.

The Role of Glyoxalase in Glycation and Carbonyl Stress Induced Metabolic Disorders

2020 ◽  
Vol 21 (9) ◽  
pp. 846-859
Author(s):  
Mohd Saeed ◽  
Mohd Adnan Kausar ◽  
Rajeev Singh ◽  
Arif J. Siddiqui ◽  
Asma Akhter
Keyword(s):  
Protein Misfolding ◽  
Covalent Binding ◽  
Critical Role ◽  
Enzymatic Reaction ◽  
Treatment Strategies ◽  
Bioactive Molecules ◽  
Carbonyl Stress ◽  
Defense System ◽  
Pathological Conditions ◽  
Age Related

Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation of irreversibly bound products known as advanced glycation end products (AGEs). AGEs are synthesized in high amounts both in pathological conditions, such as diabetes and under physiological conditions resulting in aging. The body’s anti-glycation defense mechanisms play a critical role in removing glycated products. However, if this defense system fails, AGEs start accumulating, which results in pathological conditions. Studies have been shown that increased accumulation of AGEs acts as key mediators in multiple diseases, such as diabetes, obesity, arthritis, cancer, atherosclerosis, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, aging, and Alzheimer’s disease. Furthermore, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), causes potential damage to the genome, proteome, and lipidome. Glyoxalase-1 (GLO-1) acts as a part of the anti-glycation defense system by carrying out detoxification of GO and MGO. It has been demonstrated that GLO-1 protects dicarbonyl modifications of the proteome and lipidome, thereby impeding the cell signaling and affecting age-related diseases. Its relationship with detoxification and anti-glycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide evidence for the rationale that the functional modulation of the GLO pathway could be used as a potential therapeutic target. In the present review, we summarized the newly emerged literature on the GLO pathway, including enzymes regulating the process. In addition, we described small bioactive molecules with the potential to modulate the GLO pathway, thereby providing a basis for the development of new treatment strategies against age-related complications.

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