scholarly journals CELL SYSTEMS BIOLOGY OF TRANSLATION FACTORS AND PROTEASOME-TARGETED PROTEIN COMPLEXES ASSOCIATED WITH AGC KINASE SCH9

2020 ◽  
Author(s):  
Alex Sobko
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Protein Complexes ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Protein Interactions ◽  
Functional Connections ◽  
Translation Factors

Sch9 appears to be the Saccharomyces cerevisiae homolog of protein kinase B and S6 kinase and is involved in the control of numerous nutrient-sensitive processes, including regulation of cell size, cell cycle progression, and stress resistance. Sch9 has also been implicated in the regulation of replicative and chronological life span. The availability of data from global studies of protein-protein interactions now makes it possible to predict and validate functional connections between Sch9, its putative substrates, and other proteins. Sch9 appears to be involved in control of biosynthetic and catabolic pathways. Thus, the analysis of Sch9-associated proteins indicates that this kinase may be involved in regulation of protein synthesis. Sch9 forms a complex with, and, presumably, phosphorylates starvation- and stress-induced protein kinase GCN2, which, in turn, phosphorylates translation initiation factor eIF2alpha. Sch9 also interacts with translation factors Arc1, Pab1 and prion-like protein Sup35. Thus, Sch9 may be part of the mechanism that relays availability of nutrients to utilization of glucose and to the rates of protein synthesis. One of the interesting outcomes of the proteome-wide analysis of protein-protein interactions in yeast is the finding that Sch9 associates with Shp1, Cdc48, and Ufd1, which form a complex responsible for the recognition and targeting of ubiquitinated proteins to the proteasome for degradation. It is unknown and remains to be elucidated, whether mammalian homologues of Sch9 are also associated with the proteins involved in translation/protein synthesis and proteasomal degradation.

scholarly journals Activation of mRNA translation in rat cardiac myocytes by insulin involves multiple rapamycin-sensitive steps

2000 ◽  
Vol 278 (4) ◽  
pp. H1056-H1068 ◽  
Author(s):  
Lijun Wang ◽  
Xuemin Wang ◽  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Glycogen Synthase ◽  
Mrna Translation ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Translation Factors ◽  
P70 S6k ◽  
Eef2 Kinase

Insulin acutely activates protein synthesis in ventricular cardiomyocytes from adult rats. In this study, we have established the methodology for studying the regulation of the signaling pathways and translation factors that may be involved in this response and have examined the effects of acute insulin treatment on them. Insulin rapidly activated the 70-kDa ribosomal S6 kinase (p70 S6k), and this effect was inhibited both by rapamycin and by inhibitors of phosphatidylinositol 3-kinase. The activation of p70 S6k is mediated by a signaling pathway involving the mammalian target of rapamycin (mTOR), which also modulates other translation factors. These include the eukaryotic initiation factor (eIF) 4E binding proteins (4E-BPs) and eukaryotic elongation factor 2 (eEF2). Insulin caused phosphorylation of 4E-BP1 and induced its dissociation from eIF4E, and these effects were also blocked by rapamycin. Concomitant with this, insulin increased the binding of eIF4E to eIF4G. Insulin also activated protein kinase B (PKB), which may lie upstream of p70 S6k and 4E-BP1, with the activation of the different isoforms being in the order α>β>γ. Insulin also caused inhibition of glycogen synthase kinase 3, which lies downstream of PKB, and of eEF2 kinase. The phosphorylation of eEF2 itself was also decreased by insulin, and this effect and the inactivation of eEF2 kinase were attenuated by rapamycin. The activation of overall protein synthesis by insulin in cardiomyocytes was substantially inhibited by rapamycin (but not by inhibitors of other specific signaling pathways, e.g., mitogen-activated protein kinase), showing that signaling events linked to mTOR play a major role in the control of translation by insulin in this cell type.

scholarly journals eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Jennifer Deborah Wuerth ◽  
Matthias Habjan ◽  
Markus Kainulainen ◽  
Besim Berisha ◽  
Damien Bertheloot ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Nonstructural Protein ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Mammalian Host ◽  
Eukaryotic Initiation Factor ◽  
Α Subunit ◽  
Immune Factor

ABSTRACT RNA-activated protein kinase (PKR) is a major innate immune factor that senses viral double-stranded RNA (dsRNA) and phosphorylates eukaryotic initiation factor (eIF) 2α. Phosphorylation of the α subunit converts the eIF2αβγ complex into a stoichiometric inhibitor of eukaryotic initiation factor eIF2B, thus halting mRNA translation. To escape this protein synthesis shutoff, viruses have evolved countermechanisms such as dsRNA sequestration, eIF-independent translation by an internal ribosome binding site, degradation of PKR, or dephosphorylation of PKR or of phospho-eIF2α. Here, we report that sandfly fever Sicilian phlebovirus (SFSV) confers such a resistance without interfering with PKR activation or eIF2α phosphorylation. Rather, SFSV expresses a nonstructural protein termed NSs that strongly binds to eIF2B. Although NSs still allows phospho-eIF2α binding to eIF2B, protein synthesis and virus replication are unhindered. Hence, SFSV encodes a unique PKR antagonist that acts by rendering eIF2B resistant to the inhibitory action of bound phospho-eIF2α. IMPORTANCE RNA-activated protein kinase (PKR) is one of the most powerful antiviral defense factors of the mammalian host. PKR acts by phosphorylating mRNA translation initiation factor eIF2α, thereby converting it from a cofactor to an inhibitor of mRNA translation that strongly binds to initiation factor eIF2B. To sustain synthesis of their proteins, viruses are known to counteract this on the level of PKR or eIF2α or by circumventing initiation factor-dependent translation altogether. Here, we report a different PKR escape strategy executed by sandfly fever Sicilian virus (SFSV), a member of the increasingly important group of phleboviruses. We found that the nonstructural protein NSs of SFSV binds to eIF2B and protects it from inactivation by PKR-generated phospho-eIF2α. Protein synthesis is hence maintained and the virus can replicate despite ongoing full-fledged PKR signaling in the infected cells. Thus, SFSV has evolved a unique strategy to escape the powerful antiviral PKR.

scholarly journals Molecular Structure and Functional Elucidation of IF-3 Protein of Chloroflexus Aurantiacus Involved in Protein Biosynthesis: An In-Silico Approach

2021 ◽  
Author(s):  
Abu Saim Mohammad Saikat
Keyword(s):  
Translation Initiation ◽  
Protein Interactions ◽  
In Silico ◽  
Tertiary Structure ◽  
Protein Biosynthesis ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Chloroflexus Aurantiacus ◽  
Protein Protein Interactions ◽  
Functional Interpretation

<p><i>Chloroflexus aurantiacus</i> is a thermophilic bacterium that produces a multitude of proteins within its genome. Bioinformatics strategies can facilitate comprehending this organism through functional and structural interpretation assessments. This study aimed to allocate the structure and function through an in-silico approach required for bacterial protein biosynthesis. This in-silico viewpoint provides copious properties, including the physicochemical properties, subcellular location, three-dimensional structure, protein-protein interactions, and functional elucidation of the protein (WP_012256288.1). The STRING program is utilized for the explication of protein-protein interactions. The in-silico investigation documented the protein's hydrophilic nature with predominantly alpha (α) helices in its secondary structure. The tertiary-structure model of the protein has been shown to exhibit reasonably high consistency based on various quality assessment methods. The functional interpretation suggested that the protein can act as a translation initiation factor, a protein required for translation and protein biosynthesis. Protein-protein interactions also demonstrated high credence that the protein interconnected with 30S ribosomal subunit involved in protein synthesis. This study is bioinformatically examined that the protein (WP_012256288.1) is affiliated in protein biosynthesis as a translation initiation factor IF-3 of <i>C. aurantiacus</i>. </p> <p> </p>

scholarly journals Structural and Functional Elucidation of IF-3 Protein of Chloroflexus aurantiacus Involved in Protein Biosynthesis: An In-Silico Approach

2021 ◽  
Author(s):  
Abu Saim Mohammad Saikat ◽  
Md. Ekhlas Uddin ◽  
Tasnim Ahmad ◽  
Shahriar Mahmud ◽  
Md. Abu Sayeed Imran ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Protein Interactions ◽  
In Silico ◽  
Tertiary Structure ◽  
Protein Biosynthesis ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Chloroflexus Aurantiacus ◽  
Protein Protein Interactions ◽  
Functional Interpretation

<p>Chloroflexus aurantiacus is a thermophilic bacterium that produces a multitude of proteins<br>within its genome. Bioinformatics strategies can facilitate comprehending this organism through<br>functional and structural interpretation assessments.This study aimed to allocate the structure and<br>function through an in-silico approach required for bacterial protein biosynthesis. This in-silico<br>viewpoint provides copious properties, including the physicochemical properties, subcellular location,<br>three-dimensional structure, protein-protein interactions, and functional elucidation of the protein<br>(WP_012256288.1). The STRING program is utilized for the explication of protein-protein<br>interactions. The in-silico investigation documented the protein's hydrophilic nature with<br>predominantly alpha (α) helices in its secondary structure.The tertiary-structure model of the protein<br>has been shown to exhibit reasonably high consistency based on various quality assessment<br>methods.The functional interpretation suggested that the protein can act as a translation initiation<br>factor, a protein required for translation and protein biosynthesis. Protein-protein interactions also<br>demonstrated high credence that the protein interconnected with 30S ribosomal subunit involved in<br>protein synthesis. This study is bioinformatically examined that the protein (WP_012256288.1) is<br>affiliated in protein biosynthesis as a translation initiation factor IF-3 of C. aurantiacus. <br><br></p>

scholarly journals Double-Stranded RNA-Activated Protein Kinase (PKR) Is Negatively Regulated by 60S Ribosomal Subunit Protein L18

1999 ◽  
Vol 19 (2) ◽  
pp. 1116-1125 ◽  
Author(s):  
Kotlo U. Kumar ◽  
Sri P. Srivastava ◽  
Randal J. Kaufman
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Cell Growth ◽  
Ribosomal Subunit ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Cancer Tissue ◽  
Double Stranded Rna ◽  
Dsrna Binding

ABSTRACT The double-stranded RNA (dsRNA)-activated protein kinase (PKR) provides a fundamental control step in the regulation of protein synthesis initiation through phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2α), a process that prevents polypeptide chain initiation. In such a manner, activated PKR inhibits cell growth and induces apoptosis, whereas disruption of normal PKR signaling results in unregulated cell growth. Therefore, tight control of PKR activity is essential for regulated cell growth. PKR is activated by dsRNA binding to two conserved dsRNA binding domains within its amino terminus. We isolated a ribosomal protein L18 by interaction with PKR. L18 is a 22-kDa protein that is overexpressed in colorectal cancer tissue. L18 competed with dsRNA for binding to PKR, reversed dsRNA binding to PKR, and did not directly bind dsRNA. Mutation of K64E within the first dsRNA binding domain of PKR destroyed both dsRNA binding and L18 interaction, suggesting that the two interactive sites overlap. L18 inhibited both PKR autophosphorylation and PKR-mediated phosphorylation of eIF-2α in vitro. Overexpression of L18 by transient DNA transfection reduced eIF-2α phosphorylation and stimulated translation of a reporter gene in vivo. These results demonstrate that L18 is a novel regulator of PKR activity, and we propose that L18 prevents PKR activation by dsRNA while PKR is associated with the ribosome. Overexpression of L18 may promote protein synthesis and cell growth in certain cancerous tissue through inhibition of PKR activity.

Markers of protein synthesis are increased in fetal membranes and myometrium after human labour and delivery

2018 ◽  
Vol 30 (2) ◽  
pp. 313 ◽  
Author(s):  
Stella Liong ◽  
Martha Lappas
Keyword(s):  
Protein Synthesis ◽  
Preterm Birth ◽  
Protein Kinase ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Fetal Membranes ◽  
Specific Chemical ◽  
Polycytidylic Acid ◽  
Human Labour ◽  
Gestational Tissues

Preterm birth remains one of the leading causes of neonatal death. Inflammation and maternal infection are two of the leading aetiological factors for preterm birth. Labour is associated with increased production of proinflammatory cytokines, chemokines and prolabour mediators in human gestational tissues. In non-gestational tissues, synthesis of proinflammatory and prolabour mediators is regulated by components of the protein synthesis machinery. Therefore, in the present study we investigated the effect of human labour on the expression of three protein synthesis markers, namely eukaryotic elongation factor 2 kinase (EEF2K), mitogen-activated protein kinase interacting protein kinase 1 (MKNK1) and eukaryotic translation initiation factor 4E (EIF4E), and their role in regulating inflammation in human gestational tissues. In fetal membranes and myometrium, EEF2K expression was significantly lower, whereas MKNK1 expression was significantly higher withterm and preterm labourcompared to term nolabour. In contrast, EIF4E expression did not change in fetal membranes or myometrium with labour. In primary myometrial cells, loss-of-function studies using specific chemical inhibitors of EEF2K (A484954) and MKNK1 (CGP57380) demonstrated that MKNK1, but not EEF2K, was required for polyinosinic-polycytidylic acid (poly(I:C); a viral double-stranded RNA mimetic) and interleukin (IL)-1β-induced production of IL6, C-X-C motif chemokine ligand 8 (CXCL8), prostaglandin-endoperoxide synthase 2 (PTGS2) and prostaglandin F2α. In conclusion, spontaneous term and preterm labour is associated with decreased EEF2K and increased MKNK1 expression in fetal membranes and myometrium. Moreover, MKNK1 is involved in the genesis of proinflammatory and prolabour mediators that is mediated by inflammation or infection. However, further studies are required to elucidate the role of EEF2K in human labour.

scholarly journals Leucine supplementation stimulates protein synthesis and reduces degradation signal activation in muscle of newborn pigs during acute endotoxemia

2016 ◽  
Vol 311 (4) ◽  
pp. E791-E801 ◽  
Author(s):  
Adriana D. Hernandez-García ◽  
Daniel A. Columbus ◽  
Rodrigo Manjarín ◽  
Hanh V. Nguyen ◽  
Agus Suryawan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Protein Kinase ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Ring Finger ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Leucine Supplementation ◽  
Amp Activated Protein Kinase

Sepsis disrupts skeletal muscle proteostasis and mitigates the anabolic response to leucine (Leu) in muscle of mature animals. We have shown that Leu stimulates muscle protein synthesis (PS) in healthy neonatal piglets. To determine if supplemental Leu can stimulate PS and reduce protein degradation (PD) signaling in neonatal muscle during endotoxemia, overnight-fasted neonatal pigs were infused for 8 h with LPS or saline while plasma amino acids, glucose, and insulin were maintained at fasting levels during pancreatic-substrate clamps. Leu or saline was infused during the last hour. Markers of PS and PD were determined in skeletal muscle. Compared with controls, Leu increased PS in longissimus dorsi (LD), gastrocnemius, and soleus muscles. LPS decreased PS in these three muscles by 36%, 28%, and 38%, but Leu antagonized that reduction by increasing PS by 84%, 81%, and 83%, respectively, when supplemented to LPS. Leu increased eukaryotic translation initiation factor (eIF)3b-raptor interactions, eIF4E-binding protein-1, and S6 kinase 1 phosphorylation as well as eIF4E·eIF4G complex formation in LD, gastrocnemius, and soleus muscles of control and LPS-treated pigs. In LD muscle, LPS increased the light chain (LC)3-II-to-LC3 ratio and muscle-specific RING finger (MuRF-1) abundance but not atrogin-1 abundance or AMP-activated protein kinase-α phosphorylation. Leu supplementation to LPS-treated pigs reduced the LC3-II-to-LC3 ratio, MuRF-1 abundance, and AMP-activated protein kinase-α phosphorylation compared with LPS alone. In conclusion, parenteral Leu supplementation attenuates the LPS-induced reduction in PS by stimulating mammalian target of rapamycin complex 1-dependent translation and may reduce PD by attenuating autophagy-lysosome and MuRF-1 signaling in neonatal skeletal muscle.

scholarly journals Molecular Structure and Functional Elucidation of IF-3 Protein of Chloroflexus Aurantiacus Involved in Protein Biosynthesis: An In-Silico Approach

2021 ◽  
Author(s):  
Abu Saim Mohammad Saikat
Keyword(s):  
Translation Initiation ◽  
Protein Interactions ◽  
In Silico ◽  
Tertiary Structure ◽  
Protein Biosynthesis ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Chloroflexus Aurantiacus ◽  
Protein Protein Interactions ◽  
Functional Interpretation

<p><i>Chloroflexus aurantiacus</i> is a thermophilic bacterium that produces a multitude of proteins within its genome. Bioinformatics strategies can facilitate comprehending this organism through functional and structural interpretation assessments. This study aimed to allocate the structure and function through an in-silico approach required for bacterial protein biosynthesis. This in-silico viewpoint provides copious properties, including the physicochemical properties, subcellular location, three-dimensional structure, protein-protein interactions, and functional elucidation of the protein (WP_012256288.1). The STRING program is utilized for the explication of protein-protein interactions. The in-silico investigation documented the protein's hydrophilic nature with predominantly alpha (α) helices in its secondary structure. The tertiary-structure model of the protein has been shown to exhibit reasonably high consistency based on various quality assessment methods. The functional interpretation suggested that the protein can act as a translation initiation factor, a protein required for translation and protein biosynthesis. Protein-protein interactions also demonstrated high credence that the protein interconnected with 30S ribosomal subunit involved in protein synthesis. This study is bioinformatically examined that the protein (WP_012256288.1) is affiliated in protein biosynthesis as a translation initiation factor IF-3 of <i>C. aurantiacus</i>. </p> <p> </p>

scholarly journals Murine Cytomegalovirus m142 and m143 Are both Required To Block Protein Kinase R-Mediated Shutdown of Protein Synthesis

2006 ◽  
Vol 80 (20) ◽  
pp. 10181-10190 ◽  
Author(s):  
Ralitsa S. Valchanova ◽  
Marcus Picard-Maureau ◽  
Matthias Budt ◽  
Wolfram Brune
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Rna Binding ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Murine Cytomegalovirus ◽  
Deletion Mutants ◽  
Sequence Motifs ◽  
Protein Kinase R ◽  
Double Stranded Rna

ABSTRACT Cytomegaloviruses carry the US22 family of genes, which have common sequence motifs but diverse functions. Only two of the 12 US22 family genes of murine cytomegalovirus (MCMV) are essential for virus replication, but their functions have remained unknown. In the present study, we deleted the essential US22 family genes, m142 and m143, from the MCMV genome and propagated the mutant viruses on complementing cells. The m142 and the m143 deletion mutants were both unable to replicate in noncomplementing cells at low and high multiplicities of infection. In cells infected with the deletion mutants, viral immediate-early and early proteins were expressed, but viral DNA replication and synthesis of the late-gene product glycoprotein B were inhibited, even though mRNAs of late genes were present. Global protein synthesis was impaired in these cells, which correlated with phosphorylation of the double-stranded RNA-dependent protein kinase R (PKR) and its target protein, the eukaryotic translation initiation factor 2α, suggesting that m142 and m143 are necessary to block the PKR-mediated shutdown of protein synthesis. Replication of the m142 and m143 knockout mutants was partially restored by expression of the human cytomegalovirus TRS1 gene, a known double-stranded-RNA-binding protein that inhibits PKR activation. These results indicate that m142 and m143 are both required for inhibition of the PKR-mediated host antiviral response.

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