EXPRESSION OF dsRNA-ACTIVATED PROTEIN KINASE AND EUKARYOTIC INITIATION FACTOR 2α IN THE BRAINS OF PATIENTS WITH ALZHEIMER DISEASE

1999 ◽  
Vol 58 (5) ◽  
pp. 530
Author(s):  
N. Donner ◽  
L-W. Jin ◽  
B. Sopher ◽  
D. Nochlin
Keyword(s):  
Protein Kinase ◽  
Alzheimer Disease ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor

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 Ribosomal RACK1:Protein Kinase C βII Modulates Intramolecular Interactions between Unstructured Regions of Eukaryotic Initiation Factor 4G (eIF4G) That Control eIF4E and eIF3 Binding

2018 ◽  
Vol 38 (19) ◽  
Author(s):  
Mikhail I. Dobrikov ◽  
Elena Y. Dobrikova ◽  
Matthias Gromeier
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Intramolecular Interactions ◽  
Initiation Factor ◽  
Binding Motif ◽  
Eukaryotic Initiation Factor ◽  
Kinase C ◽  
Eukaryotic Initiation Factor 4G ◽  
Β Sheet ◽  
Unstructured Regions

ABSTRACT The receptor for activated C kinase (RACK1), a conserved constituent of eukaryotic ribosomes, mediates phosphorylation of eukaryotic initiation factor 4G1(S1093) [eIF4G1(S1093)] and eIF3a(S1364) by protein kinase C βII (PKCβII) (M. I. Dobrikov, E. Y. Dobrikova, and M. Gromeier, Mol Cell Biol 38:e00304-18, 2018, https://doi.org/10.1128/MCB.00304-18). RACK1:PKCβII activation drives a phorbol ester-induced surge of global protein synthesis and template-specific translation induction of PKC–Raf–extracellular signal-regulated kinase 1/2 (ERK1/2)-responsive genes. For unraveling mechanisms of RACK1:PKCβII-mediated translation stimulation, we used sequentially truncated eIF4G1 in coimmunoprecipitation analyses to delineate a set of autoinhibitory elements in the N-terminal unstructured region (surrounding the eIF4E-binding motif) and the interdomain linker (within the eIF3-binding site) of eIF4G1. Computer-based predictions of secondary structure, mutational analyses, and fluorescent titration with the β-sheet dye thioflavin T suggest that eIF4G1(S1093) modulates a 4-stranded β-sheet composed of antiparallel β-hairpins formed by the autoinhibitory elements in eIF4G1's unstructured regions. The intact β-sheet “locks” the eIF4G configuration, preventing assembly with eIF3/40S ribosomal subunits. Upon PKC stimulation, activated RACK1:PKCβII phosphorylates eIF4G(S1093) in the tight 48S initiation complex, possibly facilitating dissociation/recycling of eIF4F.

scholarly journals Antihyperalgesia effect of AMP-activated protein kinase (AMPK) activators in a mouse model of postoperative pain

2019 ◽  
Vol 44 (8) ◽  
pp. 781-786 ◽  
Author(s):  
Vaskar Das ◽  
Jeffrey S Kroin ◽  
Mario Moric ◽  
Robert J McCarthy ◽  
Asokumar Buvanendran
Keyword(s):  
Postoperative Pain ◽  
Protein Kinase ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Drg Neurons ◽  
Mechanical Hypersensitivity ◽  
Mechanistic Target Of Rapamycin ◽  
Initiation Factor 2 ◽  
The Difference ◽  
Amp Activated Protein Kinase

Background and objectivesAMP-activated protein kinase (AMPK) activator drugs decrease hypersensitivity in mice with pain. This study examines if postsurgery treatment with the prototype AMPK activator metformin and a new mechanism-specific AMPK activator, O304, after plantar hindpaw incision in mice, would reduce mechanical hypersensitivity and produce changes in the AMPK pathway in the dorsal root ganglion (DRG).MethodsTo create postoperative pain, an incision was made in the left plantar hindpaw. Animals were randomized into four oral gavage drug treatment groups (n=8/group): (1) vehicle, (2) metformin 200 mg/kg, (3) O304 200 mg/kg and (4) O304 200 mg/kg plus metformin 200 mg/kg. Drug gavages were performed 4 hours postsurgery and were repeated for 3 days. Mechanical hypersensitivity was measured with von Frey filaments. Changes in phosphorylated AMP-activated protein kinase alpha subunit, phosphorylated mechanistic target of rapamycin and phosphorylated eukaryotic initiation factor 2 alpha in DRG neurons were examined by immunohistochemistry.ResultsO304 or metformin increased von Frey thresholds (reduced mechanical hypersensitivity) in plantar incision mice versus vehicle-treated incision mice between days 1 and 4 (difference of mean area under the curve, O304: 2.24 g*day; 95% CI of the difference 0.28 to 4.21, p=0.011; metformin: 2.56 g*day; 95% CI of the difference 1.71 to 3.41, p<0.001). The drug combination further elevated von Frey thresholds. In the vehicle-treated group, the AMP-activated protein kinase alpha subunit was downregulated and mechanistic target of rapamycin and eukaryotic initiation factor 2 alpha were upregulated in DRG neurons; these deficits were reversed by the AMPK activator treatments.ConclusionsEarly treatment with the mechanism-specific AMPK activator O304 or the prototype AMPK activator metformin reduces mechanical hypersensitivity in a postoperative pain model in mice. These drugs also normalize the AMPK pathway in the DRG.

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