scholarly journals The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

2021 ◽  
Vol 13 ◽  
Author(s):  
Nicolás W. Martinez ◽  
Felipe E. Gómez ◽  
Soledad Matus
Keyword(s):  
Protein Kinase ◽  
Pathological Process ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Kinase R ◽  
Eukaryotic Translation ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Initiation Factor 2

There is a growing evidence describing a decline in adaptive homeostasis in aging-related diseases affecting the central nervous system (CNS), many of which are characterized by the appearance of non-native protein aggregates. One signaling pathway that allows cell adaptation is the integrated stress response (ISR), which senses stress stimuli through four kinases. ISR activation promotes translational arrest through the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α) and the induction of a gene expression program to restore cellular homeostasis. However, depending on the stimulus, ISR can also induce cell death. One of the ISR sensors is the double-stranded RNA-dependent protein kinase [protein kinase R (PKR)], initially described as a viral infection sensor, and now a growing evidence supports a role for PKR on CNS physiology. PKR has been largely involved in the Alzheimer’s disease (AD) pathological process. Here, we reviewed the antecedents supporting the role of PKR on the efficiency of synaptic transmission and cognition. Then, we review PKR’s contribution to AD and discuss the possible participation of PKR as a player in the neurodegenerative process involved in aging-related pathologies affecting the CNS.

Tumour necrosis factor α up-regulates protein kinase R (PKR)-activating protein (PACT) and increases phosphorylation of PKR and eukaryotic initiation factor 2-α in articular chondrocytes

2002 ◽  
Vol 30 (6) ◽  
pp. 886-889 ◽  
Author(s):  
S. J. Gilbert ◽  
V. C. Duance ◽  
D. J. Mason
Keyword(s):  
Protein Kinase ◽  
Tumour Necrosis ◽  
Cartilage Degradation ◽  
Initiation Factor ◽  
Tumour Necrosis Factor Α ◽  
Protein Kinase R ◽  
Initiation Factor 2 ◽  
Factor Α ◽  
Necrosis Factor

Our previous analysis of the genes regulated in cartilage at the onset of spontaneous osteoarthritis in the guinea pig knee revealed up-regulation of the gene for protein kinase R (PKR)-activating protein (PACT), which encodes the cellular activator of the protein kinase, PKR. PACT and PKR are upstream components of a number of signal transduction and gene transcription pathways used by pro-inflammatory cytokines. We have investigated the role of PACT and PKR in articular cartilage degradation using cytokine treatment of bovine primary chondrocytes and cartilage explants. Tumour necrosis factor α increased expression of PACT protein after 3 h of treatment. Furthermore, increased phosphorylation of PKR and eukaryotic initiation factor 2-α was observed. The known role of PKR in cytokine-induced signalling pathways, together with our data showing cytokine regulation of PACT and PKR in chondrocytes, reveals a novel mechanism of cartilage degradation that may be important in the pathogenesis of arthritic diseases.

scholarly journals RNase L promotes the formation of unique ribonucleoprotein granules distinct from stress granules

2020 ◽  
Vol 295 (6) ◽  
pp. 1426-1438 ◽  
Author(s):  
James M. Burke ◽  
Evan T. Lester ◽  
Devin Tauber ◽  
Roy Parker
Keyword(s):  
Stress Granules ◽  
Antiviral Response ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Rnase L ◽  
Protein Kinase R ◽  
Eukaryotic Translation ◽  
P Bodies ◽  
Initiation Factor 2 ◽  
Rnp Complex

Stress granules (SGs) are ribonucleoprotein (RNP) assemblies that form in eukaryotic cells as a result of limited translation in response to stress. SGs form during viral infection and are thought to promote the antiviral response because many viruses encode inhibitors of SG assembly. However, the antiviral endoribonuclease RNase L also alters SG formation, whereby only small punctate SG-like bodies that we term RNase L–dependent bodies (RLBs) form during RNase L activation. How RLBs relate to SGs and their mode of biogenesis is unknown. Herein, using immunofluorescence, live-cell imaging, and MS-based analyses, we demonstrate that RLBs represent a unique RNP granule with a protein and RNA composition distinct from that of SGs in response to dsRNA lipofection in human cells. We found that RLBs are also generated independently of SGs and the canonical dsRNA-induced SG biogenesis pathway, because RLBs did not require protein kinase R, phosphorylation of eukaryotic translation initiation factor 2 subunit 1 (eIF2α), the SG assembly G3BP paralogs, or release of mRNAs from ribosomes via translation elongation. Unlike the transient interactions between SGs and P-bodies, RLBs and P-bodies extensively and stably interacted. However, despite both RLBs and P-bodies exhibiting liquid-like properties, they remained distinct condensates. Taken together, these observations reveal that RNase L promotes the formation of a unique RNP complex that may have roles during the RNase L–mediated antiviral response.

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 The Herpes Simplex Virus US11 Protein Effectively Compensates for the γ134.5 Gene if Present before Activation of Protein Kinase R by Precluding Its Phosphorylation and That of the α Subunit of Eukaryotic Translation Initiation Factor 2

1998 ◽  
Vol 72 (11) ◽  
pp. 8620-8626 ◽  
Author(s):  
Kevin A. Cassady ◽  
Martin Gross ◽  
Bernard Roizman
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Kinase R ◽  
Α Subunit ◽  
Eukaryotic Translation ◽  
Initiation Factor 2 ◽  
Simplex Virus ◽  
In Cells

ABSTRACT In herpes simplex virus-infected cells, viral γ134.5 protein blocks the shutoff of protein synthesis by activated protein kinase R (PKR) by directing the protein phosphatase 1α to dephosphorylate the α subunit of eukaryotic translation initiation factor 2 (eIF-2α). The amino acid sequence of the γ134.5 protein which interacts with the phosphatase has high homology to a domain of the eukaryotic protein GADD34. A class of compensatory mutants characterized by a deletion which results in the juxtaposition of the α47 promoter next to US11, a γ2 (late) gene in wild-type virus-infected cells, has been described. In cells infected with these mutants, protein synthesis continues even in the absence of the γ134.5 gene. In these cells, PKR is activated but eIF-2α is not phosphorylated, and the phosphatase is not redirected to dephosphorylate eIF-2α. We report the following: (i) in cells infected with these mutants, US11 protein was made early in infection; (ii) US11 protein bound PKR and was phosphorylated; (iii) in in vitro assays, US11 blocked the phosphorylation of eIF-2α by PKR activated by poly(I-C); and (iv) US11 was more effective if present in the reaction mixture during the activation of PKR than if added after PKR had been activated by poly(I-C). We conclude the following: (i) in cells infected with the compensatory mutants, US11 made early in infection binds to PKR and precludes the phosphorylation of eIF-2α, whereas US11 driven by its natural promoter and expressed late in infection is ineffective; and (ii) activation of PKR by double-stranded RNA is a common impediment countered by most viruses by different mechanisms. The γ134.5 gene is not highly conserved among herpesviruses. A likely scenario is that acquisition by a progenitor of herpes simplex virus of a portion of the cellular GADD34 gene resulted in a more potent and reliable means of curbing the effects of activated PKR. US11 was retained as a γ2 gene because, like many viral proteins, it has multiple functions.

Sign in / Sign up

Export Citation Format

Share Document