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Neuropathogenesis of viral infections
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Avindra Nath, Joseph R. Berger
Once a cell binds IFN-α or IFN-β, which use a common receptor, a cascade of cellular signaling occurs resulting in the transcription of several proteins that aid in conferring a hostile environment to viral infection. There are three key antiviral proteins that have been identified as a result of this transcriptional activation: 2′–5′ oligoadenylate synthetase, protein kinase PKR and Mx protein [31]. The 2′–5′ oligoadenylate synthetase polymerizes adenosine triphosphate into a series of 2′–5′ linked oligomers, which differs from normal nucleotides that are joined 3′–5′. These oligomers in turn activate RNase L, a constitutive endoribonuclease. This enzyme degrades viral RNA. Protein kinase PKR is activated by the presence of double-stranded RNA. Upon activation, PKR phosphorylates the cellular translation initiation factor eIF-2. The result of this is an inhibition of translation and protein synthesis, contributing to the inhibition of viral replication. The Mx protein is a protein that acts in the nucleus of an infected cell to confer resistance to influenza virus. The Mx protein acts in the nucleus of the cell infected with influenza and inhibits the synthesis of the influenza virus mRNA [32].
Soluble Mediators of Cellular Cooperation: The Cytokines
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Biological activities. Type 1 IFNs activate several non-specific antiviral mechanisms. IFNs induce the production of two enzymes (and others, less well-characterized) which may affect synthesis of viral proteins during infection. These are a protein kinase, and a 2’–5’ oligoadenylate synthetase. Double-stranded RNA (dsRNA) appears to be required for activity of these proteins. While dsRNA does not normally occur in eukaryotic cells, it is found as an intermediate in replication of many viruses. The protein kinase inactivates eukaryotic initiation factor-2a (eIF-2a), thereby inhibiting protein synthesis. The 2’-5’ oligo-A synthetase forms 2’-5’ oligoadenylic acid, a cofactor needed for activity of an endogenous ribonuclease, RNAse L. RNAse L degrades messenger and ribosomal RNAs.
Protein and amino acids
Published in Jay R Hoffman, Dietary Supplementation in Sport and Exercise, 2019
The EAAs play a role in regulating MPS by enhancing the efficiency of translation (34) due to a stimulation of peptide chain initiation relative to elongation (40). Peptide-chain initiation involves dissociation of the 80S ribosome into 40S and 60S ribosomal subunits, formation of the 43S preinitiation complex with binding of initiator methionyl-tRNA to the 40S subunit, binding of mRNA to the 43S preinitiation complex and association of the 60S ribosomal subunit to form an active 80S ribosome (74). First, peptide chain initiation is controlled by the binding of initiator methionyl tRNA to the 40S ribosomal subunit to form the 43S preinitiation complex, a reaction mediated by eukaryotic initiation factor 2 (eIF2) and regulated by eIF2B. Second is the binding of mRNA to the 43S preinitiation complex, which is mediated by eIF4F (73). During translation initiation, the eIF4E·mRNA complex binds to eIF4G and eIF4A to form the active eIF4F complex (63). The binding of eIF4E to eIF4G is controlled by 4E-binding protein 1 (4E-BP1), a repressor of translation. Binding of 4E-BP1 to eIF4E limits eIF4E availability for formation of active eIF4E·eIF4G complex and is regulated by phosphorylation of 4E-BP1 (73).
Isocaloric low protein diet in a mouse model for vanishing white matter does not impact ISR deregulation in brain, but reveals ISR deregulation in liver
Published in Nutritional Neuroscience, 2022
Lisanne E. Wisse, Denise Visser, Timo J. ter Braak, Abdellatif Bakkali, Eduard A. Struys, Christopher D. Morrison, Marjo S. van der Knaap, Truus E. M. Abbink
Vanishing white matter (VWM) is a chronic progressive neurological disease with rapid worsening of the disease provoked by stressors, especially febrile infections.1,2 Progression of the chronic disease is inversely correlated with the age of onset.3 VWM is caused by mutations in any of the five subunits of eIF2B with a reported genotype-phenotype correlation.3,4 eIF2B is essential for the protein synthesis and is a key factor of the integrated stress response (ISR).5 This ISR is activated by various types of proteotoxic stimuli, each activating a kinase that phosphorylates the α subunit of eIF2, e.g. protein kinase R (PKR) activated by viral infections, or general control non-derepressible 2 (GCN2) by shortage of amino acids.6 Phosphorylated eIF2 reduces eIF2B activity,5 which decreases general protein synthesis rates, yet increases the synthesis of specific proteins such as the transcription factor ATF4.7,8 These specific proteins induce a change in the transcription profile as a part of the ISR.6 Expression of this 'ISR transcriptome' is initially aimed to protect cells and restore proteostasis, but leads to cell death when the stress is long lasting or severe.
Design of novel PhMTNA inhibitors, targeting neurological disorder through homology modeling, molecular docking, and dynamics approaches
Published in Journal of Receptors and Signal Transduction, 2019
Prajisha Jayaprakash, Jayashree Biswal, Sureka Kanagarajan, Dhamodharan Prabhu, Prerana Gogoi, Shankar Prasad Kanaujia, Jeyaraman Jeyakanthan
VWM is characterized by progressive loss of brain white matter that affects the glial cells (Astrocytes and Oligodendrocytes), which comprises of the blood-brain barrier and form myelin sheaths to insulate neuronal axons. There are over hundred different eIF2B missense mutations in which any one of the ubiquitously expressed genes encoding the five subunits of eukaryotic translation initiation that have been associated with the varying levels of disorder. Eukaryotic Translation Initiation Factor 2B (eIF2B) [2] plays an essential role during the initiation and regulation of protein biosynthesis. During protein synthesis, eIF2 bound to a GTP molecule (eIF2•GTP) assists in the delivery of the initiator tRNA (Met-tRNAiMet) to the small (30S) ribosomal subunit [3]. Upon delivery, the active eIF2•GTP gets converted to inactive eIF2•GDP and thus, has to be converted back to its active form for the consecutive rounds of translation initiation to occur [4]. This reactivation is carried out by the heterodecameric Guanine Nucleotide Exchange factor (GEF). Under stress conditions, eIF2B regulates the process of protein biosynthesis by rate limiting the translation initiation [5]. It has been reported that mutations in any of the eIF2B subunits lead to severe autosomal recessive neurodegenerative disorder which is termed as leukoencephalopathy with VWM [6].
Co-exposure to silver nanoparticles and cadmium induce metabolic adaptation in HepG2 cells
Published in Nanotoxicology, 2018
Renata Rank Miranda, Vladimir Gorshkov, Barbara Korzeniowska, Stefan J. Kempf, Francisco Filipak Neto, Frank Kjeldsen
Attenuation of mRNA translation, via phosphorylation of eIF2, is an initial cellular response to a wide range of stressors, including nutrient deprivation and accumulation of misfolded proteins. In this manner, cells conserve resources while a new gene expression program is adopted to prevent further damage (Baird and Wek 2012; Donnelly et al. 2013). The eIF2 canonical pathway was significantly altered after the 24-h exposures to AgNP and Cd2+ (Figure 7(B)), owing to the downregulation of ribosome subunits and proteins involved in translation initiation (Figure 6(B,C); Supplementary Table 8). A different outcome, however, was observed following the combined exposure (AgNP + Cd2+). Although downregulation of ribosomal proteins and proteins involved in translation initiation also occurred, higher numbers of these proteins were upregulated (Figure 6(D,E)); Supplementary Table 8). Moreover, more upregulated than downregulated proteins were observed (Figure 5(B)). Cells co-exposed to several contaminants may activate transcription and translation of key proteins in response to cellular stress. In particular, we observed upregulation of proteins normally required for reestablishment of energy status, such as those involved in oxidative phosphorylation, mitochondrial functioning, and lipid metabolism, although this response was not sufficient to avoid or attenuate an abnormal ADP/ATP imbalance and cell death (Figures 2 and 3). Deregulation of this pathway may have also resulted in reduced levels of proteins involved in antioxidant defense, proteasome activity, and protein repair, as discussed above.