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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].
Anticancer therapy and lung injury: molecular mechanisms
Published in Expert Review of Anticancer Therapy, 2018
Li Li, Henry Mok, Pavan Jhaveri, Mark D Bonnen, Andrew G Sikora, N. Tony Eissa, Ritsuko U Komaki, Yohannes T Ghebre
Is an anticancer drug used for over 40 years in the treatment of cancers of the breast and upper gastrointestinal tract. As an antitumor antibiotics, one of its main mechanisms in killing bacteria and cancer cells is the potent DNA cross-linking activity by which mitomycin is chemically transformed to mitosene; a DNA reactive compound [9]. As a result, mitomycin C is involved in inhibition of DNA synthesis, induction of genetic recombination events, and mutagenesis of mammalian DNA. In addition, the drug is involved in the generation of ROS and other species that are highly tissue reactive and capable of causing apoptotic cell death and tissue injury [10]. One of the tissues that suffer collateral damage upon mitomycin C treatment is the lungs. The use of mitomycin C in some cancer patients is associated with higher incidences of interstitial pneumonitis, pulmonary fibrosis and pulmonary veno-occlusive disease (PVOD) [11]. Mechanistically, mitomycin C-induced pulmonary injury might be associated with the downregulation of members of the SMAD signaling pathway and inhibition of the general control nonderepressible 2 protein (GCN2); a protein encoded by the Eukaryotic Translation Initiation Factor 2 α Kinase 4 (EIF2 αK4) [11]. Genetic mutations in the EIF2 αK4 gene are reported to be associated with hereditary PVOD [12].