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Viral Noncoding RNAs in Modulating Cellular Defense and Their Potential for RNA Nanotechnology
Published in Peixuan Guo, Kirill A. Afonin, RNA Nanotechnology and Therapeutics, 2022
Martin Panigaj, Marina A. Dobrovolskaia, Kirill A. Afonin
The ISGs-encoded RNA-dependent protein kinase R (PKR) and oligoadenylate synthase (OAS) together with RNase L are core enzymes guarding host translation. PKR and OAS are both activated by dsRNA (dsRNA genomes, intermediates in RNA virus genome replication, and secondary structures in ssRNA or bidirectional transcription). Activated PKR phosphorylates the subunit α of eukaryotic initiation factor 2 (eIF2α) leading to inactivation of eIF2 and subsequent overall inhibition of translation initiation. The OAS activity is triggered by dsRNA, too, but in turn it synthesizes second messenger 2′-5′ oligoadenylate (2′-5′ OA) from ATP. Next, 2′-5′ OA binds to an endogenous ribonuclease RNase L, activated monomeric RNase L dimerizes and then cleaves all RNA in the cell leading to apoptosis [49].
Molecular and Cellular Pathogenesis of Systemic Lupus Erythematosus
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
George C. Tsokos, Yuang-Taung Juang, Christos G. Tsokos, Madhusoodana P. Nambiar
Studies on adenyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) system, a key metabolic pathway integral to cellular homeostasis, identified impaired cyclic adenosine monophosphate-dependent protein phosphorylation in SLE T cells.46,47 Abnormal cyclic adenosine monophosphate-dependent signaling pathway is associated with deficient CD8 suppressor T cell function and altered cytoskeletal regulation of CD3, CD4 and CD8 receptor mobility within the plane of the plasma membrane.48,49 Recently, it has been demonstrated that abnormal cyclic adenosine monophosphate-dependent signaling pathway reflects a profound reduction in protein kinase A-I (PKA-I) isozyme.50 Deficient PKA-I activity is the consequence of reduced type I regulatory subunit. Deficient T cell PKA-I activity reflects reduction of both holoenzymes RIß2C2 >RIα2C2.51 Deficient PKA-I activity possibly contributes to altered T cell effector function by altering the protein phosphorylation that regulates cellular pathways that promote cell growth and differentiation. Similar to T cell receptor ζ chain, increased mutation/polymorphism of PKA-I regulatory subunit α has been reported in a SLE patient.52 The kinase activity of protein kinase C (PKC)53 and lymphocyte-specific protein tyrosine kinase (LcK) is also impaired in SLE T cells.54 The activity of other kinases, such as protein kinase R (PKR) that is involved in the phosphorylation of translation initiation factors, is increased in SLE T cells.55
Effects of a resistance-training programme on endoplasmic reticulum unfolded protein response and mitochondrial functions in PBMCs from elderly subjects
Published in European Journal of Sport Science, 2019
Brisamar Estébanez, Osvaldo C. Moreira, Mar Almar, José A. de Paz, Javier Gonzalez-Gallego, María J. Cuevas
Aging has been related to loss of proteostasis, which leads to the accumulation of unfolded or misfolded proteins inside the endoplasmic reticulum (ER) lumen. This accumulation triggers ER stress (ERS) and alterations in unfolded protein response (UPR) (Pereira et al., 2016), linked to aging-related diseases (López-Otín, Blasco, Partridge, Serrano, & Kroemer, 2013). In order to decrease the ER protein load, and thus the ERS, the UPR drives to the upregulation of ER chaperones to promote protein refolding, such as binding immunoglobulin protein (BiP), and to the downregulation of protein translation, through the activation of stress sensors such as protein kinase R (PKR)-like ER kinase (PERK), inositol-requiring enzyme (IRE)1, and activating transcription factor (ATF)6 (Grootjans, Kaser, Kaufman, & Blumberg, 2016). Under physiological conditions, the luminal domains of BiP bind to the three main stress sensors to repress their activity. Nevertheless, unfolded proteins accumulated in the ER lumen dissociate BiP from the effectors PERK, IRE1 and ATF6, which control the expression of downstream transcription factors XBP1 (X-box binding protein 1), ATF4, and ATF6α-p50, respectively (Nakka, Prakash-Babu, & Vemuganti, 2016). These factors modulate the expression of proteins involved in redox homeostasis, protein secretion or cell death programmes (Senft & Ronai, 2015). Moreover, a prolonged ATF4 activation leads to induction of proinflammatory transcription factor C/EBP homologous protein (CHOP) (Nakka et al., 2016).