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A critical host response against viral infections entails the activation of innate immune signaling that culminates in the production of antiviral proteins. DNA viruses are sensed by the cytosolic pattern recognition receptor cyclic GMP–AMP synthase (cGAS), which initiates a signaling pathway that results in production of proinflammatory cytokines such as Interferon-β (IFN-β) and activation of the antiviral response. Precise regulation of the antiviral innate immune response is required to avoid deleterious effects of its overactivation. We previously reported that the 4EHP/GIGYF2 translational repressor complex reduces the translation of Ifnb1 mRNA, which encodes IFN-β, upon RNA viral infections. Here, we report a distinct regulatory mechanism by which 4EHP controls replication of DNA viruses by translational repression of the Cgas mRNA, which encodes the DNA viral sensor cGAS. We show that 4EHP is required for effective translational repression of Cgas mRNA triggered by miR-23a. Upon infection, 4EHP deficiency bolsters the elicited innate immune response against the diverse DNA viruses Herpes simplex virus 1 (HSV-1) and Vaccinia Virus (VacV) and concomitantly reduces their rate of replication in vitro and in vivo. This study elucidates an intrinsic regulatory mechanism of the host response to DNA viruses which may provide unique opportunities for countering viral infections. [ABSTRACT FROM AUTHOR]

The integrated stress response (ISR), a pivotal protein homeostasis network, plays a critical role in the formation of long-term memory (LTM). The precise mechanism by which the ISR controls LTM is not well understood. Here, we report insights into how the ISR modulates the mnemonic process by using targeted deletion of the activating transcription factor 4 (ATF4), a key downstream effector of the ISR, in various neuronal and non-neuronal cell types. We found that the removal of ATF4 from forebrain excitatory neurons (but not from inhibitory neurons, cholinergic neurons, or astrocytes) enhances LTM formation. Furthermore, the deletion of ATF4 in excitatory neurons lowers the threshold for the induction of long-term potentiation, a cellular model for LTM. Transcriptomic and proteomic analyses revealed that ATF4 deletion in excitatory neurons leads to upregulation of components of oxidative phosphorylation pathways, which are critical for ATP production. Thus, we conclude that ATF4 functions as a memory repressor selectively within excitatory neurons. [ABSTRACT FROM AUTHOR]

Background: Activation of the mTOR pathway is pivotal for microglia to induce and sustain neuroprotective functions (Ulland et al., 2017; Wang et al., 2022). mTOR complex 1 (mTORC1) inhibits the translation repressors, eukaryotic translation Initiation Factor 4E (eIF4E)‐Binding Proteins (4E‐BPs), via phosphorylation, which causes their release from eIF4E to promote mRNA translation (Hay and Sonenberg, 2004). mTORC1 promotes mitochondrial biogenesis via inhibition of 4E‐BPs, by preferentially stimulating the translation of mitochondria‐related mRNAs (Gandin et al., 2016; Morita et al., 2013). We investigated the mechanisms at the intersection of 4E‐BP‐dependent translational regulation and metabolism in microglial response to soluble Aβ. Method: We carried out immunoblot analysis to investigate the phosphorylation status of 4E‐BP1, the isoform most abundant in microglia, following exposure to Ab. We manipulated the mTOR pathway by knocking out the downstream effectors, 4E‐BPs, to alleviate translation suppression in microglia in vitro and in vivo. We crossed the microglia‐specific 4E‐BPs knockout mouse with a RiboTag mouse to pull‐down ribosome‐bound mRNAs, providing a genome‐wide pool of actively translating mRNAs in the absence or presence of 4E‐BPs. Finally, we examined the relationship between 4E‐BP1 levels and neuroinflammation markers in cerebrospinal fluid (CSF) of AD patients. Result: We showed that 4E‐BP1 is inhibited acutely upon exposure to soluble Ab, which is dependent on Spleen Tyrosine Kinase (SYK) activation upstream of mTORC1, but is reduced upon chronic exposure. Furthermore, 4E‐BP1 expression is induced during prolonged exposure to Ab. The deletion of 4E‐BPs in microglia in vitro leads to an increase in mitochondrial mass and reliance on oxidative phosphorylation while decreasing expression of pro‐inflammatory mediators and cell death upon exposure to Ab. We observed that increased levels of 4E‐BP1 in the CSF of patients with Aβ pathology are associated with higher neurodegeneration (Nfl) in the presence of microglial activation. Conclusion: We demonstrate that mTORC1 signaling critically impacts microglia physiology and promotes neuroprotective functions via 4E‐BP1 inhibition. 4E‐BP1 activity in microglia engenders a dysfunctional or detrimental state that may lead to increased neurodegeneration. Therefore, 4E‐BP1 is an attractive target for microglia modulation in AD. [ABSTRACT FROM AUTHOR]

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-ß. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-ß production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses. [ABSTRACT FROM AUTHOR]

The branched-chain amino acids (BCAAs), namely, valine, leucine, and isoleucine, are indispensable amino acids required for body protein synthesis. Unlike other amino acids, the BCAAs are primarily catabolised in the extrahepatic tissues. The BCAAs play role in regulation of protein synthesis and turnover as well as maintenance of the body glutamate-glutamine level. In strenuous and traumatic conditions, the BCAAs are oxidized which limits their availability in tissues. Such condition affects the body glutamate-glutamine pool and protein synthesis mechanisms. Thus BCCA supplementation is emerging as a nutritional strategy for treating many diseases. Many studies have found that BCAA administration is able to improve the health status of the patients suffering from different diseases even though there are conditions where they do not exert any effect. There are also some reports where elevated BCAAs have been shown to be associated with the pathogenesis of diseases. In this review, we have discussed the implication of BCAA supplementation in different pathological conditions and their relevant outcomes. [ABSTRACT FROM AUTHOR]

Two of the most widely and intensively cultivated jute species, Corchorus capsularis and Corchorus olitorius, suffer severely from a stem rot disease caused by the fungus Macrophomina phaseolina. Wild jute species, C. trilocularis, shows resistance to this pathogenic fungus. In this study, the technique of diferential display was applied to identify genes which are diferentially expressed, under both infected and un-infected conditions, between C. trilocularis and C. olitorius var O-72. Two xyloglucan endotransglycosylase/hydrolase (XTH) genes designated CoXTH1 (from Corchorus olitorius) and CtXTH1 (from C. trilocularis) were identiied from each of the two species which show different expression patterns upon fungal infection. A steady rise in the expression of CtXTH1 in response to infection was observed by quantitative real time PCR whereas the expression of CoXTH1 was found to be downregulated. Full length sequences of these two genes were determined using primer based gene walking and RACE PCR. This study confirms the involvement of XTH in molecular interactions between M. phaseolina and jute. However, it remains to be explored whether XTH is an essential component of the signaling pathway involved in plant-fungal interaction. [ABSTRACT FROM AUTHOR]

Messenger RNA (mRNA) translational control plays a pivotal role in regulating cellular proteostasis under physiological and pathological conditions. Dysregulated mRNA translation is pervasive in cancer, in which protein synthesis is elevated to support accelerated cell growth and proliferation. Consequently, targeting the mRNA translation machinery has emerged as a therapeutic strategy to treat cancer. In this perspective, we summarize the current knowledge of translation dysregulation in cancer, with emphasis on the eukaryotic translation initiation factor 4F (eIF4F) complex. We outline recent endeavors to apply this knowledge to develop novel treatment strategies to combat cancer., (Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Memory formation is contingent on molecular and structural changes in neurons in response to learning stimuli-a process known as neuronal plasticity. The initiation step of mRNA translation is a gatekeeper of long-term memory by controlling the production of plasticity-related proteins in the brain. The mechanistic target of rapamycin complex 1 (mTORC1) controls mRNA translation, mainly through phosphorylation of the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and ribosomal protein S6 kinases (S6Ks). mTORC1 signaling decreases throughout brain development, starting from the early postnatal period. Here, we discovered that in mice, the age-dependent decrease in mTORC1 signaling occurs selectively in excitatory but not inhibitory neurons. Using a gene conditional knockout (cKO) strategy, we demonstrate that either up- or downregulating the mTORC1-4E-BP2 axis in GAD65 inhibitory interneurons, but not excitatory neurons, results in long-term object recognition and object location memory deficits. Our data indicate that the mTORC1 pathway in inhibitory but not excitatory neurons plays a key role in memory formation., (© 2024 Huang et al.; Published by Cold Spring Harbor Laboratory Press.)