Metabolic rewiring during bone development underlies tRNA m7G-associated primordial dwarfism.

Non-communicable diseases (NCDs) are medical conditions that, by definition, are non-infectious and non-transmissible among people. Much of current NCDs are generally due to genetic, behavioral, and metabolic risk factors that often include excessive alcohol consumption, smoking, obesity, and untreated elevated blood pressure, and share many common signal transduction pathways. Alterations in cell and physiological signaling and transcriptional control pathways have been well studied in several human NCDs, but these same pathways also regulate expression and function of the protein synthetic machinery and mRNA translation which have been less well investigated. Alterations in expression of specific translation factors, and disruption of canonical mRNA translational regulation, both contribute to the pathology of many NCDs. The two most common pathological alterations that contribute to NCDs discussed in this review will be the regulation of eukaryotic initiation factor 2 (eIF2) by the integrated stress response (ISR) and the mammalian target of rapamycin complex 1 (mTORC1) pathways. Both pathways integrally connect mRNA translation activity to external and internal physiological stimuli. Here, we review the role of ISR control of eIF2 activity and mTORC1 control of cap-mediated mRNA translation in some common NCDs, including Alzheimer’s disease, Parkinson’s disease, stroke, diabetes mellitus, liver cirrhosis, chronic obstructive pulmonary disease (COPD), and cardiac diseases. Our goal is to provide insights that further the understanding as to the important role of translational regulation in the pathogenesis of these diseases.

Regulation of Maternal Messenger RNA Translation during Oogenesis and Embryogenesis in Urechis caupo

Cells are continuously exposed to physiological and environmental stressors that disrupt homeostasis, triggering adaptive mechanisms such as the integrated stress response (ISR). A central feature of ISR is the selective translation of activating transcription factor 4 (ATF4), which orchestrates gene programs essential for metabolic adaptation and survival. Stress-induced acute ATF4 expression occurs in diverse mammalian cell types and is typically protective; however, chronic activation contributes to pathologies including cancer and neurodegeneration. Canonical ISR (c-ISR) is initiated by phosphorylation of eIF2α in response to stressors such as endoplasmic reticulum or mitochondrial dysfunction, hypoxia, nutrient deprivation, and infections. This modification suppresses global protein synthesis while promoting ATF4 translation through upstream open reading frames (uORFs) in its 5′UTR. Recently, an alternative pathway, split ISR (s-ISR), enabling ATF4 translation independently of eIF2α phosphorylation, was identified in mice, suggesting ISR adaptability, though its relevance in humans remains unclear. Under normal conditions, cap-dependent translation predominates, mediated by the eIF4F complex and requiring the activity of eIF2B at its initial steps. During translational stress, eIF2α phosphorylation inhibits eIF2B activity, resulting in the formation of stalled initiation complexes, which can aggregate into stress granules (SGs). SGs sequester mRNAs and translation initiation factors, further repressing global translation, while ATF4 mRNA largely escapes sequestration, enabling selective translation. This partitioning highlights a finely tuned regulatory mechanism balancing ATF4 expression during stress. Recent advances reveal that, beyond cis-regulatory uORFs, trans-acting factors such as translation initiation factors and associated RNA-binding proteins critically influence ATF4 translation. Understanding these mechanisms provides insight into ISR plasticity and its implications for development, aging, and disease.

Cell growth is influenced by environmental stress. Mammalian target of rapamycin (mTOR), the central regulator of cell growth, can be positively or negatively regulated by various stresses through different mechanisms. The p38 MAP kinase pathway is essential in cellular stress responses. Activation of MK2, a downstream kinase of p38α, enhances mTOR complex 1 (mTORC1) activity by preventing TSC2 from inhibiting mTOR activation. The p38β-PRAK cascade targets Rheb to inhibit mTORC1 activity upon glucose depletion. Here we show the activation of p38β participates in activation of mTOR complex 1 (mTORC1) induced by arsenite but not insulin, nutrients, anisomycin, or H(2)O(2). Arsenite treatment of cells activates p38β and induces interaction between p38β and Raptor, a regulatory component of mTORC1, resulting in phosphorylation of Raptor on Ser(863) and Ser(771). The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation. Our results shown here and in previous work demonstrate that the p38 pathway can regulate different components of the mTORC1 pathway, and that p38β can target different substrates to either positively or negatively regulate mTORC1 activation when a cell encounters different environmental stresses.

A Chemical Screen Identifies a Link between Lipid Metabolism and mRNA Translation

The role of hypoxia and nitrogen monoxide in the regulation of cellular iron metabolism

A metabolic basis for motor deficits in mice lacking BCKDK.

The rapamycin-sensitive mammalian target of rapamycin (mTOR) complex 1 (mTORC1) contains mTOR, raptor, mLST8, and PRAS40 (proline-rich Akt substrate of 40 kDa). PRAS40 functions as a negative regulator when bound to mTORC1, and it dissociates from mTORC1 in response to insulin. PRAS40 has been demonstrated to be a substrate of mTORC1, and one phosphorylation site, Ser-183, has been identified. In this study, we used two-dimensional phosphopeptide mapping in conjunction with mutational analysis to show that in addition to Ser-183, mTORC1 also phosphorylates Ser-212 and Ser-221 in PRAS40 when assayed in vitro. Mutation of all three residues to Ala markedly reduces mTORC1-mediated phosphorylation of PRAS40 in vitro. All three sites were confirmed to be phosphorylated in vivo by [(32)P]orthophosphate labeling and peptide mapping. Phosphorylation of Ser-221 and Ser-183 but not Ser-212 is sensitive to rapamycin treatment. Furthermore, we demonstrate that mutation of Ser-221 to Ala reduces the interaction with 14-3-3 to the same extent as mutation of Thr-246, the Akt/protein kinase B-phosphorylated site. We also find that mutation of Ser-221 to Ala increases the inhibitory activity of PRAS40 toward mTORC1. We propose that after mTORC1 kinase activation by upstream regulators, PRAS40 is phosphorylated directly by mTOR, thus contributing to the relief of PRAS40-mediated substrate competition.

Insulin-like growth factor-1 (IGF-1) is anabolic for muscle by enhancing the rate of mRNA translation via activation of AKT and subsequent activation of the mammalian target of rapamycin complex 1 (mTOR), thereby increasing cellular protein production. IGF-1 is also anabolic for bone, but whether the mTOR pathway plays a role in the rate of bone matrix protein production by osteoblasts is unknown. We hypothesized that anabolic stimuli such as mechanical loading and IGF-1 stimulate protein synthesis in osteoblasts via activation of the AKT-mTOR pathway. MC3T3-E1 osteoblasts were either or not subjected for 1 h to mechanical loading by pulsating fluid flow (PFF) or treated with or without human recombinant IGF-1 (1-100 ng/ml) for 0.5-6 h, to determine phosphorylation of AKT and p70S6K (downstream of mTOR) by Western blot. After 4 days of culture with or without the mTOR inhibitor rapamycin, total protein, DNA, and gene expression were quantified. IGF-1 (100 ng/ml) reduced IGF-1 gene expression, although PFF enhanced IGF-1 expression. IGF-1 did not affect collagen-I gene expression. IGF-1 dose-dependently enhanced AKT and p70S6K phosphorylation at 2 and 6 h. PFF enhanced phosphorylation of AKT and p70S6K already within 1 h. Both IGF-1 and PFF enhanced total protein per cell by ∼30%, but not in the presence of rapamycin. Our results show that IGF-1 and PFF activate mTOR, thereby stimulating the rate of mRNA translation in osteoblasts. The known anabolic effect of mechanical loading and IGF-1 on bone may thus be partly explained by mTOR-mediated enhanced protein synthesis in osteoblasts.

BackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by synapse failure and cognitive decline. Brain mRNA translation is central to synaptic plasticity and cognition, and converging evidence indicates it is impaired in AD. The mammalian target of rapamycin complex 1 (mTORC1) pathway plays a key role in regulating protein synthesis, and mTORC1 signaling has received considerable attention in AD research. In this current work, we investigated whether stimulating mTORC1‐mediated protein synthesis can alleviate the impairments in synaptic plasticity and memory in AD mice.MethodTo address this question, we used two different approaches: 1. genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)‐binding protein 2 (4E‐BP2); and 2. pharmacological treatment with (2R,6R)‐hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine that stimulates mTORC1 signaling.ResultOur results showed that genetic reduction of FMRP and 4E‐BP2 prevented the inhibition of hippocampal protein synthesis and memory impairment induced by amyloid‐β oligomers (AβOs) in mice. Reduction of 4E‐BP2 further rescued memory deficits in the APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Moreover, HNK treatment prevented deficits in long‐term potentiation (LTP) and fear memory in AbO‐infused and APP/PS1 mice.ConclusionTaken together, our findings indicate that strategies targeting mRNA translation correct hippocampal protein synthesis, synaptic plasticity and memory deficits in AD models, and raise the prospect that HNK could emerge as a therapeutic approach in AD.

Fertility and embryonic viability are measures of efficient germ cell growth and development. During oogenesis and spermatogenesis, new proteins are required for both mitotic expansion and differentiation. Qualitative and quantitative changes in protein synthesis occur by translational control of mRNAs, mediated in part by eIF4E, which binds the mRNAs 5' cap. IFE-1 is one of five eIF4E isoforms identified in C. elegans. IFE-1 is expressed primarily in the germ line and associates with P granules, large mRNPs that store mRNAs. We isolated a strain that lacks IFE-1 [ife-1(bn127)] and demonstrated that the translation of several maternal mRNAs (pos-1, pal-1, mex-1 and oma-1) was inefficient relative to that in wild-type worms. At 25 degrees C, ife-1(bn127) spermatocytes failed in cytokinesis, prematurely expressed the pro-apoptotic protein CED-4/Apaf-1, and accumulated as multinucleate cells unable to mature to spermatids. A modest defect in oocyte development was also observed. Oocytes progressed normally through mitosis and meiosis, but subsequent production of competent oocytes became limiting, even in the presence of wild-type sperm. Combined gametogenesis defects decreased worm fertility by 80% at 20 degrees C; ife-1 worms were completely sterile at 25 degrees C. Thus, IFE-1 plays independent roles in late oogenesis and spermatogenesis through selective translation of germline-specific mRNAs.

Ribosomes have been long considered as executors of the translational program. The fact that ribosomes can control the translation of specific mRNAs or entire cellular programs is often neglected. Ribosomopathies, inherited diseases with mutations in ribosomal factors, show tissue specific defects and cancer predisposition. Studies of ribosomopathies have paved the way to the concept that ribosomes may control translation of specific mRNAs. Studies in Drosophila and mice support the existence of heterogeneous ribosomes that differentially translate mRNAs to coordinate cellular programs. Recent studies have now shown that ribosomal activity is not only a critical regulator of growth but also of metabolism. For instance, glycolysis and mitochondrial function have been found to be affected by ribosomal availability. Also, ATP levels drop in models of ribosomopathies. We discuss findings highlighting the relevance of ribosome heterogeneity in physiological and pathological conditions, as well as the possibility that in rate-limiting situations, ribosomes may favor some translational programs. We discuss the effects of ribosome heterogeneity on cellular metabolism, tumorigenesis and aging. We speculate a scenario in which ribosomes are not only executors of a metabolic program but act as modulators.

Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. We leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis, and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an Interleukin-17a dependent manner, thereby reducing global mRNA translation and altering nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as an increase in cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.

mTORC1 Controls Mitochondrial Activity and Biogenesis through 4E-BP-Dependent Translational Regulation

Dendritic cells (DCs) are important antigen presenting cells that sense the extra-and intracellular environment to process antigens for the instruction of T cell responses.The mammalian target of rapamycin (mTOR) is an evolutionary conservative serine/threonine kinase involved in many cellular processes.This review discusses how DCs use mTOR complexes (mTORC1 and mTOC 2) to adapt their cellular metabolism, transcriptional responses, and translation machinery to control DC development, antigen processing, cytokine production, and T cell activation.mTOR plays a central role that regulates DC differentiation and immune functions. Key words: Dendritic cells; Mammalian target of rapamycin; Immune regulation