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Results for “ribosome quality control”

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PubMed2025

Chromosome duplication causes premature aging via defects in ribosome quality control.

Down syndrome, caused by an extra copy of Chromosome 21, causes lifelong problems. One of the most common phenotypes among people with Down syndrome is premature aging, including early tissue decline, neurodegeneration, and shortened life span. Yet the reasons for premature systemic aging are a mystery and difficult to study in humans. Here we show that chromosome amplification in wild yeast also produces premature aging and shortens life span. Chromosome duplication disrupts nutrient-induced cell-cycle arrest, entry into quiescence, and cellular health during chronological aging, across genetic background and independent of which chromosome is amplified. Using a genomic screen, we discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). We show that aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates compared to euploid cells. Although they maintain proteasome activity, aneuploids also show signs of ubiquitin dysregulation and sequestration into foci. Remarkably, inducing ribosome stalling in euploids produces similar aging phenotypes, while up-regulating limiting RQC subunits or poly-ubiquitin alleviates many of the aneuploid defects. We propose that the increased translational load caused by having too many mRNAs accelerates a decline in translational fidelity, contributing to premature aging.

Ribosomes↗

PubMed2026

The Tor pathway, ribosome concentration, and wobble decoding mediate inhibitory effects of the Leu-Pro CUC-CCG codon pair in Saccharomyces cerevisiae.

Translation elongation and efficiency are modulated by the genetic code, with reduced translation efficiency and slow translation caused by 17 inhibitory codon pairs in the yeast Saccharomyces cerevisiae Nine of these inhibitory pairs are functionally important as they are disproportionately strongly conserved within orthologous genes in Saccharomyces sensu stricto For three pairs, including CGA-CGA, inhibition is triggered by ribosome collisions followed by known quality control responses, but the mechanisms by which nine other pairs cause inhibition are unknown. Here, our examination of the molecular basis of inhibition by one such pair, the highly conserved Leu-Pro CUC-CCG codon pair, yielded four findings. First, inhibition is mediated by tRNALeu(UAG), which decodes CUC by a U•C wobble interaction and effectively competes with the nonessential Watson-Crick base-pairing tRNALeu(GAG) Second, despite nearly universal conservation of U33 in tRNAs, the C33 alteration in tRNALeu(GAG) does not significantly impair its function. Third, inhibition likely is mediated by ribosome collisions, as many suppressors bear mutations known or predicted to reduce ribosome concentration, and as local reduction in ribosome concentration suppresses inhibition. Thus, differences between CUC-CCG and CGA-CGA inhibition likely occur downstream from ribosome collisions. Fourth, we find a link between the metabolic state and CUC-CCG inhibition, as we find six suppressor mutations in SCH9, a downstream effector of TORC1 that mediates ribosome production. As Sch9 is inactive during starvation, causing reduced ribosome concentration, one biological function of inhibitory pairs may be to mediate a change in relative expression during starvation conditions.

Ribosomes↗

PubMed2026

Comparative toxicoproteomics reveals distinct proteostasis and ribosomal stress signatures of CMIT and PHMG.

Methylchloroisothiazolinone (CMIT) and polyhexamethylene guanidine (PHMG) are antimicrobial biocides associated with pulmonary toxicity, although their comparative cellular stress mechanisms remain unclear. Here, we investigated how CMIT and PHMG differentially alter the proteome of human alveolar epithelial A549 cells under subcytotoxic conditions. Cells were exposed to CMIT or PHMG, and global proteomic profiling was performed using label-free liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) were identified at a 1% false discovery rate with an absolute log2 fold change ≥1. Functional analyses were conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis, and selected proteins were validated by western blotting. Comparative toxicoproteomics revealed distinct stress-response signatures induced by the two biocides. CMIT preferentially altered proteins associated with proteostasis, oxidative stress, and protein quality control, whereas PHMG was characterized by coordinated depletion of ribosome-associated and translation-related proteins. A total of 73 and 155 DEPs were identified in CMIT- and PHMG-treated cells, respectively, with 22 proteins shared between treatments. Western blotting confirmed PSMD3, TUBB2A, and GLRX1 as CMIT-responsive proteins and THRAP3, DHX15, and RPL4 as PHMG-responsive markers. These findings provide comparative mechanistic insight into how CMIT and PHMG induce distinct epithelial stress responses and identify candidate protein markers that may support future in vitro assessment of biocide-induced pulmonary toxicity.

CMIT↗

PubMed2026

Mathematical modeling of dietary timing- and protein quality-responsive liver circadian clock and its function on ribosome biogenesis.

Independent of the suprachiasmatic nucleus, peripheral clocks can be strongly entrained by dietary signals. Although feeding time has been widely studied, the effects of food quality-particularly nutrient availability and stress-on peripheral circadian entrainment and metabolic regulation remain less understood. We developed a semimechanistic mathematical model of peripheral clock synchronization and clock-controlled ribosome biogenesis (RiBi) in response to feeding/fasting cycles and rhythms in dietary essential amino acid (EAA) availability. The model integrates EAA-sensitive signaling through mammalian target of rapamycin complex 1 (mTORC1) and the general control nonderepressible 2 (GCN2)-mediated integrated stress response (ISR), together with ribosomal protein expression as a metabolic endpoint. We used the model to examine circadian entrainment under nutrient stress, adaptation during transitions between feeding schedules with EAA insufficiency, and stress-related mechanisms that may restore circadian and metabolic function. Simulations showed that mTORC1 and GCN2-ISR signaling jointly regulate metabolic entrainability and stress adaptation and are required to maintain circadian synchronization and RiBi dynamics during nutrient stress. The model also predicted that differences in homeostatic adaptation can produce individualized recovery trajectories after transient dietary disruption. Finally, appropriate modulation of GCN2-ISR signaling mitigated disruption-associated RiBi hyperactivation by leveraging dietary EAA rhythms to restore clock function. These findings identify dietary EAA stress and its regulatory pathways as important determinants of peripheral circadian entrainment and metabolic adaptation, supporting the development of personalized nutrition-based strategies for circadian disruption-related chronic disease.NEW & NOTEWORTHY This study provides a mechanistic modeling framework linking dietary protein quality, EAA-sensitive mTORC1/GCN2-ISR signaling, peripheral circadian entrainment, and ribosome biogenesis, highlighting how nutrient stress may shape individualized circadian recovery and metabolic regulation.

Circadian Clocks↗

PubMed1977

In vitro transcription of the ribosomal RNA genes of E. coli DNA.

Bacterial ribosomal RNA synthesis was studied in an in vitro system in which the presence of heparin prevented reinitiation of transcription. The number of heparin-resistant binary complexes of RNA-polymerase and E. coli DNA depended strongly on the quality of the template. High-molecular weight DNA was a much superior template than DNA prepared by conventional techniques. Using this high-molecular weight DNA as template the amount of ribosomal RNA synthetized in one round of transcription was found to be 4-5 fold higher than the amount of rDNA present. Controls have shown that the transcription probably started at the proper initiation sites and no significant read-through form distant promoters contributed to this effect. If the binary polymerase-DNA complexes were dissociated in the presence of 0.5 M KC1 prior to transcription all RNA synthesis was strongly reduced but the proportion of rRNA increased in the transcript. However, in this case the amount of rRNA did not exceed the amount of rDNA. We propose that the promoters of the rRNA genes are complex structures, able to store 4-5 molecules of RNA polymerase and of these several polymerase only one is bound in an extremely salt-resistant form.

DNA, Bacterial↗

PubMedDate not supplied

Correlation between serum high density lipoprotein content and liver function during experimental hepatic degeneration and regeneration.

Intravenous injection of praseodymium nitrate into female Wistar rats results in liver damage. The aim of this study is to investigate the quality of serum high density lipoprotein content as an index for the severity and time course of liver damage and regeneration following the administration of praseodymium. Serum high density lipoprotein content drastically decreases to a minimum after 24 - 48 h, returning to control values after four days. Liver degeneration is characterized by some intracellular parameters, i.e. the nuclear RNA polymerase reactions, the ribosomal protein synthesis, hepatic spermidine concentration and the activities of serum transaminases (GOT, GPT) and the sorbitdehydrogenase. From the data it is evident that the time course of serum high density lipoprotein content follows the intracellular changes closely. Liver regeneration is represented by the ornithin decarboxylase, the deoxycytidylate deaminase, the thymidine kinase activities and the hepatic putrescine content. The time course of these parameters shows that the regeneration reaches a maximum after 3 - 4 days. In the serum, high density lipoprotein content reflects this process by returning to control values. From our data we conclude that serum high density lipoprotein content after i.v. administration of praseodymium can be considered as an expression of the functional state of the liver.

Animals↗

PubMed2026

Long-term microbiome and clinical effects of a microbiome-guided personalized diet versus low-FODMAP diet in irritable bowel syndrome: A 12-month follow-up randomized controlled trial.

Dietary therapy is central to irritable bowel syndrome (IBS) management, yet the long-term durability of the low-FODMAP diet (LFD), and of microbiome-guided personalization, remains unclear. We assessed the long-term clinical and gut-microbiome effects of a microbiome-guided personalized diet (PD) compared with a standard LFD in adults meeting Rome IV criteria for IBS. In this multicenter, open-label randomized controlled trial with blinded outcome assessment, participants who completed a 6-week dietary intervention (PD or LFD) were followed at 6 and 12 months without further dietary intervention. Outcomes included the IBS Severity Scoring System (IBS-SSS), IBS Quality of Life (IBS-QOL), and the Hospital Anxiety and Depression Scale (HADS); gut microbiota were profiled by 16S rRNA sequencing. Longitudinal changes were evaluated using linear mixed-effects models, responder analyses, PERMANOVA, and PERMDISP. Both diets reduced IBS-SSS at 6 weeks. PD maintained symptom improvement at 6 and 12 months (-82.0 and -78.3 points from baseline), whereas LFD benefits regressed by 12 months (+29.3 points; between-group p = 0.001). At 12 months, IBS-SSS responder rates were higher with PD than LFD (62.5% vs 34.5%; absolute risk difference +28.0%, 95% CI 4.2-47.7; Fisher p = 0.029), and IBS-QOL, HADS-anxiety, and HADS-depression showed more favourable trajectories with PD. PD was associated with sustained Shannon alpha-diversity gains (+0.488 at 6 weeks; +0.205 at 12 months; both p < 0.01). A modest between-group beta-diversity difference at 6 months (R2 = 0.035; p = 0.011) was not significant at 12 months. This hypothesis-generating follow-up suggests more durable benefit with PD; larger trials powered for long-term clinical and microbiome outcomes are warranted.

Humans↗

PubMed2026

Genes near tRNAs are enriched in translational machinery.

Transfer RNAs (tRNAs) are known for delivering amino acids to the growing polypeptide chain during translation. They can also influence gene expression, especially in times of nutrient starvation, through differential tRNA expression and modification. Transfer RNAs have a highly consistent cloverleaf structure, but relatively few known regulatory elements govern this conserved structure despite the 20 different standard isotypes. This study examines gene enrichment patterns near tRNA genes across 1149 fungal genomes. Genes enriched in proteasome regulation, ion transport, and rRNA were found to be significantly closer to tRNAs than other pathways. These results were consistent across KEGG overrepresentation analysis (ORA), KEGG gene set enrichment analysis (GSEA), and gene ontology (GO) analysis. Proteasome, ion transport, and RNA are all important aspects of protein production and regulation, suggesting that genes required for the synthesis and quality control of proteins, including tRNAs, are located near each other. Protein regulation is an energetically expensive process, and local co-regulation could increase efficiency and stress impacts on proteins.

RNA, Transfer↗

PubMed2026

Effects of Fecal Microbiota Transplantation on Intestinal Microbial Characteristics and Clinical Phenotypes in Patients with Parkinson's Disease.

Alterations in the gut microbiota have been associated with Parkinson's disease (PD), but longitudinal microbial changes after fecal microbiota transplantation (FMT) and their clinical associations remain poorly understood. This single-center retrospective observational study included 6 patients with PD, stratified into high- and low-severity subgroups based on disease duration (>6 years vs ≤6 years). Thirty-six fecal samples were collected before FMT and monthly for five months afterward. Microbial diversity, community structure, taxonomic composition, and predicted functional profiles were assessed using 16S ribosomal RNA gene sequencing. Analyses included alpha and beta diversity, taxonomic abundance, linear discriminant analysis effect size, Tax4Fun2-based functional prediction, and Spearman rank correlations between microbial features and clinical indicators. Descriptive analyses indicated differences in microbial richness, diversity, community structure, and predicted functions between severity subgroups and across post-FMT time points. At baseline, the low-severity subgroup had greater microbial richness and diversity than the high-severity subgroup, with relatively higher abundances of taxa including Bifidobacterium and Lactobacillus. One month after FMT, richness and diversity increased from baseline in the high-severity subgroup, accompanied by changes in taxonomic composition. Both subgroups showed time-associated variation in microbial diversity and predicted Kyoto Encyclopedia of Genes and Genomes pathway enrichment after FMT. Predicted functions included carbohydrate and amino acid metabolism, secondary metabolite biosynthesis, membrane transport, and signal transduction. Several operational taxonomic units correlated with indicators of motor impairment, constipation, sleep quality, functional status, and neuropsychiatric symptoms. FMT was therefore associated with longitudinal changes in gut microbial diversity, composition, and predicted functions, and specific microbial features were associated with motor and non-motor indicators. Given the small retrospective cohort, these findings are preliminary and warrant confirmation in larger controlled studies. Future studies should determine whether these microbial alterations are reproducible, persist beyond five months, reflect donor engraftment, and correspond to measurable clinical improvement after transplantation in PD.

Humans↗

PubMed2025

Analysis of Blood Microbiome From People Living With HIV and Donors by 16S rRNA Metagenomic Sequencing.

Utilize 16S rRNA sequencing technology to characterize bacterial species susceptible to people living with HIV (PLWH) across different stages. This mapping aims to establish a foundational framework for preventing secondary HIV infections, prolonging patient survival, enhancing quality of life, and advancing the diagnosis, treatment, and research of bacterial co-infections. In this study, we classified the participants into three groups: The blood of donors living with HIV (DI group), AIDS patients who have received ART treatment (PI group), and healthy blood donors as the control group (DH group). Each group was divided into three parallel subgroups, with 30 samples pooled from each parallel group for plasma extraction. As initial processing steps, the nine parallel subgroups were subjected to nucleic acid extraction and PCR amplification targeting the 16SV34 region. The resulting amplified products were subsequently forwarded to a sequencing company. It can be seen from the Venn diagram that the DI groups showed significantly higher bacterial diversity than the PI group and the DH group. The PI group had lower bacterial relative abundance and diversity compared to the DI group, with a community structure more similar to the control group. The DI group is particularly susceptible to several significant pathogens, including Ralstonia, Pseudomonas, Acinetobacter, Methyloversatilis, and Vibrio. The study revealed a greater quantity and diversity of bacteria in the DI blood compared to the PI and DH groups. This observation may be attributed to PI group patients in this study being hospitalized and receiving treatment.

Humans↗

PubMed2026

Microbial allies in a cotton pest: A descriptive account of associated microbiota dynamics in Dysdercus cingulatus across development.

BACKGROUND: Hemipteran insects harbour several symbiotic partners, mainly bacteria, which play pivotal roles for hosts like dietary provision, support overall physiology, xenobiotic degradation and manipulate/regulate behaviour. Most of these symbionts usually reside and operate from the digestive tracts of the animals. Cotton is one of the major cash crops in India and Dysdercus cingulatus (D. cingulatus) though a secondary pest, is causing significant destruction of cotton bolls, poor lint quality and reduce oil content of seeds. Premature opening of cotton bolls often leads to bacterial and fungal infections, thus resulting in extensive economic loss worldwide. D. cingulatus is a hemimetabolous insect that comprises of developmental stages like egg, nymph (5 instar stages), and adult. The present work explored the ontogeny specific diversity in the associated microbiota and predicted their probable functional inputs in D. cingulatus. RESULTS: The data obtained using 16S rRNA gene sequencing (NovaSeq 6000) revealed presence of members of Proteobacteria (65.83%), Firmicutes (24%), Actinobacteria (10%) phyla throughout the ontogeny of D. cingulatus. Highest alpha diversity of these symbiotic bacteria was recorded in the third instar nymphs in contrast to rest of the developmental stages. Among all the observed genera, Stenotrophomonas, Hungatella and Glutamicibacter were predominant from egg to adult stages. MicFunPred, a tool used for predicting the probable functional inputs of these symbionts, hinted at their probable stage specific contribution in crucial biochemical pathways such as polyketide biosynthesis, ascorbate/aldarate metabolism, pentose phosphate and glyoxylate cycles, steroid hormone and peptidoglycan biosynthesis, and glycolysis/pyruvate metabolism. CONCLUSIONS: The primary investigations on the ontogenetic composition and diversity of associated microbiota, suggest dynamic shifts in D. cingulatus, concurrent with their probable functions/roles in the host development and metabolism. To the best of our knowledge, this is the first report on symbiotic microbiota variation across the developmental stages of D. cingulatus that provides preliminary descriptive observations that may guide future functional and experimental investigations into microbiota-based pest management.

Animals↗