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At least 19 recordsLinked to original sources

PubMed2025

Arginine methylation-dependent METTL14-SMN interaction regulates RNA m6A homeostasis.

N6-methyladenosine (m6A) homeostasis is essential for development, and its dysregulation is linked to cancers and neurological disorders. However, the mechanisms regulating m6A remain unclear. Here, we identify the survival of motoneuron (SMN) protein as a novel interaction partner of METTL14, a key component of the m6A methyltransferase complex. SMN binds METTL14 via its Tudor domain in an arginine methylation-dependent manner. Mutations in the SMN Tudor domain identified in spinal muscular atrophy (SMA) disrupt its interaction with METTL14 and reduce m6A levels in patient-derived fibroblasts, linking m6A dysregulation to SMA pathology. Both SMN knockdown and SMA mutations impair m6A deposition on the mRNAs of DNA repair genes, mirroring the effects of METTL14 hypomethylation. Consequently, SMA patient fibroblasts are hypersensitive to DNA-damaging agents due to reduced levels of DNA repair gene expression. To explore the function of METTL14 arginine methylation in vivo, we generated a Mettl14 methylation-deficient mouse model (Mettl14RK). Although this model does not show SMA-like phenotypes, the mutants are partially embryonic lethal and show abnormal hematopoiesis, underscoring a role for methylated METTL14 in early development.

Methyltransferases↗

PubMed2026

Maternal PAN2 selectively maintains mRNA Poly(A) tail homeostasis to regulate RNA degradation during oocyte-to-early embryo transition in mice.

In mammals, the precise degradation of maternal mRNAs is essential for oocyte maturation and early embryonic development, as it facilitates the "maternal-to-zygotic transition (MZT)" by eliminating maternal transcripts and enabling zygotic genome activation (ZGA). However, the physiological role of the poly(A)-specific nuclease 2 (PAN2), a deadenylase that initiates cascade degradation of long-tailed transcripts, remains unknown. Here, we generated oocyte-specific Pan2 conditional knockout (cKO) mice to investigate its role. We found that Pan2 cKO females exhibit severe female subfertility despite normal oocyte maturation and ovulation, with embryos arresting at the 2-cell stage. PAIso-seq2 and transcriptome sequencing reveal that PAN2 coordinates maternal mRNA deadenylation and decay. Mechanistically, PAN2 recognizes its substrates through a PAN3-PABPC1 bridging complex, and it preferentially targets transcripts whose poly(A) tails lack guanosine (G) but are enriched for uridine (U). PAN2 deficiency causes poly(A) tail dyshomeostasis, leading to global accumulation of maternal mRNAs, impaired zygotic genome activation, and abnormal protein accumulation in 2-cell embryos. Overexpression of these proteins phenocopies developmental defects. Notably, the PAN2-regulated transcriptome is largely non-overlapping with the LC3B-mediated degradation pathway, highlighting the unique and non-redundant role of PAN2 in maternal mRNA clearance. Our study establishes maternal PAN2 as a critical regulator of poly(A) tail homeostasis, ensuring timely maternal mRNA clearance and proper ZGA, highlighting the stage-specific and tail-composition-dependent functions of the deadenylase cascade during the maternal-to-zygotic transition. These findings offer new perspectives on post-transcriptional regulatory mechanisms in early mammalian embryogenesis.

Deadenylation↗

PubMed2026

Genome-Wide Impact of Human DBR1 Depletion on RNA Processing Networks Reveal a Connection Between Pre-mRNA Splicing, mRNA Surveillance and Stress Granule Dynamics.

The RNA lariat debranching enzyme DBR1 is essential for intron turnover and RNA metabolism, yet its broader impact on transcriptome regulation remains incompletely defined. To elucidate the consequences of DBR1 depletion, we performed transcriptome-wide RNA sequencing of DBR1-knockdown and wild-type HEK293 cells. Differential expression analysis revealed widespread perturbations in pathways linked to RNA splicing, mRNA surveillance, translational control, and stress-granule biology. Many of the most significantly altered transcripts encode splicing factors and RNA quality-control components, underscoring DBR1's influence on post-transcriptional regulation. Alternative splicing analysis showed changes across multiple event types, with exon skipping accounting for >50% of events, followed by mutually exclusive exons, alternative 5' and 3' splice sites, and retained introns, indicating that DBR1 depletion induces pervasive splicing defects. Direct spliceosome inhibition using isoginkgetin (blocks tri-snRNP recruitment) and pladienolide B (targets SF3B1) reproduced the DBR1-KD mis-splicing patterns of cell signaling genes and factors involved in RNA metabolism, supporting a functional link between DBR1 activity and alternative splicing. Notably, DBR1 knockdown revealed a subset of transcripts that are both NMD-sensitive and enriched within stress granules. Consistent with this observation, G3BP1 immunopurification and confocal microscopy further support a role for DBR1 and UPF1 in stress-granule dynamics, suggesting that these factors may participate at distinct stages to influence mRNA fate under stress conditions. Together, these findings indicate that DBR1 functions beyond lariat RNA turnover as a common regulator of RNA processing, transcriptome stability, and stress granule homeostasis, revealing intricate crosstalk between RNA splicing and RNA quality control pathways in human cells.

Humans↗

PubMed2025

Defining the networks that connect RNase III and RNase J-mediated regulation of primary and specialized metabolism in Streptomyces venezuelae.

UNLABELLED: RNA metabolism involves coordinating RNA synthesis with RNA processing and degradation. Ribonucleases play fundamental roles within the cell, contributing to the cleavage, modification, and degradation of RNA molecules, with these actions ensuring appropriate gene regulation and cellular homeostasis. Here, we employed RNA sequencing to explore the impact of RNase III and RNase J on the transcriptome of Streptomyces venezuelae. Differential expression analysis comparing wild-type and RNase mutant strains at distinct developmental stages revealed significant changes in transcript abundance, particularly in pathways related to multicellular development, nutrient acquisition, and specialized metabolism. Both RNase mutants exhibited dysregulation of the BldD regulon, including altered expression of many cyclic-di-GMP-associated enzymes. We also observed precocious chloramphenicol production in these RNase mutants and found that in the RNase III mutant, this was associated with PhoP-mediated regulation. We further found that RNase III directly targeted members of the PhoP regulon, suggesting a link between RNA metabolism and a regulator that bridges primary and specialized metabolism. We connected RNase J function with translation through the observation that RNase J directly targets multiple ribosomal protein transcripts for degradation. These findings establish distinct but complementary roles for RNase III and RNase J in coordinating the gene expression dynamics critical for S. venezuelae development and specialized metabolism. IMPORTANCE: RNA processing and metabolism are mediated by ribonucleases and are fundamental processes in all cells. In the morphologically complex and metabolically sophisticated Streptomyces bacteria, RNase III and RNase J influence both development and metabolism through poorly understood mechanisms. Here, we show that both ribonucleases are required for the proper expression of the BldD developmental pathway and contribute to the control of chloramphenicol production, with an interesting connection to phosphate regulation for RNase III. Additionally, we show that both RNases have the potential to impact translation through distinct mechanisms and can function cooperatively in degrading specific transcripts. This study advances our understanding of RNases in Streptomyces biology by providing insight into distinct contributions made by these enzymes and the intriguing interplay between them.

Streptomyces↗

PubMed2026

Context-dependent roles of DHX9 in Cancer: Molecular mechanisms, biomarker potential, and therapeutic perspectives.

DExH-box helicase 9 (DHX9) is a multifunctional nucleic acid helicase that participates in R-loop homeostasis, genome maintenance, RNA metabolism, and innate immune signaling. Accumulating evidence has linked aberrant DHX9 expression or activity to tumorigenesis, tumor progression, treatment response, and patient prognosis. However, its role in cancer is highly context-dependent, rather than uniformly oncogenic or tumor suppressive. Depending on its molecular partners, subcellular localization, post-translational modifications, tumor genotype, and immune microenvironment, DHX9 may either promote malignant phenotypes or contribute to tumor-restraining processes. In this review, we summarize the molecular characteristics and regulatory properties of DHX9, discuss its roles in genome stability, transcriptional and post-transcriptional control, circular RNA (circRNA) biogenesis, and tumor-immune crosstalk, and evaluate its emerging value as a potential biomarker and therapeutic target. We also highlight key challenges in this field, including mechanistic heterogeneity, insufficient translational validation, and the urgent need for context-informed patient stratification to maximize the clinical utility of DHX9-targeted strategies.

Humans↗

PubMed2025

Gene and pathway analysis of genome-wide genetic associations of bladder cancer.

BACKGROUND: Although genetic variants associated with bladder cancer (BCa) risk have been identified through hypothesis-driven and genome-wide association studies, a systematic understanding of BCa genetic susceptibility at the gene and pathway levels remains to be achieved. MATERIALS AND METHODS: In this 2-stage functional genomics study, we used 5 independent tools for genome-wide gene mapping and ranking based on BCa genome-wide association studies summary statistics, followed by a meta-analysis of gene-level significance p values, to obtain a consensus gene ranking in terms of association with BCa. Subsequently, we performed preranked gene-set enrichment analysis to identify the functional pathways involved in BCa genetic susceptibility. Joint analysis with gene-set enrichment analysis, based on somatic alteration frequency, was performed to explore the pathway-level relationships between genetic susceptibility and somatic alterations in BCa. RESULTS: Other than the well-known BCa genes (such as FGFR3, MYC, TERT, CCNE1, and TP63), we additionally prioritized a set of novel genes likely to be genetically implicated in BCa development, including SETD2, a possible tumor suppressor gene involved in chromatin remodeling. We further demonstrated convergence between genetic associations and somatic alterations at both the gene (eg, FGFR3 and TERT) and pathway levels (eg, cell cycle and chromatin modification), as well as functional ontologies specifically implicated in germline predisposition to BCa (eg, CD8/TCR signaling, immune checkpoints, and cytokine signaling). CONCLUSIONS: We identified several novel genes associated with BCa and demonstrated that genetic variants contribute to the development of BCa by affecting antitumor immunity, response to toxic exposure, and RNA and protein homeostasis and synergizing with somatic alterations in various cancer-related pathways.

Bladder cancer↗

PubMed2022

Battle for Metals: Regulatory RNAs at the Front Line.

Metal such as iron, zinc, manganese, and nickel are essential elements for bacteria. These nutrients are required in crucial structural and catalytic roles in biological processes, including precursor biosynthesis, DNA replication, transcription, respiration, and oxidative stress responses. While essential, in excess these nutrients can also be toxic. The immune system leverages both of these facets, to limit bacterial proliferation and combat invaders. Metal binding immune proteins reduce the bioavailability of metals at the infection sites starving intruders, while immune cells intoxicate pathogens by providing metals in excess leading to enzyme mismetallation and/or reactive oxygen species generation. In this dynamic metal environment, maintaining metal homeostasis is a critical process that must be precisely coordinated. To achieve this, bacteria utilize diverse metal uptake and efflux systems controlled by metalloregulatory proteins. Recently, small regulatory RNAs (sRNAs) have been revealed to be critical post-transcriptional regulators, working in conjunction with transcription factors to promote rapid adaptation and to fine-tune bacterial adaptation to metal abundance. In this mini review, we discuss the expanding role for sRNAs in iron homeostasis, but also in orchestrating adaptation to the availability of other metals like manganese and nickel. Furthermore, we describe the sRNA-mediated interdependency between metal homeostasis and oxidative stress responses, and how regulatory networks controlled by sRNAs contribute to survival and virulence.

Bacteria↗

PubMed2026

Exploring genomic regions regulating the liver transcriptome and energy homeostasis in pigs.

In pigs, energy homeostasis has an impact on meat quality and health. In a Duroc pig population, 30 quantitative trait locus (QTL) regions associated with fatty acid (FA) composition in adipose tissue, plasma, liver and muscle were previously identified. Mapping of expression quantitative trait locus (eQTL) regions will provide a molecular hypothesis for genotype-phenotype interactions and may allow the identification of shared causal variants, key to increasing our understanding of the genetic regulation of FA composition and energy homeostasis. However, gene expression is impacted by environmental factors, while individual-level allelic imbalance (AI) can be more reliable and can be surveyed via allelic-specific expression (ASE) analysis. Furthermore, treatment of ASE as a quantitative trait allows the identification of allele-specific expression quantitative trait loci (aseQTLs), which are variants whose heterozygosity is linked to the AI of a nearby single-nucleotide polymorphism (SNP), pointing to regulatory elements. In this study, liver was selected as a key metabolic hub with an important role in the regulation of energy homeostasis, and 310 liver RNA sequencing samples were analysed using a combination of (1) eQTL mapping, (2) ASE analysis, and (3) aseQTL mapping methods. A total of 2 188 eQTL regions were identified, mostly cis-eQTL regions (73.17%). ASE analysis reported 1 964 ASE SNPs, associated with 633 genes. Finally, aseQTL mapping reported 64 172 aseQTL, associated with the AI of 31 genes. Colocalisation analysis combined with ASE analysis showed that the expression of FADS1 and FADS2 genes is associated with the polyunsaturated FA composition in several tissues, where microRNA regulation may be present. Finally, in the DGAT2 gene, annotated in a QTL region associated with multiple FAs in adipose tissue, ASE revealed allelic imbalance in the 3' untranslated region (UTR) of this gene. Allelic differential expression can be caused by a 13-bp insertion affecting messenger RNA stability, previously described, exemplifying how allelic imbalance is caused by a post-transcriptional regulatory mechanism undetectable by eQTL mapping. Furthermore, aseQTLs were associated with this gene, linked to a previously identified copy number variant not yet associated with DGAT2 expression. These results demonstrate how ASE analysis and aseQTL mapping can complement eQTL mapping, as they resolved a complex region affected by allelic heterogeneity, a main confounding effect of QTL mapping. In conclusion, the combination of eQTL mapping, ASE analysis and aseQTL mapping allowed the characterisation of the regulation of liver gene expression, improving our understanding of the genetic determinism of energy homeostasis.

Allele-specific expression↗

PubMed1979

Seasonal variation in the effect of dietary RNA on criteria of energy homoeostasis in the rat.

1. RNA was administered to rats as part of a meal while standardizing food intake and minimizing the effects of psychological stress and diurnal metabolic rhythms. It was demonstrated that circulating levels of glucose and free fatty acids (FFA) in the animals, which were deprived of food for 48 h, were responsive to orally administered caffeine. 2. Inclusion of RNA in the diet slightly but consistently reduced the normal postprandial hyperglycaemia. Its effect on plasma FFA was variable although statistically significant in some experiments. The differences between RNA-and control-fed animals were not attributable to differences in the rate of passage of digesta along the gastrointestinal tract. 3. Evidence was obtained that the variability in the FFA response was related to a seasonally-dependent change in the state of animals. The synchronizer ('Zeitgeber') responsible for this change was not identified and no satisfactory way of suppressing its effect was found. 4. The present findings, taken in conjunction with those of previous workers, suggest that there is a seasonal influence on the sympathetic nervous system manifesting itself as a variable susceptibility to arousal or excitation.

Animals↗

PubMed2025

Marine-Inspired Antimicrobial Peptides Disrupt Gene Expression at the DNA Level.

Genome mining of Streptomyces sp. H-KF8 combined with sequence engineering yielded two serum-stable, noncytotoxic, nonlytic antimicrobial peptides, L3 and L3-K. Initial studies in uropathogenic Escherichia coli suggested membrane effects and nucleoid relaxation, prompting a comprehensive investigation of their mode of action. In this study tandem mass tag (TMT)-based quantitative proteomics revealed extensive proteome remodeling, with 175 and 120 differentially expressed proteins (DEPs) after treatment with L3 and L3-K, respectively. L3 induced predominantly upregulated responses linked to metabolism, RNA processing, transport, and homeostasis, whereas L3-K mainly caused the downregulation of proteins involved in metabolism, transport, and cell structure. Both peptides disrupted ABC transporter-mediated nutrient uptake and elicited stress responses, while L3 specifically perturbed the mal regulon, indicative of broader transcriptional dysregulation. Complementary fluorescent dye displacement and in vitro transcription/translation assays demonstrated nonspecific DNA binding, stronger for L3 than L3-K, and potent inhibition of transcriptional and translational processes. Strikingly, inhibitory concentrations paralleled their minimum inhibitory concentrations, directly linking DNA binding and interference with central information processing to antimicrobial activity. These findings reveal that L3 and L3-K primarily act by targeting DNA and interfering with the transcription-translation machinery. Beyond offering mechanistic insights, this study underscores peptides' potential to act as scaffolds for next-generation antimicrobial peptides with DNA-binding and nonmembrane-lytic activity.

Antimicrobial Peptides↗

PubMed2026

Marked for Success: How RNA m6A Methylation Fine-Tunes Gut Epithelial Function.

Post-transcriptional gene regulation-particularly through RNA modifications-plays an essential but understudied role in development, homeostasis, and regeneration of rapidly changing tissues like the mammalian intestinal epithelium. RNA modifications such as N6-methyladenosine (m⁶A) represent a burgeoning area of research in posttranscriptional regulation, with m⁶A being the most abundant modification found in approximately 25% of all mRNA transcripts. Multiple groups have begun to report m⁶A and associated regulation of mRNA fate as critical to key process in the intestinal epithelium. In this review, we synthesize key findings to date into the following 3 categories: m⁶A changes in response to the homeostatic luminal environment, m⁶A as a mediator of stemness in the crypt, and m⁶A as a tool for reacting to inflammation and injury. Over the course of this review, we will demonstrate how m⁶A is uniquely positioned to regulate homeostasis and disease states in the challenging and dynamic environment of the intestinal epithelium.

Humans↗

PubMed2025

A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy.

Transfer RNA-derived small RNAs (tsRNAs or tDRs) perform a range of cellular functions. Here, we showed that tRNA-Asp-GTC-3'tDR, a hypoxia-induced tDR derived from the 3' end of tRNA-Asp-GTC, activated autophagic flux in kidney cells and its silencing blocked autophagic flux. Functional gain-/loss-of-function studies in murine kidney disease models demonstrated a substantial renoprotective function of tRNA-Asp-GTC-3'tDR. Mechanistically, tRNA-Asp-GTC-3'tDR assembled stable G-quadruplex structures and sequestered pseudouridine synthase 7 (PUS7), preventing catalytic pseudouridylation of histone mRNAs. The resulting pseudouridylation deficiency directed histone mRNAs to the autophagosome-lysosome pathway, triggering RNA autophagy. This tDR-induced RNA autophagy pathway was activated during murine and human kidney diseases, suggesting clinical relevance. Thus, tRNA-Asp-GTC-3'tDR plays a role in regulating RNA autophagy, which helps to maintain homeostasis in kidney cells and protects against kidney injury.

Animals↗

PubMed2026

Disruption of mitonuclear coadaptation and compensatory evolution after an extreme dietary shift in carnivorous butterflies.

Mitochondrial function depends on tight coordination between mitochondrial and nuclear genomes, which requires long-term coevolution to maintain mitonuclear coadaptation. While mitonuclear incompatibility is typically studied in the context of hybridization, other evolutionary scenarios that may disrupt coadaptation between the two genomes remain less explored. Here, we propose that extreme ecological niche shifts may disrupt mitonuclear coadaptation, which we test in carnivorous Miletinae butterflies with an extreme dietary transition. By generating high-quality genome assemblies, we found that Miletinae exhibit extensive chromosomal rearrangements. Comparative phylogenomic analyses revealed a striking asymmetric mitonuclear evolutionary response: Miletinae exhibit elevated mitochondrial nucleotide substitution rates compared to phytophagous relatives, whereas nuclear rates remain stable. This shift reverses the typical lepidopteran pattern where nuclear rates exceed mitochondrial rates. Interestingly, this mitochondrial acceleration is driven primarily by relaxed purifying selection rather than positive selection. To sustain mitochondrial function, the nuclear genome of Miletinae underwent pervasive, multilayered compensatory evolution. We detected strong signatures of positive selection and accelerated evolution in nuclear genes directly interacting with mitochondrial components across oxidative phosphorylation (OXPHOS) complexes, the mitochondrial translation, and replication and transcription machinery. Furthermore, this nuclear compensatory response extends to systems governing mitochondrial homeostasis, including protein quality control and RNA degradation and stabilization. Our results support a model in which extreme ecological transitions can disrupt ancestral mitonuclear coadaptation and promote the emergence of a new coadapted state through systemic nuclear compensation. This study broadens the conceptual framework of mitonuclear coevolution and highlights its role in facilitating evolutionary persistence after major ecological shifts.

Animals↗

PubMed2026

RBFOX3 regulates hippocampal transcriptomic programs to maintain synaptic and ultrastructural integrity.

RBFOX3 is a neuron-specific RNA-binding protein essential for maintaining brain circuit homeostasis and functional connectivity. Genetic disruptions in RBFOX3 are clinically linked to cognitive impairment, epilepsy, and sleep disorders. Although global Rbfox3 knockout (Rbfox3-/-) mouse models have established its necessity in hippocampus-dependent neuronal circuits and behaviors, the underlying hippocampal transcriptomic landscape and synaptic ultrastructure remain poorly understood. To address these gaps, we integrated hippocampal RNA-sequencing from Rbfox3-/- mice with high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation analysis. We identified 3,401 differentially expressed genes in the hippocampus of Rbfox3-/- mice, confirming 1,920 as candidate RBFOX3 targets. Gene Ontology enrichment analysis revealed that these candidate targets converge on pathways governing neuronal morphogenesis, synaptic transmission, dendritic development, and cognition. Furthermore, transmission electron microscopy of the hippocampal dentate gyrus revealed that while the overall presynaptic area remained unaltered, Rbfox3 deletion reduced presynaptic vesicle number, presynaptic mitochondria area, and postsynaptic density thickness. Collectively, our findings demonstrate that RBFOX3 acts as a critical regulator orchestrating the transcriptomic programs required for hippocampal structural and functional maturation, revealing that its loss compromises both the metabolic and structural architecture of the synapse.

Hippocampus↗

PubMed2026

The CTNNB1-TRIM28 complex governs hormone-induced RNA polymerase II dynamics in kidney epithelial cells.

Arginine vasopressin maintains water homeostasis by regulating epithelial water permeability through complex transcriptional mechanisms in kidney collecting duct cells. Although CTNNB1 (β-catenin) functions as a transcriptional coregulator in vasopressin-responsive gene transcription, its role remains poorly understood. To identify CTNNB1-dependent components mediating the vasopressin-responsive transcription, we profiled transcriptomic changes following Ctnnb1 knockdown in mouse kidney collecting duct cells using RNA sequencing (RNA-Seq). RNA-Seq and promoter enrichment analyses identified bromodomain-containing proteins (TRIM28, TRIM33, BRD4, CREBBP, and EP300) as components of a CTNNB1-dependent complex regulating RNA Polymerase II (Pol II) activity. Biochemical analyses revealed physical interactions between TRIM28, CTNNB1, Pol II, and CDK9. Functionally, Trim28 knockdown blunted vasopressin-induced expression of the Aqp2 gene. Quantitative genomic binding assays demonstrated that TRIM28 is required for robust genomic occupancy and stabilization of Pol II at the transcription start site of Aqp2. Additionally, dynamic formation of phase-separated nuclear TRIM28 condensates in response to vasopressin suggests that TRIM28-associated machinery functions at specialized chromatin hubs. These findings reveal that TRIM28 facilitates Pol II recruitment, pause release, and elongation upon vasopressin stimulation. Our study establishes the CTNNB1-TRIM28 machinery as a critical transcriptional scaffold that controls Pol II dynamics and chromatin structure, thereby driving osmotic water reabsorption and urine concentration.

Animals↗

PubMed2026

The SigD regulon of Mycobacterium abscessus determines cell envelope composition and antibiotic susceptibility.

A major determinant of the exceptional intrinsic resistance of M. abscessus is the lipid-rich cell envelope, yet the regulatory systems that remodel envelope-associated pathways remain poorly defined. Here, we determine the σD regulon in M. abscessus and establish its role in cell envelope homeostasis and intrinsic resistance to hydrophobic antibiotics. RNA-Seq analysis of a MabΔsigD mutant identified 447 differentially expressed genes, while ChIP-Seq mapped 72 σD binding sites and defined a conserved promoter motif (GTAACA/G-N16-CGAT). Using a combination of σD binding, motif orientation and expression data, we identified a core set of directly regulated genes, distinct from what was previously observed in M. tuberculosis, many of which encode proteins involved in envelope-associated functions. These include loci involved in trehalose polyphleate (TPP) biosynthesis, the antigen 85 complex and peptidoglycan remodeling enzymes. Deletion of sigD resulted in a significant reduction in TPPs in the cell envelope and an increase in ethidium bromide accumulation. Consistent with these changes, loss of σD selectively sensitized M. abscessus to hydrophobic antibiotics, including rifampicin and tigecycline. Deletion of mmpL10, which is required for transport of TPP precursors, recapitulated the drug sensitivity of MabΔsigD, implicating envelope composition as a key effector of the phenotype. Expression of the σD regulon further increased during starvation and in response to SDS, isoniazid, and ethambutol, mediated by degradation of RsdA, consistent with a role in stress-responsive envelope adaptation. Together, these findings demonstrate σD is active during logarithmic growth in rich media where it regulates the expression of envelope-associated genes that influence envelope permeability and basal level susceptibility to hydrophobic antibiotics; its activity further increases in response to cell envelope stress, presumably promoting envelope remodeling to counteract damage.

Regulon↗

PubMed2026

A CRISPR-Cas9 screen identifies LAPTM4A (lysosomal protein transmembrane 4 alpha) as a key host barrier against PRRSV infection.

Porcine reproductive and respiratory syndrome virus (PRRSV) manipulates host intracellular processes, particularly macroautophagy/autophagy and lysosomal function, to facilitate its replication and spread. However, the precise host factors and molecular mechanisms by which PRRSV remodels the autophagy-lysosome axis remain poorly defined. Here, we performed a CRISPR-Cas9 knockout screen targeting 1,332 genes involved in protein degradation, metabolism, and vesicular trafficking, and identified LAPTM4A (lysosomal protein transmembrane 4 alpha) as a critical antiviral factor involved in the lysosomal pathway. A yeast two-hybrid screen identified LAPTM4A as an interactor of PRRSV GP5 (glycoprotein 5). Mechanistically, GP5 recruits the E3 ubiquitin ligase NEDD4 and the autophagy receptor SQSTM1/p62 to promote K63-linked polyubiquitination of LAPTM4A, leading to its autophagic degradation. This selective degradation activates the AMPK-ULK1-MAP1LC3/LC3 signaling cascade, initiating autophagy while facilitating MTOR-lysosome colocalization, thereby suppressing TFEB nuclear translocation and transcription of lysosome-related genes. The resulting incomplete autophagic flux enhances viral replication. Additionally, in terms of host defense, LAPTM4A maintains lysosomal homeostasis by restraining excessive autophagy through AMPK-ULK1-LC3 signaling and promoting TFEB-dependent lysosomal gene expression by impairing the binding of RPTOR/raptor to MTOR, thus providing broad antiviral protection against multiple RNA viruses. Collectively, our findings identify LAPTM4A as a central regulator of lysosome-autophagy homeostasis and reveal a viral strategy that dismantles this defense axis to facilitate infection.Abbreviations: ATG5: autophagy related 5; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; Baf A1: bafilomycin A1; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DMVT library: protein degradation, metabolism, and vesicular trafficking library; LAPTM4A: lysosomal protein transmembrane 4 alpha; MAGeCK: model-based analysis of genome-wide CRISPR-Cas9 knockout; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NC: negative control; PAMs: porcine alveolar macrophages; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PRRSV: porcine reproductive and respiratory syndrome virus; qRT-PCR: quantitative real-time PCR; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TCID50: 50% tissue culture infective dose; TFEB: transcription factor EB; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type.

Animals↗

PubMedDate not supplied

[Autoregulation of hormonogenesis in the adrenal cortex].

Experiments were conducted on 60 rats. An attempt was made to ascertain with the aid of histochemical methods the possibility of a direct action of glucocorticoids on the adrenal glands. Incomplete coincidence of histochemical changes following hypophysectomy with the changes caused by the action of cortisone for the same period (10 days), and also a distinct depression with cortisone of histochemical shifts characteristic of the action of ACTH in hypophysectomized animals pointed to the direct (not mediated through the hypophysis) influence of cortisone on the adrenal cortex.

Acid Phosphatase↗