Cellular Stress Response Research Articles

Backbone resonance assignment of the catalytic and ATP-binding domain of CpxA from Escherichia coli.

CpxA is an extensively studied histidine kinase implicated in cellular stress responses. The highly conserved CA domain of CpxA (CpxACA) is an essential domain for the hydrolysis of ATP and the binding of inhibitors and considered to be a promising target for broad-spectrum antimicrobial drugs development. The ATP-binding pocket in the CA domain contains a flexible ATP lid motif. Although the crystal structure of CA domain has been defined, the structure of the ATP lid remains uncertain, posing a challenge to the study of its catalytic mechanism. In this study, we report the backbone 1H, 13C and 15N chemical shift assignments of CpxACA by heteronuclear multidimensional spectroscopy and predict its secondary structure in solution using TALOS+. The residues of ATP lid motif are well-assigned. Therefore, this study provides a foundation for understanding the role of CpxACA in cellular signaling and the development of novel antimicrobial therapies.

Metabolic profiling reveals distinctive ripening dynamics in ethylene-treatedMusa balbisiana cv. 'Pisang Klutuk Wulung' comparedtocommercial Cavendish banana.

As an important crop, bananas still encounter fruit quality and shelf-life problems that are affected by the ripening process. Improving postharvest technologies may effectively address these challenges, such as by studying the ripening mechanism of banana cultivars with a slow ripening process. A banana cultivar that exhibits this characteristic is Musa balbisiana cv. 'Pisang Klutuk Wulung' (BB Group) or Pisang Klutuk Wulung (PKW), which has a ripening duration of 14-28 days. However, the metabolomics study on the ripening mechanism of this banana is still limited. This study aimed to analyze metabolite changes in ethylene-treated Pisang Klutuk Wulung during ripening in comparison to commercial bananas (Cavendish). Both bananas were subjected to exogenous ethylene treatment and analyzed using gas chromatography-mass spectrometry to perform metabolite profiling throughout the ripening process. The principal component analysis showed sample separation based on the ripening stages and banana species in pulp and peel. Orthogonal projection to latent structure analysis suggested that metabolite changes accompanied the ripening stages. Potential metabolite markers that distinguished the ripening of PKW and Cavendish were found, such as quinic acid, inositol, and 2-aminoethanol. This study shows differences in metabolite profiles between these bananas, especially the metabolites involved in sugar metabolism, cell wall metabolism, stress response, and biosynthesis of aromatic compounds. This study provides novel insights into the metabolic changes occurring during PKW ripening, contributing to the improvement of banana postharvest strategies.

Harnessing the fundamental roles of vitamins: the potent anti-oxidants in longevity.

Aging is a complex and heterogeneous biological process characterized by telomere attrition, genomic instability, mitochondrial dysfunction, and disruption in nutrient sensing. Besides contributing to the progression of cancer, metabolic disorders, and neurodegenerative diseases, these manifestations of aging also adversely affect organ function. It is crucial to understand these mechanisms and identify interventions to modulate them to promote healthy aging and prevent age-related diseases. Vitamins have emerged as potential modulators of aging beyond their traditional roles in health maintenance. There is an increasing body of evidence that hormetic effects of vitamins are responsible for activating cellular stress responses, repair mechanisms, and homeostatic processes when mild stress is induced by certain vitamins. It is evident from this dual role that vitamins play a significant role in preventing frailty, promoting resilience, and mitigating age-related cellular damage. Moreover, addressing vitamin deficiencies in the elderly could have a significant impact on slowing aging and extending life expectancy. A review of recent advances in the role of vitamins in delaying aging processes and promoting multiorgan health is presented in this article. The purpose of this paper is to provide a comprehensive framework for using vitamins as strategic tools for fostering longevity and vitality. It offers a fresh perspective on vitamins' role in aging research by bridging biological mechanisms and clinical opportunities.

The Heme Oxygenase/Biliverdin Reductase System and Its Genetic Variants in Physiology and Diseases

Heme oxygenase (HO) metabolizes heme into ferrous iron, carbon monoxide (CO), and biliverdin-IXα (BV), the latter being reduced into bilirubin-IXα (BR) by the biliverdin reductase-A (BVR). Heme oxygenase exists as two isoforms, HO-1, inducible and involved in the cell stress response, and HO-2, constitutive and committed to the physiologic turnover of heme and in the intracellular oxygen sensing. Many studies have identified genetic variants of the HO/BVR system and suggested their connection in free radical-induced diseases. The most common genetic variants include (GT)n dinucleotide length polymorphisms and single nucleotide polymorphisms. Gain-of-function mutations in the HO-1 and HO-2 genes foster the ventilator response to hypoxia and reduce the risk of coronary heart disease and age-related macular degeneration but increase the risk of neonatal jaundice, sickle cell disease, and Parkinson’s disease. Conversely, loss-of-function mutations in the HO-1 gene increase the risk of type 2 diabetes mellitus, chronic obstructive pulmonary disease, and some types of cancers. Regarding BVR, the reported loss-of-function mutations increase the risk of green jaundice. Unfortunately, the physiological role of the HO/BVR system does not allow for the hypothesis gene silencing/induction strategies, but knowledge of these mutations can certainly facilitate a medical approach that enables early diagnoses and tailored treatments.

Effects of hypoxia on the heart of the juvenile four-finger threadfin (Eleutheronema tetradactylum) based on physiological indicators and transcriptome analysis

This study evaluated the effects of hypoxia on the heart of juvenile four-finger threadfin (Eleutheronema tetradactylum) through physiological and transcriptome analysis. Juveniles with an average weight of 122.82 g and length of 24.60 cm were used. Hypoxia significantly increased serum myocardial enzyme activities, including creatine kinase (CK), creatine kinase-MB isoenzyme, lactate dehydrogenase (LDH), and α-hydroxybutyrate dehydrogenase (HDBH). These indicators initially rose and then declined, reflecting cardiac stress and suggesting their potential as early hypoxia biomarkers for real-time aquaculture monitoring. Histological analysis revealed structural damage in myocardial fibers under hypoxia, with increasing severity over time. This underscores the need to minimize oxygen fluctuations to prevent cardiac tissue degeneration. Transcriptome analysis identified upregulated genes involved in cell communication, immune responses, and intracellular signaling, offering potential targets for breeding hypoxia-tolerant species. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis highlighted key pathways such as mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1 (HIF-1), endocytosis, and phagosome formation. The MAPK pathway plays a critical role in cellular stress responses, including survival, proliferation, and apoptosis. Hypoxia-induced activation of MAPKs like ERK, JNK, and p38 regulates stress-responsive genes. HIF-1 signaling regulates oxygen homeostasis, with HIF-1α stabilizing hypoxia-responsive genes such as VEGFA, which promotes vascular remodeling and enhances oxygen delivery. These findings collectively offer practical applications for enhancing aquaculture management, such as monitoring biochemical markers, adopting hypoxia-tolerant breeding, and adjusting environmental conditions to mitigate stress, ensuring better productivity and sustainability. This research provides a foundation for further studies on the molecular mechanisms of hypoxia stress in aquaculture species.

ROCK1 promotes B-cell differentiation and proteostasis under stress through the heme-regulated proteins, BACH2 and HRI.

The mechanisms utilized by differentiating B cells to withstand highly damaging conditions generated during severe infections, like the massive hemolysis that accompanies malaria, are poorly understood. Here we demonstrate that ROCK1 regulates B cells differentiation in hostile environments replete with PAMPs (pathogen-associated molecular patterns) and high levels of heme by controlling two key heme-regulated molecules, BACH2 and Heme-regulated eIF2a kinase (HRI). ROCK1 phosphorylates BACH2 and protects it from heme-driven degradation. As B cells differentiate, furthermore, ROCK1 restrains their proinflammatory potential and helps them handle the heightened stress imparted by the presence of PAMPs and heme by controlling HRI, a key regulator of the integrated stress response and cytosolic proteotoxicity. ROCK1 controls the interplay of HRI with HSP90 and limits the recruitment of HRI and HSP90 to unique p62/SQSTM1 complexes that also contain critical kinases like mTORC1 and TBK1, and proteins involved in RNA metabolism, oxidative damage, and proteostasis like TDP-43. Thus, ROCK1 helps B cells cope with intense pathogen-driven destruction by coordinating the activity of key controllers of B cell differentiation and stress responses. These ROCK1-dependent mechanisms may be widely employed by cells to handle severe environmental stresses, and these findings may be relevant for immune-mediated and age-related neurodegenerative disorders.

The transcriptomic footprint of Mytella strigata: de novo transcriptome assembly of a major invasive species

Mytella strigata, a potentially invasive species native to South America, is rapidly spreading across various aquatic ecosystems around the globe, posing a threat to native mussels. This study presents the first comprehensive de novo transcriptome assembly of M. strigata. We generated 254 million reads, which were processed and assembled using the Trinity assembler, resulting in 60362 transcripts with an N50 of 1,578 bp and over 93–98% completeness, as confirmed by BUSCO analysis with multiple ortho-datasets. A number of databases were used for functional annotation, including UniProt, KEGG, Reactome, InterPro, and eggNOG. Gene Ontology and pathway analyses identified transcripts associated with key biological processes, including those associated with cell signalling, metabolism, stress responses, cancer pathways, and immune regulation. This dataset enriches the bivalve database by advancing the understanding of the adaptive success and evolutionary resilience of this invasive species. The present study provides a fundamental framework for future research on the ecological and evolutionary impacts of this invasive species.

Dynamic Modulation of IRE1α-XBP1 Signaling by Adenovirus

The abundant production of foreign proteins and nucleic acids during viral infection elicits a variety of stress responses in host cells. Viral proteins that accumulate in the endoplasmic reticulum (ER) can trigger the unfolded protein response (UPR), a coordinated signaling program that culminates in the expression of downstream genes that collectively restore protein homeostasis. The model pathogen adenovirus serotype 5 (HAdV5) activates the UPR via the signaling axis formed by inositol-requiring enzyme type 1 (IRE1α) and the X-box binding protein 1 (XBP1), a transcription factor required for immune function. Recent studies have suggested that IRE1α-XBP1 activity supports adenovirus replication. Here, we show that HAdV5 exerted opposing effects on IRE1α and XBP1. IRE1α was activated in response to HAdV5, but the production of the XBP1 isoform, XBP1s, was post-transcriptionally blocked. The tumor suppressor p53, which is eliminated by HAdV5 after infection, inhibited IRE1α activation. The de-repression of IRE1α following the degradation of p53 conceivably reflects a novel antiviral mechanism, which HAdV5 ultimately evades by co-opting IRE1α and suppressing XBP1s. Our findings illustrate the opposing mechanisms used by adenoviruses and their host cells to exert control over the UPR, a critical determinant of cell fate.

Common alterations to astrocytes across neurodegenerative disorders.

Astrocytes perform multiple functions in the nervous system, many of which are altered in neurodegenerative disorders. In this review, we explore shared astrocytic alterations across neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobe degeneration. Assessing recent datasets of single-nucleus RNA-sequencing of human brains, a theme emerges of common alterations in astrocyte state across disorders including in neuroinflammation, synaptic organization, metabolic support, and the cellular stress response. Immune pathways are upregulated by astrocytes across disorders and may exacerbate neurodegeneration. Dysregulated expression of synaptogenic factors could contribute to synaptic loss, while compromised metabolic support affects neuronal homeostasis. On the other hand, upregulated responses to cellular stress may represent a protective response of astrocytes and thus mitigate pathology. Understanding these shared responses offers insights into disease progression and provides potential therapeutic targets for various neurodegenerative disorders.

Maternal Protein Restriction and Postnatal Sugar Consumption increases Inflammatory Response and Deregulates Metabolic Pathways in the Liver of Male Offspring Rats with Aging.

This study investigated the late effects of maternal protein restriction (MPR) and early postnatal sugar consumption on liver health in male Sprague-Dawley rat offspring, focusing on changes observed throughout the aging process. The animals were divided into the following groups: Control (CTR): Male offspring whose dams consumed a normal protein diet (NPD, 17% protein) and water ad libitum during gestation and lactation, and then fed a NPD and water until PND 540; Control+Sugar (CTR+SUG): The same treatment as CTR, but consuming a sugar solution (10% diluted in water) from postnatal day (PND) 21 to 90, and then fed a NPD and water until PND 540; Gestational and Lactational Low Protein (GLLP): Male offspring whose dams consumed a low-protein diet (LPD, 6% protein) during gestation and lactation and, then fed a NPD and water ad libitum until PND 540; Gestational and Lactational Low Protein+Sugar (GLLP+SUG): male offspring whose dams consumed a LPD during gestation and lactation, and then fed a NPD and a sugar solution (10% diluted in water) ad libitum from PND 21 to 90. On PND 540, the animals were anesthetized, weighed, and euthanized, and their livers were collected for morphological and molecular analyses. The GLLP and GLLP+SUG groups showed lower body weight and lower retroperitoneal fat weight compared to the CTR and CTR+SUG groups. Morphological analysis revealed inflammatory foci in the liver from the CTR+SUG, GLLP, and GLLP+SUG groups, compared to the CTR group. Hepatic activities of CAT, SOD, and GSH-Px were increased in the GLLP+SUG group and decreased in the GLLP group, compared to the CTR group. Immunohistochemistry showed a significant increase in occupied area per foci de hepatocytes positive for GSTpi (placental form) in the CTR+SUG, GLLP, and GLLP+SUG groups, compared to the CTR group. Proteomic analysis of the groups revealed significant changes in hepatic metabolic and inflammatory pathways. In the CTR+SUG group, upregulated pathways associated with non-alcoholic fatty liver disease (NAFLD) and downregulated pathways related to autophagy were observed. In the GLLP and GLLP+SUG groups, there was a significant impact on metabolic pathways, including glucose metabolism, gluconeogenesis, glycogenesis, and cellular stress responses. An upregulation of pathways associated with chemokine- and cytokine-mediated inflammatory processes was also identified, indicating activation of the immune system in the liver during aging. Therefore, MPR, with or without postnatal sugar consumption, resulted in hepatic changes in metabolism and the antioxidant defense in old male offspring.

Evidence of oxidative stress in the soft coral Pinnigorgia flava (Nutting, 1910) exposed to secondary plastic nanofibers and related leachates

Awareness of plastic pollution in marine habitats, such as coral reefs, has grown in recent years. Several studies have shown that tiny particles resulting from plastic breakdown, especially microplastics, can potentially harm corals. However, to date, there is very little evidence regarding the impact that nanoplastics (< 1 μm) can have on the physiology and health of corals, particularly soft corals. In this study, we exposed the soft coral Pinnigorgia flava to two concentrations (0.1 and 1 mg/L) of secondary nanoplastics—specifically nanofibers obtained from the photodegradation of polypropylene nonwoven fabrics—and their related leachates, to evaluate the coral's cellular response through the analysis of antioxidant enzyme activities (SOD, CAT, GST, GR). Chemo-physical characterization of the nano-aggregates displayed an average size of 224.3 ± 8.1 nm, while GC-MS analyses of the leachates showed a variety of mono- and dicarboxylic acids. Although both nanoplastic treatments generated a cellular oxidative stress response, the physical interaction with secondary plastic fiber nano-aggregates affected cellular homeostasis more than the chemical interaction with the released compounds, triggering a stronger antioxidant response. The activity of all antioxidant enzymes increased with higher nanofiber concentrations, while this trend was not consistently observed for the leachates. Overall, SOD and CAT were the two most responsive antioxidant enzymes in cellular detoxification. Our study highlights the significant threat that plastic nanofibers and the polymers they release may pose to coral reefs.

Comprehensive genome-wide identification and functional characterization of mapk gene family in northern snakeheads (Channa argus)

The mitogen-activated protein kinase (MAPK) signaling cascade, integral to cellular regulation, orchestrates cell growth, differentiation, stress response, and inflammatory reactions to adapt to challenging environments. The northern snakeheads (Channa argus), a valuable freshwater species known for its hypoxia tolerance, rapid growth, and high nutritional value, lacks comprehensive research on its mapk gene family. In this study, we identified 16 mapk genes in northern snakeheads, among which mapk8, mapk12 and mapk14 have duplicate copies. Phylogenetic analysis confirmed the evolutionary conservation of this gene family. Structural and motif analyses further underscored the conserved nature of these genes. Expression pattern analysis under abiotic and biotic stress conditions showed significant differences expression of mapks in the gills and suprabranchial organ (SBO) after air exposure, as well as in the brain following cold stress, highlighting the extensive role of mapks in stress regulation. It was worth noting that the significant expression differences of mapks were also observed in the spleen after N. seriolae infection, implicating that these genes may be involved in the regulation of innate immune responses. Additionally, analysis of protein-protein interaction (PPI) networks suggested that the co-activation of multiple MAPK signaling pathways may play a key role in regulating an organism's response to biotic and abiotic stresses. This study provides a detailed description of the mapk gene family in the northern snakeheads and elucidates its biological functions under various stress conditions, offering valuable insights into the regulatory mechanisms of the mapk gene family.

Adaptation of Escherichia coli to ciprofloxacin and enrofloxacin: Differential proteomics of the SOS response and RecA-independent mechanisms.

Antibiotic resistance is a growing global healthcare challenge, treatment of bacterial infections with fluoroquinolones being no exception. These antibiotics can induce genetic instability through several mechanisms, one of the most significant being the activation of the SOS response. During exposure to sublethal concentration, this stress response increases mutation rates, accelerating resistance evolution. To explore the role of the SOS response in fluoroquinolone adaptation, we induced de novo resistance by exposure to step-wise increasing concentrations Escherichia coli wild-type (MG1655) and a ΔrecA mutant strain, which is deficient in SOS activation. Both strains were exposed to stepwise increasing concentrations of ciprofloxacin and enrofloxacin - two fluoroquinolones that differ only by a single methyl group. Development of resistance against both fluoroquinolones was severely hampered in the ΔrecA mutant. While these antibiotics are often assumed to elicit similar cellular responses, our data revealed distinct genomic and adaptive differences. Building on these findings, we performed a comparative proteomics analysis to investigate how E. coli adapts to ciprofloxacin and enrofloxacin at the protein level. The results demonstrate that the slight structural variation between ciprofloxacin and enrofloxacin leads to unique proteomic adaptations. These findings suggest that even subtle chemical differences can lead to distinct adaptive trajectories and illustrate the flexibility of cellular stress responses.

SUMO1 modification reduces oxidative stress and SUMO1ylated AKAP4 degradation affects frozen-thawed boar sperm quality.

Low-temperature injury affects normal physiological function and viability of boar sperm during cryopreservation. Small ubiquitin-like modifier (SUMO) modification of proteins after translation is related to the cell stress response but the relationship between SUMO modification and oxidative stress in freeze-thawed sperm remains unclear. A-kinase ankyrin 4 (AKAP4) and its precursor proAKAP4 are two main proteins in mammalian sperm. Although AKAP4 expression has been studied in many species, its expression in porcine sperm has not been described in detail. In this study, liquid chromatography-mass spectrometry was used to determine the differentially expressed SUMO-modified proteins in porcine sperm after freezen and thawed. The results identified 26 down-regulated SUMO-modified proteins, with AKAP4 identified as one of the target proteins of SUMO1 under sperm stress. In addition, the level of SUMO1 protein increased significantly (P < 0.001) and the level of AKAP4 protein decreased (P < 0.05) after freezing and oxidative stress treatment. Inhibition of SUMO1 modification of AKAP4 protein did not affect its degradation (P > 0.05), indicating that SUMO1 is not involved in the degradation of AKAP4. The inhibition of SUMO1 modification by sperm protein decreased sperm motility (P < 0.05), ATP content, and DNA integrity (P < 0.05). In summary, cryopreservation and oxidative stress can induce SUMO modification of porcine sperm proteins and the modification of sperm protein SUMO1 can help sperm resist oxidative stress; and its role in protecting sperm quality is not via regulating the degradation of AKAP4. These findings provide new insights into the mechanisms underlying SUMO1 modifications during sperm cryopreservation and oxidative stress.

Comparing the cannabidiol-induced transcriptomic profiles in human and mouse Sertoli cells.

Cannabidiol (CBD), a major cannabinoid found in Cannabis sativa L., has been used in the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Recently, concerns have been raised regarding the male reproductive toxicity of CBD in animal models, such as monkeys, rats, and mice. In our previous studies, we reported that CBD inhibited cell proliferation in both primary human Sertoli cells and mouse Sertoli TM4 cells. Transcriptomic analysis revealed that in primary human Sertoli cells CBD disrupted DNA replication, cell cycle, and DNA repair, ultimately causing cellular senescence. In this study, we further investigated the molecular changes induced by CBD in mouse Sertoli TM4 cells using RNA-sequencing analyses and compared the transcriptomic profile with that of primary human Sertoli cells. Our findings demonstrated that, unlike in primary human Sertoli cells, CBD did not induce cellular senescence but caused apoptosis in mouse Sertoli TM4 cells. Through transcriptomic data analysis in mouse Sertoli TM4 cells, immune and cellular stress responses were identified. Moreover, transcriptomic comparisons revealed major differences in molecular changes induced by CBD between mouse Sertoli TM4 and primary human Sertoli cells. This suggests that primary human Sertoli cells and mouse Sertoli cells may respond differently to CBD.

Modulation of Autophagy by Oncosuppressor FAM46C and Its Implications for Cancer Therapy: An Intriguing Perspective

Cancer is one of the major challenges in medicine, necessitating continuous advancements in therapeutic approaches. Autophagy, an intracellular pathway essential for cellular homeostasis and stress response, has emerged as a promising target for cancer treatment. In this context, FAM46C, a novel pan-cancer tumour suppressor, has been shown to induce apoptosis in multiple myeloma cells through indirect inhibition of autophagy. Here, we discuss how FAM46C-induced autophagic dampening could offer new opportunities for global cancer therapy. Specifically, we explore two scenarios in which the expression of a functional FAM46C may either sensitize cancer cells to autophagic inhibition or antagonize their sensitivity. We further comment on how this synergism/antagonism could be used to refine strategies for cancer treatment, positioning FAM46C as a pivotal factor in future cancer therapy development.

Emerging of Ultrafine Membraneless Organelles as the Missing Piece of Nanostress: Mechanism of Biogenesis and Implications at Multilevels.

Understanding the interaction between nanomaterials and cellular structures is crucial for nanoparticle applications in biomedicine. We have identified a subtype of stress granules, called nanomaterial-provoked stress granules (NSGs), induced by gold nanorods (AuNRs). These NSGs differ from traditional SGs in their physical properties and biological functions. Uptake of AuNRs causes reactive oxygen species accumulation and protein misfolding in the cell, leading to NSG formation. Physically, NSGs have a gel-like core and a liquid-like shell, influenced positively by HSP70 and negatively by HSP90 and the ubiquitin-proteasome system. AuNRs promote NSG assembly by interacting with G3BP1, reducing the energy needed for liquid-liquid phase separation (LLPS). NSGs impact cellular functions by affecting mRNA surveillance and activating Adenosine 5'-monophosphate (AMP)-activated protein kinase signaling, crucial for a cellular stress response. Our study highlights the role of LLPS in nanomaterial metabolism and suggests NSGs as potential targets for drug delivery strategies, advancing the field of nanomedicine.

Understanding retinal tau pathology through functional 2D and 3D iPSC-derived in vitro retinal models

The generation of retinal models from human induced pluripotent stem cells holds significant potential for advancing our understanding of retinal development, neurodegeneration, and the in vitro modeling of neurodegenerative disorders. The retina, as an accessible part of the central nervous system, offers a unique window into these processes, making it invaluable for both study and early diagnosis. This study investigates the impact of the Frontotemporal Dementia-linked IVS 10 + 16 MAPT mutation on retinal development and function using 2D and 3D retinal models derived from human induced pluripotent stem cells. Our findings reveal that the MAPT mutation leads to delayed retinal cell differentiation and maturation, with tau-mutant disease models exhibiting sustained higher expression of retinal progenitor cell markers and a reduced presence of post-mitotic neurons. Both 2D and 3D tau-mutant retinal models demonstrated an imbalance in tau isoforms, favoring 4R tau, along with increased tau phosphorylation, altered neurite morphology, and impaired cytoskeletal maturation. These changes are associated with impaired synaptic development, reduced neuronal connectivity, and enhanced cellular stress responses, including the increased formation of stress granules, markers of apoptosis and autophagy, and the presence of intracellular toxic tau aggregates. This study highlights the value of retinal models derived from human induced pluripotent stem cells in exploring the mechanisms underlying retinal pathology associated with tau mutations. These models offer essential insights into the development of therapeutic strategies for neurodegenerative diseases characterized by tau aggregation.

Alu-Sc-mediated exonization generated a mitochondrial LKB1 gene variant found only in higher order primates

The tumor suppressor LKB1/STK11 plays important roles in regulating cellular metabolism and stress responses and its mutations are associated with various cancers. We recently identified a novel exon 1b within intron 1 of human LKB1/STK11, which generates an alternatively spliced, mitochondria-targeting LKB1 isoform important for regulating mitochondrial oxidative stress. Here we examined the formation of this novel exon 1b and uncovered its relatively late emergence during evolution. Analyses of putative exon 1b genomic sequences within the primate superfamily indicated that the exonization of LKB1/STK11 exon 1b was mediated by the conserved retrotransposable element Alu-Sc. While putative exon 1b sequences are recognizable in most members of the primate family from New World Monkeys onwards, characteristically functional LKB1/STK11 exon 1b, with translation start and 5ʹ and 3ʹ splice sites, could only be found in greater apes and human, and interestingly, correlates with their increased body mass and longevity development.

Transcriptomics Unveil Canonical and Non-Canonical Heat Shock-Induced Pathways in Human Cell Lines

The cellular stress response (CSR) is a conserved mechanism that protects cells from -environmental and physiological stressors. The heat shock response (HSR), a critical component of the CSR, utilizes molecular chaperones to mitigate proteotoxic stress caused by elevated temperatures. We hypothesized that while the canonical HSR pathways are conserved across cell types, specific cell lines may exhibit unique transcriptional responses to heat shock. To test this, we compared the transcriptomic responses of HEK293, HepG2, and HeLa cells under control conditions immediately following heat shock and after an 8-h recovery period. RNA sequencing revealed the conserved activation of canonical HSR pathways, including the unfolded protein response, alongside the -enrichment of the non-canonical “Receptor Ligand Activity” pathway across all cell lines. Cell-line-specific variations were observed, with HepG2 cells exhibiting significantly higher ex-pression levels of certain genes compared to other cell lines under stress conditions, as well as greater fold changes in gene expression relative to its control conditions. Validation by qPCR confirmed the activation of key genes within the “Receptor Ligand Activity” pathway across time points. These findings provide insights into conserved and context-specific aspects of the HSR, contributing to a more comprehensive understanding of stress response mechanisms across mammalian cells.