bims-cemest 2025-01-12 papers

bims-cemest

Biomed News

on Cell metabolism and stress

Issue of 2025–01–12
thirteen papers selected by
Jessica Rosarda, Uniformed Services University

eIF2α Phosphorylation-ATF4 Axis-Mediated Transcriptional Reprogramming Mitigates Mitochondrial Impairment During ER Stress.
The interplay between gut microbiota and the unfolded protein response: Implications for intestinal homeostasis preservation and dysbiosis-related diseases.
Aging and voluntary exercise's effects on Aβ1-42 levels, endoplasmic reticulum stress factors, and apoptosis in the hippocampus of old male rats.
Activators of the 26S proteasome when protein degradation increases.
The integrated stress response drives MET oncogene overexpression in cancers.
Mapping the Genetic Architecture of the Adaptive Integrated Stress Response in S. cerevisiae.
Endoplasmic Reticulum Calcium Signaling in Hippocampal Neurons.
Regulation of physiological and pathological condensates by molecular chaperones.
Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis.
Involvement of ATF6 in Octreotide-Induced Endothelial Barrier Enhancement.
Transcriptomics Unveil Canonical and Non-Canonical Heat Shock-Induced Pathways in Human Cell Lines.
Protein quality control machinery: regulators of condensate architecture and functionality.
Mechanisms of metabolism-coupled protein modifications.

Mol Cells. 2025 Jan 03. pii: S1016-8478(24)00201-2. [Epub ahead of print] 100176

eIF2α Phosphorylation-ATF4 Axis-Mediated Transcriptional Reprogramming Mitigates Mitochondrial Impairment During ER Stress.

Hien Thi Le, Jiyoung Yu, Hee Sung Ahn, Mi-Jeong Kim, In Gyeong Chae, Hyun-Nam Cho, Juhee Kim, Hye-Kyung Park, Hyuk Nam Kwon, Han-Jung Chae, Byoung Heon Kang, Jeong Kon Seo, Kyunggon Kim, Sung Hoon Back.

  Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, which regulates all three unfolded protein response pathways, helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. However, transcriptional regulation of mitochondrial homeostasis by eIF2α phosphorylation during ER stress is not fully understood. Here, we report that the eIF2α phosphorylation-activating transcription factor 4 (ATF4) axis is required for expression of multiple transcription factors (TFs) including nuclear factor erythroid 2-related factor 2 (Nrf2) and their target genes responsible for mitochondrial homeostasis during ER stress. eIF2α phosphorylation-deficient (A/A) cells displayed dysregulated mitochondrial dynamics and mitochondrial DNA replication, decreased expression of oxidative phosphorylation complex proteins, and impaired mitochondrial functions during ER stress. ATF4 overexpression suppressed impairment of mitochondrial homeostasis in A/A cells during ER stress by promoting expression of downstream TFs and their target genes. Our findings underscore the importance of the eIF2α phosphorylation-ATF4 axis for maintaining mitochondrial homeostasis through transcriptional reprogramming during ER stress.

Keywords:  ATF4; ER stress; Mitochondrial homeostasis; Nrf2; eIF2α phosphorylation

DOI:  https://doi.org/10.1016/j.mocell.2024.100176
Microb Pathog. 2025 Jan 04. pii: S0882-4010(25)00004-X. [Epub ahead of print]200 107279

The interplay between gut microbiota and the unfolded protein response: Implications for intestinal homeostasis preservation and dysbiosis-related diseases.

Miriam Di Mattia, Michele Sallese, Loris Riccardo Lopetuso.

  The unfolded protein response (UPR) is a complex intracellular signal transduction system that orchestrates the cellular response during Endoplasmic Reticulum (ER) stress conditions to reestablish cellular proteostasis. If, on one side, prolonged ER stress conditions can lead to programmed cell death and autophagy as a cytoprotective mechanism, on the other, unresolved ER stress and improper UPR activation represent a perilous condition able to trigger or exacerbate inflammatory responses. Notably, intestinal and immune cells experience ER stress physiologically due to their high protein secretory rate. Indeed, there is evidence of UPR's involvement in both physiological and pathological intestinal conditions, while less is known about its bidirectional interaction with gut microbiota. However, gut microbes and their metabolites can influence ER stress and UPR pathways, and, in turn, ER stress conditions can shape gut microbiota composition, with important implications for overall intestinal health. Thus, targeting UPR components is an intriguing strategy for treating ER stress-linked dysbiosis and diseases, particularly intestinal inflammation.

Keywords:  Autophagy; Immunity; KDEL receptors; Microbiota; Proteostasis

DOI:  https://doi.org/10.1016/j.micpath.2025.107279
Brain Res. 2025 Jan 04. pii: S0006-8993(25)00005-8. [Epub ahead of print] 149447

Aging and voluntary exercise's effects on Aβ1-42 levels, endoplasmic reticulum stress factors, and apoptosis in the hippocampus of old male rats.

Leila Derafshpour, Mona Niazi, Bagher Pourheydar, Shiva Roshan-Milani, Morteza Asghariehahari, Leila Chodari.

  Within the aging cortex, amyloid beta peptide (Aβ) is a crucial element of the senile plaques, a hallmark feature often observed in cases of Alzheimer's disease (AD). The UPR (unfolded protein response), a cellular mechanism for protein folding, is switched on by Aβ accumulation. Endoplasmic reticulum (ER) stress has been identified as playing a role in aging and the development of neurodegenerative diseases. The exact molecular pathways leading to perishing of cells from Aβ-induced ER stress, as well as the impact of voluntary exercise on these mechanisms, are still subjects awaiting a definitive answer yet. In the current study, 18 male Wistar rats were included: 6 young rats (3 months old; 200-250 g) in the Young Control group, and 12 old rats (18 months old; 400-430 g) randomly allocated to the Old Control and Old Exercise groups. The rat cages had running wheels for them to voluntarily run on for 8 weeks. This was followed by Western blotting, immunohistochemical staining, biochemical as well as morphological analyses. Voluntary exercise reduced Aβ1-42 deposition (P < 0.001) and inhibited the activation of caspase-8 (P < 0.001) and caspase-12 (P < 0.01), and on top of that down-regulated the expression of ATF6 (P < 0.001), CHOP (P < 0.01), and p-PERK (P < 0.05) proteins in the hippocampus of old male rats. Exercise amplified the population of Bcl-2-expressing cells and decreased the population of Bax-expressing cells in the hippocampus of the Old Exercise group (P < 0.001). Voluntary exercise inhibited the apoptotic pathways and suppressed the activation of UPR signaling pathways. Hence, voluntary exercise may be a therapeutic strategy and a promising approach to prevent AD through modulation of Aβ-induced ER stress.

Keywords:  Aging; Amyloid Beta1-42; Apoptosis; Endoplasmic reticulum stress; Voluntary exercise

DOI:  https://doi.org/10.1016/j.brainres.2025.149447
Exp Mol Med. 2025 Jan 08.

Activators of the 26S proteasome when protein degradation increases.

Donghoon Lee.

In response to extra- and intracellular stimuli that constantly challenge and disturb the proteome, cells rapidly change their proteolytic capacity to maintain proteostasis. Failure of such efforts often becomes a major cause of diseases or is associated with exacerbation. Increase in protein breakdown occurs at multiple steps in the ubiquitin-proteasome system, and the regulation of ubiquitination has been extensively studied. However, the activities of the 26S proteasome are also stimulated, especially under highly catabolic conditions such as those associated with atrophying skeletal muscle, proteotoxic stress such as heat shock and arsenite, or hormonal cues such as cAMP or cGMP agonists. Among the proteins that enhance proteasomal degradation are the PKA, PKG, UBL-UBA proteins and the Zn finger AN1-type domain (ZFAND) family proteins. ZFAND proteins are of particular interest because of their inducible expression in response to various stimuli and their abilities to control protein quality by stimulating the 26S proteasome and p97/VCP. The regulatory roles of ZFAND proteins appear to be important not only for the control of protein degradation but also for other cellular processes, such as mRNA stability and signaling pathways. This review summarizes the known functions of proteasome activators and discusses their possible roles in regulating proteostasis and other cellular processes.

DOI: https://doi.org/10.1038/s12276-024-01385-x
EMBO J. 2025 Jan 07.

The integrated stress response drives MET oncogene overexpression in cancers.

Marina Cerqua, Marco Foiani, Carla Boccaccio, Paolo M Comoglio, Dogus M Altintas.

  Cancer cells rely on invasive growth to survive in a hostile microenvironment; this growth is characterised by interconnected processes such as epithelial-to-mesenchymal transition and migration. A master regulator of these events is the MET oncogene, which is overexpressed in the majority of cancers; however, since mutations in the MET oncogene are seen only rarely in cancers and are relatively infrequent, the mechanisms that cause this widespread MET overexpression remain obscure. Here, we show that the 5' untranslated region (5'UTR) of MET mRNA harbours two functional stress-responsive elements, conferring translational regulation by the integrated stress response (ISR), regulated by phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) at serine 52. ISR activation by serum starvation, leucine deprivation, hypoxia, irradiation, thapsigargin or gemcitabine is followed by MET protein overexpression. We mechanistically link MET translation to the ISR by (i) mutation of the two uORFs within the MET 5'UTR, (ii) CRISPR/Cas9-mediated mutation of eIF2α (S52A), or (iii) the application of ISR pathway inhibitors. All of these interventions reduce stress-induced MET overexpression. Finally, we show that blocking stress-induced MET translation blunts MET-dependent invasive growth. These findings indicate that upregulation of the MET oncogene is a functional requirement linking integrated stress response to cancer progression.

Keywords:  Integrated Stress Response; Invasive Growth; MET Oncogene

DOI:  https://doi.org/10.1038/s44318-024-00338-4
bioRxiv. 2024 Dec 22. pii: 2024.12.19.629525. [Epub ahead of print]

Mapping the Genetic Architecture of the Adaptive Integrated Stress Response in S. cerevisiae.

Rachel Baum, Jinyoung Kim, Ryan Y Muller, Nicholas Ingolia.

The integrated stress response (ISR) is a conserved eukaryotic signaling pathway that responds to diverse stress stimuli to restore proteostasis. The strength and speed of ISR activation must be tuned properly to allow protein synthesis while maintaining proteostasis. Here, we describe how genetic perturbations change the dynamics of the ISR in budding yeast. We treated ISR dynamics, comprising timecourses of ISR activity across different levels of stress, as a holistic phenotype. We profiled changes in ISR dynamics across thousands of genetic perturbations in parallel using CRISPR interference with barcoded expression reporter sequencing (CiBER-seq). We treated cells with sulfometuron methyl, a titratable inhibitor of branched-amino acid synthesis, and measured expression of an ISR reporter. Perturbations to translation such as depletion of aminoacyl-tRNA synthetases or tRNA biogenesis factors reduced cell growth and caused a strikingly proportionate activation of the ISR activation. In contrast, impaired ribosome biogenesis reduced basal ISR activity and weakened ISR dynamics. Reduced ribosome capacity may lower the demand for amino acids and thereby explain these changes. Our work illustrates how CiBER-seq enables high-throughput measurements of complex and dynamic phenotypes that shed light on adaptive and homeostatic mechanisms.

DOI: https://doi.org/10.1101/2024.12.19.629525
Biomolecules. 2024 Dec 18. pii: 1617. [Epub ahead of print]14(12):

Endoplasmic Reticulum Calcium Signaling in Hippocampal Neurons.

Vyacheslav M Shkryl.

  The endoplasmic reticulum (ER) is a key organelle in cellular homeostasis, regulating calcium levels and coordinating protein synthesis and folding. In neurons, the ER forms interconnected sheets and tubules that facilitate the propagation of calcium-based signals. Calcium plays a central role in the modulation and regulation of numerous functions in excitable cells. It is a versatile signaling molecule that influences neurotransmitter release, muscle contraction, gene expression, and cell survival. This review focuses on the intricate dynamics of calcium signaling in hippocampal neurons, with particular emphasis on the activation of voltage-gated and ionotropic glutamate receptors in the plasma membrane and ryanodine and inositol 1,4,5-trisphosphate receptors in the ER. These channels and receptors are involved in the generation and transmission of electrical signals and the modulation of calcium concentrations within the neuronal network. By analyzing calcium fluctuations in neurons and the associated calcium handling mechanisms at the ER, mitochondria, endo-lysosome and cytosol, we can gain a deeper understanding of the mechanistic pathways underlying neuronal interactions and information transfer.

Keywords:  calcium signaling; endoplasmic reticulum; inositol 1,4,5-trisphosphate receptor; neurons; ryanodine receptor

DOI:  https://doi.org/10.3390/biom14121617
FEBS J. 2025 Jan 05.

Regulation of physiological and pathological condensates by molecular chaperones.

Nadeen Akaree, Valentina Secco, Flonia Levy-Adam, Amal Younis, Serena Carra, Reut Shalgi.

  Biomolecular condensates are dynamic membraneless compartments that regulate a myriad of cellular functions. A particular type of physiological condensate called stress granules (SGs) has gained increasing interest due to its role in the cellular stress response and various diseases. SGs, composed of several hundred RNA-binding proteins, form transiently in response to stress to protect mRNAs from translation and disassemble when the stress subsides. Interestingly, SGs contain several aggregation-prone proteins, such as TDP-43, FUS, hnRNPA1, and others, which are typically found in pathological inclusions seen in autopsy tissues from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. Moreover, mutations in these genes lead to the familial form of ALS and FTD. This has led researchers to propose that pathological aggregation is seeded by aberrant SGs: SGs that fail to properly disassemble, lose their dynamic properties, and become pathological condensates which finally 'mature' into aggregates. Here, we discuss the evidence supporting this model for various ALS/FTD-associated proteins. We further continue to focus on molecular chaperone-mediated regulation of ALS/FTD-associated physiological condensates on one hand, and pathological condensates on the other. In addition to SGs, we review ALS/FTD-relevant nuclear condensates, namely paraspeckles, anisosomes, and nucleolar amyloid bodies, and discuss their emerging regulation by chaperones. As the majority of chaperoning mechanisms regulate physiological condensate disassembly, we highlight parallel themes of physiological and pathological condensation regulation across different chaperone families, underscoring the potential for early disease intervention.

Keywords:  ALS; FTD; FUS; LLPS; TDP‐43; aggregation; chaperones; condensates; proteostasis; stress granules

DOI:  https://doi.org/10.1111/febs.17390
Elife. 2025 Jan 10. pii: e75393. [Epub ahead of print]14

Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis.

Shixuan Liu, Ceryl Tan, Chloe Melo-Gavin, Miriam B Ginzberg, Ron Blutrich, Nish Patel, Michael Rape, Kevin G Mark, Ran Kafri.

  Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018). While we previously identified the p38 MAPK pathway as a key regulator of the mammalian cell size checkpoint (S. Liu et al., 2018), the mechanism of size-dependent growth rate regulation has remained elusive. Here, we quantified global rates of protein synthesis and degradation in cells of varying sizes, both under unperturbed conditions and in response to perturbations that trigger size-dependent compensatory growth slowdown. We found that protein synthesis rates scale proportionally with cell size across cell cycle stages and experimental conditions. In contrast, oversized cells that undergo compensatory growth slowdown exhibit a superlinear increase in proteasome-mediated protein degradation, with accelerated protein turnover per unit mass, suggesting activation of the proteasomal degradation pathway. Both nascent and long-lived proteins contribute to the elevated protein degradation during compensatory growth slowdown, with long-lived proteins playing a crucial role at the G1/S transition. Notably, large G1/S cells exhibit particularly high efficiency in protein degradation, surpassing that of similarly sized or larger cells in S and G2, coinciding with the timing of the most stringent size control in animal cells. These results collectively suggest that oversized cells reduce their growth efficiency by activating global proteasome-mediated protein degradation to promote cell size homeostasis.

Keywords:  cell biology; human

DOI:  https://doi.org/10.7554/eLife.75393
Pharmaceuticals (Basel). 2024 Nov 28. pii: 1604. [Epub ahead of print]17(12):

Involvement of ATF6 in Octreotide-Induced Endothelial Barrier Enhancement.

Saikat Fakir, Nektarios Barabutis.

  Background/Objectives: Endothelial hyperpermeability is the hallmark of severe disease, including sepsis and acute respiratory syndrome (ARDS). The development of medical countermeasures to treat the corresponding illness is of utmost importance. Synthetic somatostatin analogs (SSA) are FDA-approved drugs prescribed in patients with neuroendocrine tumors, and they act via growth hormone (GH) suppression. Preclinical investigations suggest that Octreotide (OCT) alleviates Lipopolysaccharide (LPS)-induced injury. The aim of the study is to investigate the involvement of activating transcription factor 6 (ATF6) in the protective effects of OCT in endothelial dysfunction. To the best of our knowledge, the available information on that topic is limited. Methods: Human lung microvascular endothelial cells (HULEC-5a) and bovine pulmonary artery endothelial cells (BPAEC) which expressed elevated levels of ATF6 due to AA147 were exposed to OCT or vehicle. Protein expression, endothelial permeability, and reactive oxygen species (ROS) generation were assessed utilizing Western blot analysis, Fluorescein isothiocyanate (FITC)-Dextran assay, and Dichlorofluorescein diacetate measurements, respectively. Results: Our observations suggest that ATF6 activation significantly improves OCT-induced endothelial barrier enhancement. This combination led to increased expression of binding immunoglobulin protein (BiP) and glucose-regulated protein 94 (Grp94), which are downstream unfolded protein response (UPR) targets. Moreover, ATF6 activation prior to OCT treatment resulted in decreased activation of myosin light chain 2 (MLC2) and cofilin; and reduced reactive oxygen species (ROS) generation. ATF6 activation enhanced the anti-inflammatory effects of OCT, as reflected in the suppression of transducer and activator of transcription (STAT) 1, STAT3, and P38 phosphorylation. Conclusions: Our findings suggest that ATF6 activation prior to OCT treatment enhances the beneficial effects of OCT in the endothelium.

Keywords:  ARDS; inflammation; lung injury; somatostatin

DOI:  https://doi.org/10.3390/ph17121604
bioRxiv. 2024 Dec 23. pii: 2024.12.22.629972. [Epub ahead of print]

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

Andrew Reinschmidt, Luis Solano, Yonny Chavez, William Drew Hulsy, Nikolas Nikolaidis.

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-hour recovery period. RNA sequencing revealed conserved activation of canonical HSR pathways, including the unfolded protein response, alongside enrichment of the non-canonical "Receptor Ligand Activity" pathway across all cell lines. Cell line-specific variations were also observed, with HepG2 cells displaying more uniquely expressed genes and elevated expression levels (fold changes) of shared genes under stress 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.

DOI: https://doi.org/10.1101/2024.12.22.629972
Trends Biochem Sci. 2025 Jan 03. pii: S0968-0004(24)00275-5. [Epub ahead of print]

Protein quality control machinery: regulators of condensate architecture and functionality.

Anitha Rajendran, Carlos A Castañeda.

  Protein quality control (PQC) mechanisms including the ubiquitin (Ub)-proteasome system (UPS), autophagy, and chaperone-mediated refolding are essential to maintain protein homeostasis in cells. Recent studies show that these PQC mechanisms are further modulated by biomolecular condensates that sequester PQC components and compartmentalize reactions. Accumulating evidence points towards the PQC machinery playing a pivotal role in regulating the assembly, disassembly, and viscoelastic properties of several condensates. Here, we discuss how the PQC machinery can form their own condensates and also be recruited to known condensates under physiological or stress-induced conditions. We present molecular insights into how the multivalent architecture of polyUb chains, Ub-binding adaptor proteins, and other PQC machinery contribute to condensate assembly, leading to the regulation of downstream PQC outcomes and therapeutic potential.

Keywords:  chaperones; condensates; phase separation; polyphasic linkage; protein quality control; ubiquitination

DOI:  https://doi.org/10.1016/j.tibs.2024.12.003
Nat Chem Biol. 2025 Jan 07.

Mechanisms of metabolism-coupled protein modifications.

Bingsen Zhang, Frank C Schroeder.

Intricate coupling between metabolism and protein post-translational modifications (PTMs) has emerged as a fundamental aspect of cellular regulation. Recent studies demonstrate that protein modifications can originate from diverse metabolites, and that their regulation is closely tied to the cellular metabolic state. Here we explore recently uncovered PTMs, including the concept of 'modification of a modification', as well as associated feedback and feedforward regulatory mechanisms, in which modified proteins impact not only related metabolic pathways but also other signaling cascades affecting physiology and diseases. The recently uncovered role of nucleus-localized metabolic enzymes for histone modifications additionally highlights the importance of cell-compartment-specific metabolic states. We further comment on the utility of untargeted metabolomics and proteomics for previously unrecognized PTMs and associated metabolic patterns. Together, these advances have uncovered a dynamic interplay between metabolism and PTMs, offering new perspectives for understanding metabolic regulation and developing targeted therapeutic strategies.

DOI: https://doi.org/10.1038/s41589-024-01805-z