bims-proreb Biomed News
on Proteostasis and redox biology
Issue of 2025–11–16
fourteen papers selected by
Shayan Motiei, Universität des Saarlandes
  1. Iron-deplete diet enhances Caenorhabditis elegans lifespan via oxidative stress response pathways.
  2. Targeted RNAi screen reveals novel regulators of RNA-binding protein phase transitions in Caenorhabditis elegans oocytes.
  3. Sphingolipid and methionine metabolism in aging.
  4. Redox homeostasis in ferroptosis and aging: a causal role for fard-1 and dhs-25 in Caenorhabditis elegans.
  5. UBQLN2 is necessary for UBE3A-mediated proteasomal degradation of the domesticated retroelement PEG10.
  6. DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans.
  7. Autophagy-dependent modulation of ER calcium release drives KCNMA1/BKCa signaling and seizure susceptibility.
  8. Current Understanding of Protein Aggregation in Neurodegenerative Diseases.
  9. Beyond Folding: Expanding the Functional Landscape of Hsp90 Chaperone Machinery in Health and Disease.
  10. Dysfunctional Chondroitin 4-O-Sulfotransferase-1 Impairs Cellular Redox State and Promotes Tau Aggregation.
  11. Investigating NFE2L1 activators for targeted protein aggregate clearance: a follow-up study.
  12. Discovery and Profiling of Protein Cysteine S-2-Carboxypropylation.
  13. Endoplasmic reticulum quality control and metal tolerance: reduced activity of glucosidase II enzyme affects positively cadmium tolerance in Arabidopsis thaliana.
  14. Emerging functions for nonhistone protein acetylation in budding yeast.
  1. EMBO J. 2025 Nov 10.
    Iron-deplete diet enhances Caenorhabditis elegans lifespan via oxidative stress response pathways.
    Priyanka Das, Ravi, Jogender Singh.
      Gut microbes play a crucial role in modulating host lifespan. However, the microbial factors that influence host longevity and their mechanisms of action remain poorly understood. Using the expression of Caenorhabditis elegans FAT-7, a stearoyl-CoA 9-desaturase, as a proxy for lifespan modulation, we conduct a genome-wide bacterial mutant screen and identify 26 Escherichia coli mutants that enhance host lifespan. Transcriptomic and biochemical analyses reveal that these mutant diets induce oxidative stress and activate the mitochondrial unfolded protein response (UPRmt). Antioxidant supplementation abolishes lifespan extension, confirming that oxidative stress drives these effects. The extension of lifespan requires the oxidative stress response regulators SKN-1, SEK-1, and HLH-30. Mechanistically, these effects are linked to reduced iron availability, as iron supplementation restores FAT-7 expression, suppresses UPRmt activation, and abolishes lifespan extension. Iron chelation mimics the pro-longevity effects of the mutant diets, highlighting dietary iron as a key modulator of aging. Our findings reveal a bacterial-host metabolic axis that links oxidative stress, iron homeostasis, and longevity in C. elegans.
    Keywords:  HLH-30; Iron; Lifespan; Oxidative Stress; SKN-1
    DOI:  https://doi.org/10.1038/s44318-025-00634-7
  2. G3 (Bethesda). 2025 Nov 10. pii: jkaf266. [Epub ahead of print]
    Targeted RNAi screen reveals novel regulators of RNA-binding protein phase transitions in Caenorhabditis elegans oocytes.
    Mohamed T Elaswad, Grace M Thomas, Corrin Hays, Nicholas J Trombley, Jennifer A Schisa.
      The ability of oocytes to maintain their quality is essential for successful reproduction. One critical aspect of oocyte quality and successful embryogenesis after fertilization is the proper regulation of the stores of maternal mRNA by RNA-binding proteins. Many RNA-binding proteins undergo regulated phase transitions during oogenesis, and alterations of the protein phase can disrupt its ability to regulate mRNA stability and translation. In C. elegans, regulators of RNA-binding protein phase transitions in maturing oocytes of young adult hermaphrodites remain poorly characterized. However, a few recently identified genes are also required for the clearance of damaged proteins during maturation, suggesting coordination between these processes. To explore this relationship and gain insight into the regulation of phase transitions, we conducted a targeted RNAi screen of genes required for removal of protein aggregates in maturing oocytes. Here, we identify six novel regulators of phase transitions of the KH-domain protein MEX-3. We present strong evidence that the regulation of MEX-3 phase transitions in the oocyte overlaps with, but is distinct from, the regulatory network of protein aggregate clearance.
    Keywords:   Caenorhabditis elegans ; Animalia; MEX-3; RNA-binding proteins; WormBase; condensates; oocyte quality; phase transitions
    DOI:  https://doi.org/10.1093/g3journal/jkaf266
  3. J Cell Sci. 2025 Nov 01. pii: jcs264026. [Epub ahead of print]138(21):
    Sphingolipid and methionine metabolism in aging.
    Daniel Adebayo, Eseiwi Obaseki, Kashvi Vasudeva, Marwa Aboumourad, Ahmad Sleiman, Sumit Bandyopadhyay, Lindsey Kreinbring, Hanaa Hariri.
      Sphingolipids are essential for cell membrane structure and the regulation of organelle functions. Sphingolipid synthesis requires the coordinated activity of multiple organelles, including the endoplasmic reticulum, Golgi, lysosomes and mitochondria, which are connected via membrane contact sites. Metabolic remodeling of sphingolipid pathways is observed in aging and numerous age-related disorders. However, numerous studies have highlighted the complex and species-specific roles of sphingolipid metabolism in aging. In budding yeast, inhibition of sphingolipid synthesis extends lifespan by a mechanism that is poorly understood. Recent findings suggest that inhibition of sphingolipid synthesis in cells mimics methionine restriction, a condition known to extend lifespan across different experimental models. However, how sphingolipid remodeling alters cellular methionine levels, and whether this directly influences aging, remains unclear. In this Review, we explore the roles of sphingolipids in organelle function, highlighting their metabolic connections to methionine restriction and aging.
    Keywords:  Aging; Metabolism; Methionine; Sphingolipids
    DOI:  https://doi.org/10.1242/jcs.264026
  4. Redox Biol. 2025 Nov 01. pii: S2213-2317(25)00425-2. [Epub ahead of print]88 103912
    Redox homeostasis in ferroptosis and aging: a causal role for fard-1 and dhs-25 in Caenorhabditis elegans.
    Roberta Pensotti, Barbara Sciandrone, Federica Bovio, Laura Schröter, Silvia Maglioni, Leonie Thewes, Matilde Emma Forcella, Andrea Rossi, Paola Alessandra Fusi, Carsten Berndt, Natascia Ventura, Maria Elena Regonesi.
      Aging is a natural process characterized by a progressive physiological decline that undermines health and well-being in the elderly population. Oxidative stress is a widely accepted hallmarks of aging, and its role as one of the main drivers of ferroptosis is quite recent. Ferroptosis is an iron-dependent cell death caused by massive phospholipid peroxidation. The excessive accumulation of intracellular reactive oxygen species and iron, as well as the failure of the main cellular antioxidant systems, cause ferroptotic cell death. While clear roles for ferroptosis in pathological conditions such as cancer or neurodegeneration have been described, its physiological roles and regulators are less understood. Here, using Caenorhabditis elegans as a powerful model organism for aging studies, we uncover a role for ferroptosis in physiological aging mediated by disturbed redox homeostasis. We evaluated healthspan parameters in C. elegans highlighting how several age-related features differentially decline during physiological aging. A progressive loss of the capability to contrast external stressors, with an increase in hydroxyl radicals and a decrease of glutathione demonstrated the disruption of redox homeostasis in older age. Moreover, transcription of selected genes involved in redox metabolism is downregulated with aging. Among them, loss of the fatty acyl-CoA reductase encoded by fard-1 and of the dehydrogenase encoded by dhs-25 display higher sensitivity to ferroptosis, increased lipid peroxidation, lower total glutathione levels and reduced lifespan. Accordingly, the expression of hydroxysteroid 17-beta dehydrogenase 8, one of the closest mammalians dhs-25 homologs, is downregulated in cells which are more sensitive to ferroptosis. Our results clearly prove a causal role for ferroptosis in C. elegans aging driven by mitochondrial redox unbalance, unveiling novel genes involved in this connection that may constitute targets for possible interventions to improve healthy aging.
    Keywords:  Aging; Caenorhabditis elegans; Ferroptosis; Frataxin; Mitochondria; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.redox.2025.103912
  5. J Cell Sci. 2025 Nov 14. pii: jcs.264105. [Epub ahead of print]
    UBQLN2 is necessary for UBE3A-mediated proteasomal degradation of the domesticated retroelement PEG10.
    Julia E Roberts, Phuoc T Huynh, Luis O Carale, Alexandra M Whiteley.
      Ubiquilins are a family of extrinsic ubiquitin receptors that are thought to facilitate protein degradation by shuttling proteins to the proteasome. However, the defining characteristics of Ubiquilin clients, and the steps of Ubiquilin-mediated degradation, have been elusive. Previously, we showed Ubiquilin 2 (UBQLN2) regulates the proteasomal degradation of PEG10, a unique virus-like protein which comes in two forms: a gag protein which is not regulated by UBQLN2, and a gag-pol protein which is dependent on UBQLN2. Here, we refine the model of Ubiquilin activity through further investigation of the UBQLN2-mediated degradation of PEG10. Gag-pol and gag proteins undergo distinct degradation processes; while both forms bind to UBQLN2 independent of their ubiquitination status, only gag-pol protein is degraded in a UBQLN2, ubiquitin, and proteasome-dependent fashion. Cellular gag-pol is ubiquitinated, and mutation of key lysine residues in the pol region rendered gag-pol insensitive to UBQLN2. Degradation of gag-pol was also dependent on the E3 ubiquitin ligase UBE3A, which requires UBQLN2 to regulate gag-pol levels. Together, these data clarify our understanding of UBQLN2-mediated degradation and highlight the importance of UBE3A in regulating PEG10.
    Keywords:  E6AP; PEG10; UBE3A; UBQLN2; Ubiquilin; proteasome
    DOI:  https://doi.org/10.1242/jcs.264105
  6. Nat Commun. 2025 Nov 10. 16(1): 9878
    DAF-16/FOXO and HLH-30/TFEB comprise a cooperative regulatory axis controlling tubular lysosome induction in C. elegans.
    Cristian Ricaurte-Perez, Joshua P Gill, P Kerr Wall, Olga Dubuisson, Kathryn R DeLeo, K Adam Bohnert, Alyssa E Johnson.
      Transcription factors DAF-16/FOXO and HLH-30/TFEB have been linked to aging regulation, but how they synergize to promote longevity is not fully understood. Here, we reveal a functional interaction between these two transcription factors that supports healthier aging in Caenorhabditis elegans. Namely, DAF-16 and HLH-30 cooperate to trigger robust lysosomal tubulation under various contexts, which contributes to systemic health benefits in late age. Remarkably, lysosome tubulation can be artificially induced via overexpression of a small lysosomal gene, dSVIP, in the absence of one transcription factor, but not both. Mechanistically, intestinal overexpression of dSVIP leads to nuclear accumulation of DAF-16 and HLH-30 in gut and non-gut tissues and triggers global gene expression changes, including induction of vps-34 and related lipid-metabolism genes, that promote tubular-lysosome activity. Collectively, our work reveals a cellular process under control of DAF-16 and HLH-30 that elicits pro-health effects in aging.
    DOI:  https://doi.org/10.1038/s41467-025-64832-x
  7. Autophagy. 2025 Nov 10. 1-3
    Autophagy-dependent modulation of ER calcium release drives KCNMA1/BKCa signaling and seizure susceptibility.
    Gaga Kochlamazashvili, Marijn Kuijpers.
      Macroautophagy/autophagy is best known for its role in maintaining cellular homeostasis through degradation of damaged proteins and organelles. In neurons, autophagy also contributes to the regulation of activity by adjusting the availability of cellular components to physiological demand. In a recent study, we show that autophagy shapes neuronal excitability by restraining a calcium-dependent pathway that couples endoplasmic reticulum calcium release to KCNMA1/BKCa activity at the plasma membrane. When autophagy is lost, this pathway is enhanced, and seizure susceptibility increases.
    Keywords:  Autophagy; BKCa; ERphagy; axon; calcium; endoplasmic reticulum; epilepsy; excitability; neuron; ryanodine receptor
    DOI:  https://doi.org/10.1080/15548627.2025.2580436
  8. Int J Mol Sci. 2025 Oct 30. pii: 10568. [Epub ahead of print]26(21):
    Current Understanding of Protein Aggregation in Neurodegenerative Diseases.
    Chen Hu, Menghan Lin, Chuangui Wang, Shengping Zhang.
      Protein aggregates are central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. This comprehensive review explores the mechanisms of protein misfolding and aggregation, their prion-like propagation, and the critical role of oligomeric species in neurotoxicity. It further examines cellular clearance pathways, including the ubiquitin-proteasome system and autophagy, alongside the regulatory functions of molecular chaperones. The review also covers advanced diagnostic imaging and biomarker techniques, as well as emerging therapeutic strategies such as pharmacological agents, gene therapy, and immunotherapy. Controversies regarding the toxicity of aggregates and future directions, including novel degradation technologies and targeted therapeutic approaches, are discussed. By integrating current knowledge, this review aims to provide a broad yet detailed overview of the field, highlighting both established concepts and promising avenues for research and treatment.
    Keywords:  aggregate clearance; neurodegenerative diseases; oligomers; protein aggregates; therapeutic strategies
    DOI:  https://doi.org/10.3390/ijms262110568
  9. Int J Mol Sci. 2025 Oct 22. pii: 10279. [Epub ahead of print]26(21):
    Beyond Folding: Expanding the Functional Landscape of Hsp90 Chaperone Machinery in Health and Disease.
    Manish Kumar Singh, Jyotsna S Ranbhise, Minghao Fu, Songhyun Ju, Sunhee Han, Hyeong Rok Yun, Wonchae Choe, Sung Soo Kim, Insug Kang.
      Molecular chaperones are crucial for maintaining protein homeostasis by assisting in the proper folding, stabilization, and function of proteins. Among them, Heat shock protein 90 (Hsp90), represents a highly conserved protein family of molecular chaperones that plays an essential role in diverse biological processes and is fundamental to cellular health and survival. As a highly abundant molecular chaperone, Hsp90 comprises 1-2% of cellular proteins, increasing to 4-6% under stress conditions. It interacts with client proteins, assisting them in proper folding and stability. Unlike classical chaperonins, Hsp90 operates through a highly regulated, ATP-dependent cycle that involves multiple co-chaperones. This process allows Hsp90 to selectively engage with numerous client proteins, including signaling proteins, kinases, hormone receptors, and transcription factors. Recent discoveries have revealed its involvement in processes beyond protein folding, demonstrating its role in diverse cellular functions such as epigenetic regulation, immune signaling, and oncogenic transformation. This current review highlighted the specific characteristics of cytoplasmic and endoplasmic reticulum (ER) as well as mitochondrial paralogs and functions, focusing on its contribution to buffering genetic variation, facilitating oncogene addiction, and modulating disease phenotypes in conditions such as cancer, neurodegeneration, cardiovascular diseases (CVD), and diabetes. We also discuss the therapeutic potential of targeting Hsp90 and its co-chaperones, outlining the challenges and prospects in drug development. These insights not only reshape our understanding of chaperone biology but also present opportunities for precision medicine in various human diseases.
    Keywords:  ATPase; Hsp90; cancer; cardiac disease; client proteins; co-chaperone; diabetes
    DOI:  https://doi.org/10.3390/ijms262110279
  10. Cells. 2025 Oct 28. pii: 1686. [Epub ahead of print]14(21):
    Dysfunctional Chondroitin 4-O-Sulfotransferase-1 Impairs Cellular Redox State and Promotes Tau Aggregation.
    Satomi Nadanaka, Yuto Imamoto, Toru Takarada, Masafumi Tanaka, Hiroshi Kitagawa.
      Chondroitin sulfate (CS) chains on the cell surface are sulfated in various patterns, and this structure is the basis of CS function. We aimed to investigate the role of chondroitin 4-O-sulfotransferase-1 (C4ST-1), the enzyme responsible for the 4-sulfation of CS, in redox homeostasis and protein aggregation in mouse neuroblastoma Neuro2a and neural progenitor C17.2 cells. Results showed that C4ST-1 deficiency significantly reduced 4-sulfated CS, which led to markedly decreased intracellular glutathione levels and increased reactive oxygen species production. Mechanistically, C4ST-1 loss reduced the CS modification of neurocan, decreased the stability of the cystine transporter xCT, and decreased intracellular glutathione levels. This redox imbalance promoted protein aggregation and caused lysosomal membrane damage, indicating a failure of protein quality control. Although C4ST-1 deficiency alone did not cause tau protein aggregation, it significantly accelerated the aggregation of a familial tauopathy mutant following the introduction of seeds. These findings suggest that C4ST-1-mediated CS sulfation regulates the intracellular redox state and tau pathology. Thus, C4ST-1 may serve as a therapeutic target for neurodegenerative diseases.
    Keywords:  chondroitin sulfate; glutathione; oxidative stress; proteoglycan; tau aggregation
    DOI:  https://doi.org/10.3390/cells14211686
  11. RSC Med Chem. 2025 Oct 22.
    Investigating NFE2L1 activators for targeted protein aggregate clearance: a follow-up study.
    Zuzana Smahelova, Lucie Svobodova, Jindrich Sedlacek, Michael Adamek, Marketa Pimkova Polidarova, Pavel Majer, Ales Machara, Klara Grantz Saskova.
      Disruption of protein homeostasis (proteostasis), whether by acute proteotoxic stress or chronic expression of mutant proteins, can lead to the accumulation of toxic protein aggregates. Such aggregation is a hallmark of numerous diseases and is often associated with impaired protein clearance mechanisms. The transcription factor nuclear factor erythroid 2-related factor 1 (encoded by NFE2L1, also known as Nrf1) plays a central role in restoring proteostasis by increasing proteasome synthesis. Therefore, pharmacological activation of NFE2L1 under non-stress conditions represents a promising therapeutic strategy for neurodegenerative and other proteostasis-related diseases. In our previous study, we identified bis(phenylmethylene)cycloalkanone derivatives as NFE2L1 activators capable of inducing proteasome subunit expression, increasing heat shock protein levels, and stimulating autophagy. Building upon these findings, we have now developed a new library of structurally related compounds to identify novel more potent NFE2L1 activators. By systematically examining how specific chemical substitutions affect NFE2L1 activation, this work advances our understanding of the structure-activity relationships within this pathway.
    DOI:  https://doi.org/10.1039/d5md00584a
  12. Molecules. 2025 Oct 31. pii: 4255. [Epub ahead of print]30(21):
    Discovery and Profiling of Protein Cysteine S-2-Carboxypropylation.
    Jiabao Song, Kejun Yin, Ronghu Wu, Y George Zheng.
      Methacrylyl-CoA is a key metabolic intermediate in the valine catabolic pathway. Its accumulation has been found to be cytotoxic and associated with pathological conditions. Nevertheless, detailed biological effects of methacrylyl-CoA and methacrylate in human physiology and pathology are poorly understood. We propose that the electrophilicity of the alkene bond in the methacrylyl group can react with the cysteine residues in proteins resulting in an unexplored protein post-translational modification (PTM), cysteine S-2-carboxypropylation (C2cp). To test and validate this mechanistic hypothesis, we experimentally detected and profiled S-2-carboxypropylated proteins from the complex cellular proteome with the design and application of a bioorthogonal chemical probe, N-propargyl methacrylamide. We tested the probe in different mammalian cell models and demonstrated its versatility and sensitivity to protein cysteine S-2-carboxypropylation. We established quantitative chemical proteomics for global and site-specific profiling of protein S-2-carboxypropylation, which successfully identified 403 S-2-carboxypropylated proteins and 120 cysteine modification sites from HEK293T cells. Through bioinformatic analysis, we found that C2cp-modified proteins were involved in a variety of critical cellular functions including translation, RNA splicing, and protein folding. Our chemoproteomic studies demonstrating the proteome-wide distribution of cysteine S-2-carboxypropylation provide a new biochemical mechanism for the functional investigation of methacrylyl-CoA and understanding valine-related metabolic disorders.
    Keywords:  PTM; chemical proteomics; cysteine S-2-carboxypropylation (C2cp); methacrylyl-CoA; valine metabolism
    DOI:  https://doi.org/10.3390/molecules30214255
  13. Plant Physiol Biochem. 2025 Nov 04. pii: S0981-9428(25)01265-3. [Epub ahead of print]229(Pt D): 110737
    Endoplasmic reticulum quality control and metal tolerance: reduced activity of glucosidase II enzyme affects positively cadmium tolerance in Arabidopsis thaliana.
    Maria De Benedictis, Antonia Gallo, Danilo Migoni, Paride Papadia, Francesco Paolo Fanizzi, Gian Pietro Di Sansebastiano, Pietro Roversi, Angelo Santino.
      The Endoplasmic Reticulum Quality Control (ERQC) machinery is highly conserved among eukaryotes and assists the newly synthetized proteins in the folding process. Previous works have reported the involvement of ERQC in plant immunity and biotic stress response. However, the interaction between ERQC pathway and heavy metals exposure has been poorly investigated in plants. In the present study, we showed that the Arabidopsis thaliana rsw3 mutant, characterised by a reduced activity of the ER Glucosidase II enzyme, exhibits an increased tolerance to cadmium (Cd) stress. Under standard conditions, rsw3 seedlings exhibit shorter primary roots compared to Wild-type (Wt) plantlets, because of a constitutive ER stress and a consequent upregulation of both ERQC and Unfolded Protein Response (UPR) stress markers in root or shoot tissues. Interestingly, differently from Wt seedlings, these markers remain unchanged in rsw3 under Cd stress. Biochemical data here provided linked the enhanced Cd tolerance of rsw3 to the brassinosteroid receptor 1, BRI1, as the partial impairment of GII activity positively affects the accumulation of the active form of BRI1 receptor on the plasma membrane under Cd stress.
    Keywords:  Abiotic stress; BRI1; Cadmium; ER glucosidase II; Endoplasmic reticulum quality control
    DOI:  https://doi.org/10.1016/j.plaphy.2025.110737
  14. Trends Biochem Sci. 2025 Nov 10. pii: S0968-0004(25)00246-4. [Epub ahead of print]
    Emerging functions for nonhistone protein acetylation in budding yeast.
    Cameron Gibson, Idin Lantz, Michael Downey.
      Lysine acetylation is a post-translational modification (PTM) that is traditionally studied as a modifier of histones. In recent years, nonhistone protein acetylation has also emerged as a ubiquitous modification in eukaryotes. Recent advances in mass spectrometry (MS) workflows suggest that a majority of proteins are acetylated at some point during their life cycle. However, only a few of these acetylations have been studied for their functional significance. Here, we review the function of acetylations on key nonhistone proteins involved in chromatin remodeling and DNA damage repair, protein homeostasis, and metabolic coordination of the cell cycle in Saccharomyces cerevisiae. We discuss the diverse roles of acetylation in regulating these pathways, while highlighting emerging themes and open questions in the field.
    Keywords:  DNA damage response; autophagy; cell cycle; heat shock; metabolism; post-translational modifications
    DOI:  https://doi.org/10.1016/j.tibs.2025.10.005
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