bims-proreb Biomed News
on Proteostasis and redox biology
Issue of 2025–12–14
twelve papers selected by
Shayan Motiei, Universität des Saarlandes
  1. Functionally diversified Caenorhabditis elegans BiP orthologs control body growth, reproduction, stress resistance, aging, and autophagy.
  2. Meta-analysis of extracellular vesicles-associated protein abundance and aggregation during aging and disease in C. elegans.
  3. Dithiothreitol induced endoplasmic reticulum stress and its role in neurodegeneration in Caenorhabditis elegans.
  4. Phosphatidylcholine coordinates ER-autonomous and ER-nonautonomous adaptations to unfolded protein response dysfunction.
  5. NEDD8, stress granules, and amyotrophic lateral sclerosis: unveiling the therapeutic potential of the NEDP1 protease.
  6. Selaginella extracts extend lifespan and mitigate oxidative stress in Caenorhabditis elegans.
  7. Small heat shock protein HSPB5 uses disorder to bind zinc with high affinity.
  8. A widespread protein misfolding mechanism is differentially rescued in vitro by chaperones based on gene essentiality.
  9. Endoplasmic Reticulum Redoxome: Protein Folding and Beyond.
  10. Proximity labeling of DAF-16 FOXO highlights aging regulatory proteins.
  11. Proteostasis Stress Drives Stem Cell Aging, Clonal Hematopoiesis and Leukemia.
  12. Engineering the auxin-inducible degron system for tunable in vivo control of organismal physiology.
  1. Nat Commun. 2025 Dec 12. 16(1): 11094
    Functionally diversified Caenorhabditis elegans BiP orthologs control body growth, reproduction, stress resistance, aging, and autophagy.
    Nicholas D Urban, Shannon M Lacy, Kate M Van Pelt, Benedict Abdon, Zachary Mattiola, Adam Klaiss, Sarah Tabler, Eric K F Donahue, Kristopher Burkewitz, Matthias C Truttmann.
      Cellular systems governing protein folding depend on functional redundancy and diversification to maintain proteostasis. Here, using Caenorhabditis elegans, we show two homologous ER-resident HSP70 chaperones, HSP-3 and HSP-4, have overlapping and distinct roles in ER proteostasis and organismal physiology. Their expression and function vary by tissue, age, and stress, impacting ER stress resistance, reproduction, body size, and lifespan. We also find HSP-3 and HSP-4 uniquely regulate dietary restriction and reduced insulin signaling-mediated longevity in C. elegans. Notably, knockdown of hsp-4, but not hsp-3, induces autophagy and enhances tolerance to protein aggregation stress; this process requires the ortholog of ER-Phagy receptor Sec-62 (C18E9.2) and IRE-1. Finally, human cell data suggests that the dissociation of chaperone Binding Immunoglobulin Protein (BiP) from IRE-1 during times of ER stress promotes autophagy by enhancing the interaction of IRE-1 and Sec-62. These findings reveal how ER chaperone diversification maximizes stress resilience and suggest a BiP-dependent regulation of autophagy.
    DOI:  https://doi.org/10.1038/s41467-025-65998-0
  2. Biogerontology. 2025 Dec 07. 27(1): 13
    Meta-analysis of extracellular vesicles-associated protein abundance and aggregation during aging and disease in C. elegans.
    Prasun Kumar Bhunia, Prasad Kasturi.
      Extracellular vesicles (EVs) contribute to the maintenance of organism-wide proteostasis by mediating intercellular communication. Loss of proteostasis and altered intercellular communication are associated with aging and age-related diseases, suggesting key roles for EVs. However, it is unclear how the proteome of the EVs changes with age. To identify EV-associated proteins (EVAPs) and their fate with age, we curated publicly available EV proteome data from C. elegans model organism and human. Our analysis reveals that EVs carry proteins with diverse functions, including those involved in protein quality control. We found that abundance of the EVAPs changes significantly with age, heat stress, pathogen infections and diseases. Many of these EVAPs also aggregate with age and overlap with Aβ-driven protein aggregates. Further, we identified human orthologs of C. elegans EVAPs from human brain tissues affected with Alzheimer's disease and breast cancer. This meta-analysis highlights EVs proteome composition, their abundance changes, and aggregation during aging, stress, infection and disease conditions. Overall, this study provides new insights into the dynamics of EV proteins during aging and may possibly help in identifying potential biomarkers for age-related diseases.
    Keywords:   C. elegans ; Aging; Extracellular vesicles; Proteostasis
    DOI:  https://doi.org/10.1007/s10522-025-10362-4
  3. World J Biol Chem. 2025 Dec 05. 16(4): 111110
    Dithiothreitol induced endoplasmic reticulum stress and its role in neurodegeneration in Caenorhabditis elegans.
    Govind Raj, Manish Kumar, Smriti Shreya, Shikha Bhardwaj, Ratna Priya, Kailash C Mangalhara, Buddhi Prakash Jain.
       BACKGROUND: Neurodegeneration refers to the progressive loss of neurons, affecting both their structure and function. It is driven by synaptic dysfunction, disruptions in neural networks, and the accumulation of abnormal protein variants. Endoplasmic reticulum (ER) stress, caused by the accumulation of misfolded or unfolded protein, is a major contributor to neurodegeneration. Dithiothreitol (DTT) is a widely used redox reagent that disrupts the oxidative protein folding environment, inducing ER stress and leading to the imbalance in protein homeostasis can activate stress response pathway, potentially contributing to neurodegenerative processes. Caenorhabditis elegans (C. elegans) is a widely used model organism for studying neurodegeneration due to its well-mapped nervous system, approximately one-third of neuron cells in their body, complete genome sequenced, and conserved stress response pathway.
    AIM: To study the neurodegeneration in C. elegans caused by DTT-induced ER stress, assessed by behavioral, molecular, and lifespan changes.
    METHODS: C. elegans were cultured on nematode growth medium plates with OP50, and ER stress was induced using DTT. Effects were assessed via behavioral assays such as locomotion, chemotaxis, lifespan assay, and molecular studies.
    RESULTS: DTT exposure led to a significant decline in locomotion and chemotaxis response, indicating neurotoxicity. A reduction in lifespan was observed, suggesting an overall impact on health. Molecular analysis confirmed ER stress activation. DTT-induced ER stress negatively affects C. elegans, leading to behavioral impairments and molecular alterations associated with neurodegeneration.
    CONCLUSION: These findings establish C. elegans as a potential model for studying ER stress-mediated neurotoxicity and its implications in neurodegenerative diseases.
    Keywords:  Behavioral assay; Caenorhabditis elegans; Dithiothreitol toxicity; Endoplasmic reticulum stress; Neurodegeneration
    DOI:  https://doi.org/10.4331/wjbc.v16.i4.111110
  4. J Biol Chem. 2025 Dec 06. pii: S0021-9258(25)02878-9. [Epub ahead of print] 111026
    Phosphatidylcholine coordinates ER-autonomous and ER-nonautonomous adaptations to unfolded protein response dysfunction.
    Haixiang Tong, Wei Li, Pangui Yuan, Xinyu Wang, Shanshan Pang, Haiqing Tang.
      The ER UPR plays a crucial role in maintaining proteostasis, with its dysfunction closely associated with aging and various diseases. However, how cells cope with ER UPR dysfunction remains largely unexplored. Here, we report that both ER-autonomous and ER-nonautonomous adaptive responses are activated by defects in the IRE-1/XBP-1 UPR branch in C. elegans. IRE-1/XBP-1 dysfunction not only triggers the activation of the PEK-1 UPR branch but also induces a lysosome-dependent cytosolic proteostatic response. Mechanistically, IRE-1/XBP-1 dysfunction downregulates phosphatidylcholine (PC) metabolism, reducing levels of membrane lipid PC. This PC deficiency drives BORC complex recruitment to lysosomes, triggering lysosomal activation. Furthermore, suppression of phosphatidylcholine metabolism alone sufficiently activates both the ER UPR and lysosomal pathways, thereby enhancing resilience to proteostatic stress and contributing to longevity. These findings provide insights into how cells integrate distinct adaptive responses to maintain systemic proteostasis when the ER UPR is compromised and identify phosphatidylcholine as a potent regulator of proteostasis and aging.
    Keywords:  UPR; aging; lysosome; phosphatidylcholine; proteostasis
    DOI:  https://doi.org/10.1016/j.jbc.2025.111026
  5. Essays Biochem. 2025 Dec 12. pii: EBC20253036. [Epub ahead of print]
    NEDD8, stress granules, and amyotrophic lateral sclerosis: unveiling the therapeutic potential of the NEDP1 protease.
    Dimitra Mitsiadou, Dimitris P Xirodimas, Jolanta Polanowska.
      Protein quality control (PQC) systems are crucial for maintaining cellular proteostasis, particularly under stress that promotes misfolded protein accumulation. A central component of this response is the assembly of stress granules (SGs), cytoplasmic condensates of RNA and proteins that temporarily stall translation. Aberrant SG dynamics, often linked to mutations in SG proteins, contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where persistent protein aggregates are hallmarks. This review examines the emerging role of the ubiquitin-like modifier NEDD8 and its deconjugating enzyme NEDP1 in regulating SG homeostasis. Recent studies identify NEDP1 as a critical factor controlling SG clearance. Inhibition of NEDP1 enhances SG turnover, prevents pathological solidification, and promotes the disassembly of toxic aggregates through hyper-NEDDylation of PARP1, a DNA repair enzyme that also governs SG dynamics. Unlike broad-spectrum PARP1 inhibitors, which can impair DNA repair and cause cytotoxicity, NEDP1 inhibition offers a stress-specific approach that preserves normal cellular functions. Encouragingly, NEDP1 inhibition effectively causes aggregate elimination in ALS patient-derived fibroblasts and restores motility in Caenorhabditis elegans disease models. Altogether, these findings highlight NEDP1 as a key regulator of SG regulation and a promising therapeutic target for ALS and related neurodegenerative disorders.
    Keywords:  NEDD8; NEDP1/SENP8; PARP1; amyotrophic lateral sclerosis; stress granules
    DOI:  https://doi.org/10.1042/EBC20253036
  6. Front Pharmacol. 2025 ;16 1658991
    Selaginella extracts extend lifespan and mitigate oxidative stress in Caenorhabditis elegans.
    Xueqing Chen, Bingjian Yan, Yingmei Wu, Wenjing Quan, Yu Liu, Yaning Huang, Yinjie Shao, Yuan Wang, Qi Zhou, Yifei Liu, Songlin Liu, Jin Wang, Pan Li, Zhaohua Shi, Peng Shu, Junbo Gou.
       Introduction: Selaginella species hold a traditional place in medicine and cosmetics, but their potential to extend lifespan and the underlying bioactive compounds remain inadequately investigated. This study aims to systematically evaluate the anti-aging properties of diverse Selaginella extracts and to identify the key bioactive components and mechanisms involved.
    Methods: We collected 23 Selaginella samples from 13 different provinces across China to assess their geographical influence. Two representative methanol extracts, S4 (high in amentoflavone) and S16 (low in amentoflavone), were selected for in-depth evaluation using the Caenorhabditis elegans model. We employed lifespan assays, stress resistance tests, and comparative transcriptomics to analyze the effects on longevity, and pathway modulation.
    Results: Both S4 and S16 extracts significantly extended the lifespan of C. elegans under normal conditions and modulated conserved longevity pathways, including MAPK and FOXO signaling, with daf-16 and egl-8 emerging as key hub genes. Amentoflavone was identified and validated as a critical bioactive component, which alone extended lifespan by 63.81% and enhanced stress resistance. Mechanistically, amentoflavone promoted the nuclear translocation of DAF-16 and up-regulated the expression of antioxidant genes (e.g., sod-3, gst-3/4, hsp-16.48/12.6), leading to a significant reduction in intracellular ROS levels.
    Discussion: Our findings demonstrate that Selaginella extract and its key component, amentoflavone, delay aging primarily by activating the DAF-16/FOXO transcription factor and bolstering the antioxidant defense system. This study not only highlights amentoflavone as a major contributor to the lifespan-extending effects of Selaginella but also underscores the potential of these natural compounds as promising agents for healthy aging.
    Keywords:  Caenorhabditis elegans; DAF-16/FOXO pathway; amentoflavone; lifespan; selaginella tamariscina; transcriptome
    DOI:  https://doi.org/10.3389/fphar.2025.1658991
  7. J Biol Chem. 2025 Dec 09. pii: S0021-9258(25)02882-0. [Epub ahead of print] 111030
    Small heat shock protein HSPB5 uses disorder to bind zinc with high affinity.
    Maria K Janowska, Vanesa Racigh, Christoper N Woods, María Silvina Fornasari, Rachel E Klevit.
      Zinc is an essential metal that supports diverse cellular functions. Zinc exerts its biological activity through protein binding, serving as catalytic cofactors and structural stabilizers of many enzymes, transcription factors, and ubiquitin E3 ligases, among others. Despite total cellular zinc concentrations reaching hundreds of micromolar, free zinc levels are tightly buffered. Elevated free zinc promotes protein mismetalation and aggregation. While zinc is redox-inert, its cysteine-based protein ligands are readily oxidized. Oxidative modification of cysteines leads to zinc dissociation and a rapid increase in free zinc. With ∼3000 proteins in the human zinc proteome, uncontrolled zinc release could be highly deleterious. Metallothioneins buffer zinc under basal conditions, but their re-synthesis following oxidative inactivation occurs on the timescale of hours, raising the question of how free zinc is managed in the interim. Histidine, the second most prevalent zinc-coordinating residue, is resistant to oxidative modification. We characterized zinc binding by the small heat shock protein HSPB5 (αB-crystallin), a cysteine-free, histidine-rich protein chaperone that responds to cellular stress and found: (1) HSPB5 binds zinc with high affinity and rapid reversibility; (2) zinc binding requires the disordered HSPB5 N-terminal region; (3) zinc binding increases HSPB5 disorder; and (4) prolonged zinc exposure promotes formation of assemblies of oligomers cross-bridged by zinc. We propose that HSPB5 has evolved specialized zinc-dependent properties distinct among human sHSPs, enabling it to function not only as a protein chaperone but also as a conditional zinc reservoir under oxidative stress.
    Keywords:  HSPB5; alphaB crystallin; chaperone; intrinsic disorder; metalloproteins; small heat shock proteins; zinc
    DOI:  https://doi.org/10.1016/j.jbc.2025.111030
  8. Nat Commun. 2025 Dec 12. 16(1): 10870
    A widespread protein misfolding mechanism is differentially rescued in vitro by chaperones based on gene essentiality.
    Ian Sitarik, Quyen V Vu, Justin Petucci, Paulina Frutos, Hyebin Song, Edward P O'Brien.
      Protein misfolding involving changes in non-covalent lasso entanglement (NCLE) status has been proposed based on simulations and biochemical assays of a small number of proteins. Here, we detect hallmarks of these misfolded states across hundreds of proteins by integrating E. coli proteome-wide limited-proteolysis mass spectrometry data with structural datasets of protein native structures. Proteins containing native NCLEs are twice as likely to misfold, predominantly in regions where these NCLEs naturally occur. Surprisingly, the chaperones DnaK and GroEL do not typically correct this misfolding, except in the case of essential proteins. Statistical analysis links this differential rescue activity to weaker loop-closing contacts in the NCLEs of essential proteins, suggesting misfolding involving these loops is easier to rectify by chaperones. Molecular simulations indicate a mechanism where premature NCLE loop closure, prior to proper placement of the threading segment, leads to persistent misfolded states. This mechanism can explain why, in this mass spectrometry dataset, proteins with NCLEs are more likely to misfold and misfold in NCLE regions. These results suggest the potential for widespread NCLE misfolding, that such misfolded states in non-essential proteins could bypass the refolding action of chaperones, and that some protein sequences may have evolved to allow chaperone rescue from this class of misfolding.
    DOI:  https://doi.org/10.1038/s41467-025-66236-3
  9. Biochemistry. 2025 Dec 12.
    Endoplasmic Reticulum Redoxome: Protein Folding and Beyond.
    Percillia V S Oliveira, Tiphany C De Bessa, Francisco R M Laurindo.
      The endoplasmic reticulum (ER), the largest cellular organelle, is crucially dependent on its redox organization. First, to optimize disulfide bond formation in nascent proteins, it maintains a relatively oxidizing environment, reminiscent of the extracellular space. Second, it harbors several oxidoreductases from the protein disulfide isomerase (PDI) family, together with Ero1α oxidase and chaperones, which compose interplaying oxidative, reductive, and chaperone pathways to optimize protein processing. Third, disulfide formation and reshuffling in client proteins, involving thiol oxidation and disulfide exchange reactions, connect proteostasis to ER/cellular redox homeostasis. ER redox folding involves Ca2+-dependent liquid phase separation of PDI complexes. Calcium fluxes heavily interplay with dynamic redox regulation. ER stress disrupts the ER redox state and, in turn, is also regulated by cellular redox processes. Moreover, the ER makes membrane contacts with many other organelles such as plasma membrane, peroxisomes, and mitochondria, which are hubs for mutually dependent oxidant and calcium-linked effects. Furthermore, the ER redoxome extends to other subcellular and extracellular locations, a process we termed the "ER-dependent outreach redoxome (ERDOR)". ERDOR can occur by overflow of ER products such as H2O2, mobility of ER-associated domains or, mainly, via ER oxidoreductase translocation. The ER establishes a particular communication with the extracellular milieu via translocation of PDIs. Despite the low levels of extracellularly located ER oxidoreductases, they redox-regulate several molecular targets and may compose a peri/epicellular redox network. This article provides a comprehensive overview of the ER redoxome as an important emerging frontier to understand not only redox proteostasis but also intra- and intercellular redox communication.
    Keywords:  NADPH oxidase; NOX; oxidants; phenotype; protein disulfide isomerase; vascular smooth muscle cells
    DOI:  https://doi.org/10.1021/acs.biochem.5c00527
  10. Nat Commun. 2025 Dec 11.
    Proximity labeling of DAF-16 FOXO highlights aging regulatory proteins.
    Murat Artan, Hanna Schoen, Mario de Bono.
      Insulin/insulin-like growth factor signaling inhibits FOXO transcription factors to control development, homeostasis, and aging. Here, we use proximity labeling to identify proteins interacting with the C. elegans FOXO DAF-16. We show that in well-fed, unstressed animals harboring active insulin signaling, DAF-16 forms a complex with the PAR-1/MARK serine/threonine kinase, a key regulator of cell polarity. PAR-1 inhibits DAF-16 accumulation and promotes DAF-16 phosphorylation at S249, at a conserved motif that PAR-1/human MARK2 phosphorylates in vitro. DAF-2 insulin-like receptor signaling stimulates DAF-16 S249 phosphorylation, suggesting DAF-2 activates PAR-1. DAF-2 also promotes PAR-1 expression by inhibiting DAF-16. PAR-1 knockdown, or DAF-16 S249A, prolong lifespan, whereas phosphomimetic DAF-16 S249D suppresses the longevity of daf-2 mutants. At low insulin signaling, DAF-16 proximity labeling highlights transcription factors, chromatin regulators, and DNA repair proteins. One interactor, the zinc finger/homeobox protein ZFH-2/ZFHX3, forms a complex with DAF-16 and prolongs lifespan. Our work provides entry points for hypothesis-driven studies of FOXO function and longevity.
    DOI:  https://doi.org/10.1038/s41467-025-66409-0
  11. bioRxiv. 2025 Dec 01. pii: 2025.11.27.690982. [Epub ahead of print]
    Proteostasis Stress Drives Stem Cell Aging, Clonal Hematopoiesis and Leukemia.
    Fanny J Zhou, Michelle K Le, Helen C Wang, Wei Yang, Huan-You Wang, Arukshita Tiwari, Xinjian Cen, Mary Jean Sunshine, Jeffrey A Magee, Robert A J Signer.
      Aging is the primary risk factor for clonal hematopoiesis and the development of hematologic malignancies ( 1-5 ), yet the selective pressures that shape stem cell behavior and clonal expansion during aging remain poorly defined. Here, we identify proteostasis stress as a central driver of hematopoietic stem cell (HSC) aging and clonal evolution. We show that Heat shock factor 1 (Hsf1) is activated in aging HSCs to preserve proteostasis and sustain self-renewal. However, this physiological, age-associated adaptive mechanism is co-opted by pre-leukemic Dnmt3a -mutant HSCs to resist proteostasis and inflammatory stress required to fuel clonal expansion during aging. In the context of co-occurring Dnmt3a and Nras mutations, which are frequently observed in human acute myeloid leukemia (AML) ( 6-13 ), mutant HSCs and progenitors exhibit heightened dependence on Hsf1 for expansion, malignant transformation and disease progression. Loss of Hsf1 , or disruption of proteostasis, impairs expansion of mutant progenitors, delays leukemia onset, and prolongs survival. Together, these findings reveal proteostasis as a key constraint in the aging hematopoietic system that imposes a selective bottleneck. Hsf1 activation enables both physiological adaptation in aging stem cells and pathological clonal outgrowth in pre-leukemic and leukemic states, establishing proteostasis control as a pivotal mechanism linking stem cell aging to clonal hematopoiesis and malignancy.
    DOI:  https://doi.org/10.1101/2025.11.27.690982
  12. Nat Commun. 2025 Dec 12. 16(1): 10848
    Engineering the auxin-inducible degron system for tunable in vivo control of organismal physiology.
    Jeremy Vicencio, Daisuke Chihara, Matthias Eder, Lucia Sedlackova, Julie Ahringer, Nicholas Stroustrup.
      The auxin-inducible degron (AID) system is designed for the rapid and near-complete degradation of a specific target protein in vivo. However, to understand the dynamics of complex physiological networks, researchers often need methods that produce graded, quantitative changes in degradation rates for multiple proteins simultaneously. Here, we develop the AID system for in vivo, quantitative control over the abundance of multiple proteins simultaneously. First, by measuring and modeling the on- and off-target activities of different AID system variants in Caenorhabditis elegans, we characterize a variant of the E3 ubiquitin ligase subunit TIR1, which provides improved degradation activity compared to the original AID and AID2 systems. Then, we develop a TIR1 expression construct that enables simultaneous pan-somatic and germline protein degradation. Finally, we expand the AID toolkit to allow independent, simultaneous degradation of two distinct tissue-specific proteins. Together, these technologies enable new in vivo approaches for studying quantitative cellular biology and organismal dynamics.
    DOI:  https://doi.org/10.1038/s41467-025-66347-x
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