bims-proreb 2026-02-22 papers

bims-proreb

Biomed News

on Proteostasis and redox biology

Issue of 2026–02–22
eleven papers selected by
Shayan Motiei, Universität des Saarlandes

Coordinated control of proteasome subunit gene expression promotes stress resistance, proteostasis, and longevity.
SIRT6 Regulates Protein Synthesis and Folding Through Nucleolar Remodeling.
Differential inclusion formation of an aggregation-prone protein reveals differences in the proteostasis capacity of neuronal cell lines.
Pro-longevity compounds extend Caenorhabditis elegans male lifespan and reproductive healthspan.
The Hsp40 co-chaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.
Stress endurance mediates the healthspan-promoting effect of two newly described iridoid glycosides from Verbascum nigrum ssp. abietinum in Caenorhabditis elegans.
The Effects of Aging and Anti-Aging Dietary Restriction on Brain Glutathione and Thioredoxin Redox Systems.
The autophagy-senescence axis as a threshold model of aging and therapeutic targeting.
Structures of the 26S proteasome in complex with the Hsp70 co-chaperone Bag1 reveal a mechanism for direct substrate transfer.
Transcriptomic and chromatin accessibility profiling unveils new regulators of heat hormesis in Caenorhabditis elegans.
Chaetoglobosin F Attenuates Amyloid-β-Induced Neurotoxicity in Caenorhabditis elegans by Regulating Autophagy and Oxidative Stress Via the Insulin/IGF-1 and p38 MAPK Pathways.

Geroscience. 2026 Feb 17.

Coordinated control of proteasome subunit gene expression promotes stress resistance, proteostasis, and longevity.

Irini Topalidou, Nicolas Lehrbach.

  The proteasome is essential for cellular protein homeostasis through selective destruction of damaged and misfolded proteins. Failure of proteasome-dependent turnover accompanied by accumulation and aggregation of aberrant proteins is a hallmark of aging and late-onset neurodegenerative diseases. SKN-1A/Nrf1, a member of the NFE2L/Nrf family of transcription factors, is a master regulator of proteasome biogenesis. Through transcriptional control of proteasome subunit gene expression, SKN-1A/Nrf1 controls homoeostatic and stress-responsive upregulation of proteasome levels in adaptation to proteasome dysfunction or protein misfolding. SKN-1A/Nrf1 acts in concert with another Nrf family transcription factor, SKN-1C/Nrf2, to regulate many aspects of physiology including stress responses, redox balance, immunity, and metabolism. Here, we demonstrate that a small deletion in the promoter of the pbs-5 gene, which encodes an essential proteasome subunit, uncouples its expression from transcriptional regulation by SKN-1A/Nrf1. This disruption leads to compensatory SKN-1A/Nrf1-dependent upregulation of other proteasome subunit genes, resulting in a homeostatic imbalance in proteasomal gene expression. This pbs-5 regulatory mutation phenocopies some, but not all, aspects of SKN-1A/Nrf1 inactivation, providing evidence that coordinated regulation of proteasomal subunit gene expression underlies a subset of SKN-1A/Nrf1's physiological roles. In comparing the effects of the pbs-5 promoter deletion with isoform-specific inactivation of SKN-1A or SKN-1C, we show that the pbs-5 promoter mutation completely abrogates multiple lifespan extension paradigms. These results reveal that coordinated homeostatic regulation of proteasome subunit gene expression is critical for longevity and healthy aging.

Keywords:  NFE2L1; Nrf1; PSMB5; Proteasome; Proteostasis; SKN-1A

DOI:  https://doi.org/10.1007/s11357-026-02146-6
Aging Cell. 2026 Feb;25(2): e70384

SIRT6 Regulates Protein Synthesis and Folding Through Nucleolar Remodeling.

Daniel Stein, Christian Gallrein, Miguel Portillo, Shai Kaluski-Kopach, Alfredo Garcia-Venzor, Yuval Lachberg, Ekaterina Eremenko, Dmitrii Smirnov, Shiran Dror, Monica Einav, Ekaterina Khrameeva, Anat Ben-Zvi, Björn Schumacher, Debra Toiber.

  An important hallmark of aging-and particularly of neurodegeneration-is the loss of proteostasis, leading to cellular stress. However, the causal mechanisms driving this loss are unclear. We show that SIRT6 has a critical role in maintaining proteostasis. Mechanistically, SIRT6 negatively regulates global translation by controlling ribosomal genes, nucleolar function and TIP5 chromatin localization. SIRT6 deletion increases nucleolar size, rRNA production and protein translation. However, the expression of chaperones remains unchanged, failing to compensate for the excessive translation, leading to reduced folding capacity and production of aggregates. In vivo, we establish a C. elegans model (sir-2.4 KO) that shows reduced heat shock resistance and an accelerated age-dependent reduction in motility. Sir-2.4 depletion crossed with a neuron-specific polyQ strain led to premature motility loss and premature death. These results point to proteostasis-stress intolerance in the absence of SIRT6, that can be rescued by pharmacologically reducing protein translation rates. Our data suggest that SIRT6 deficiency results in proteostasis loss through nucleolar dysfunction. These results highlight that deficient proteostasis begins with chromatin dysregulation resulting in neurodegeneration.

Keywords:  SIRT6; aging; neurodegeneration; nucleolar expansion; proteostasis

DOI:  https://doi.org/10.1111/acel.70384
Biochim Biophys Acta Mol Cell Res. 2026 Feb 17. pii: S0167-4889(26)00020-0. [Epub ahead of print] 120124

Differential inclusion formation of an aggregation-prone protein reveals differences in the proteostasis capacity of neuronal cell lines.

Shannon McMahon, Dezerae Cox, Flora Cheng, Albert Lee, Justin J Yerbury, Heath Ecroyd.

  Maintaining proteome integrity is essential for cellular function and survival. Disruptions in proteostasis lead to the aggregation of proteins into inclusions, a process that underlies many neurodegenerative diseases. To quantitatively assess the proteostasis capacity of neuronal cells, we employed an aggregation-prone double mutant form of firefly luciferase (denoted FlucDM) as a reporter protein. We compared two commonly used neuronal cell lines, mouse neuroblastoma cells (Neuro-2a) and a motor neuron-like hybrid line (NSC-34), to evaluate their ability to prevent the aggregation of proteins into intracellular inclusions. We observed a significantly greater propensity of FlucDM to form inclusions in NSC-34 cells compared to Neuro-2a cells. This suggests a reduced capacity of NSC-34 cells for managing aggregation-prone proteins. Proteomic profiling of FlucDM inclusions purified from both cell types revealed cell-type-specific engagement of the proteostasis machinery with aggregation-prone proteins. Comparing the proteomic profiles of key arms of the proteostasis network between these two cell lines revealed that the endoplasmic reticulum (ER) unfolded protein response is differentially expressed. This study establishes a quantitative platform for assessing cellular proteostasis capacity and underscores the importance of cell-type context in proteome maintenance. These insights have implications for understanding the selective vulnerability of neurons in protein misfolding disorders.

Keywords:  Aggregation index; Inclusions; Neurodegenerative disorders; Protein aggregation; Proteostasis capacity

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120124
Geroscience. 2026 Feb 17.

Pro-longevity compounds extend Caenorhabditis elegans male lifespan and reproductive healthspan.

Rose S Al-Saadi, Patrick C Phillips.

  Sex differences in aging are robust and ubiquitous. Demographic differences in aging generated by sex have long been recognized, but the underlying biological basis for these differences and the potential for sex-specific interventions remain understudied. To explore sex differences in the response to pro-longevity interventions, we utilized the C. elegans aging model and asked whether male lifespan and reproductive healthspan can be extended via compounds known to have pro-longevity effects in hermaphrodites. We tested seven different compounds at two concentrations each and found that lifespan was extended under all tested conditions. However, reproductive healthspan measured by mating success in late life improved under only two tested conditions, sulforaphane and metformin. These results demonstrate that lifespan and healthspan can be decoupled in C. elegans males and offer a new framework for screening pro-longevity compounds and for studying sex differences in aging in a classical aging model.

Keywords:   C. elegans ; Healthspan; Pro-longevity interventions; Sex differences

DOI:  https://doi.org/10.1007/s11357-026-02144-8
J Biol Chem. 2026 Feb 16. pii: S0021-9258(26)00162-6. [Epub ahead of print] 111292

The Hsp40 co-chaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.

Biswarathan Ramani, Kean Ehsani, Martin Kampmann.

  Protein-encoding nucleotide repeat expansion diseases, including polyglutamine (polyQ) and polyglycine (polyG) diseases, are characterized by the accumulation of aggregation-prone proteins. In the polyQ diseases, including Huntington's disease and several spinocerebellar ataxias, substantial prior evidence supports a pathogenic role for mutant polyQ-expanded protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. The goal of this study is to establish a scalable cell-based model to systematically evaluate genetic modifiers of protein aggregation in both polyQ and polyG diseases. We developed FRET-based reporter systems that model polyQ and polyG aggregation in human cells and used them to perform high-throughput CRISPR interference screens targeting all known molecular chaperones. In the polyQ model, the screen identified multiple Hsp70 chaperones and Hsp40 co-chaperones previously implicated in polyQ aggregation and additionally revealed the Hsp40 co-chaperone DNAJC7 as a potent and previously unrecognized suppressor of polyQ aggregation. In contrast, in a FRET-based polyG aggregation model of neuronal intranuclear inclusion disease, CRISPRi screening showed minimal overlap of chaperone modifiers of the polyQ screen. Direct knockdown of DNAJC7 also did not affect polyG aggregation, yet overexpressed DNAJC7 co-localized with both polyQ and polyG aggregates in cells and reduced their aggregation. In addition to establishing new inducible, scalable cellular models for polyQ and polyG aggregation, this work expands the role of DNAJC7 in regulating folding of disease-associated proteins.

Keywords:  aggregation; chaperone; high-throughput screening; neurodegeneration; polyglutamine disease

DOI:  https://doi.org/10.1016/j.jbc.2026.111292
Phytomedicine. 2026 Feb 09. pii: S0944-7113(26)00182-0. [Epub ahead of print]153 157944

Stress endurance mediates the healthspan-promoting effect of two newly described iridoid glycosides from Verbascum nigrum ssp. abietinum in Caenorhabditis elegans.

Slaveya Krustanova, Monika N Todorova, Vanya Gerasimova, Martina S Savova, Stoyan Stoyanov, Milena P Popova, Milen I Georgiev, Kalina Alipieva.

   BACKGROUND: Natural products are emerging as promising options for promoting health and managing age-related diseases. Iridoid glycosides, a diverse class of monoterpenoids, exert multiple beneficial effects and are of significant interest in pharmaceutical research. They are abundant in Scrophulariaceae, particularly in the genus Verbascum L. (mulleins). However, the infraspecific taxon V. nigrum ssp. abietinum (Borbas) I.K. Ferguson, native to the Balkan Peninsula, has not been previously investigated regarding chemical composition or healthspan-modulating potential.
PURPOSE: This study aimed to isolate and characterize the main secondary metabolites of V. nigrum ssp. abietinum and to evaluate the effects of iridoid glycosides on age-related physiological changes and stress tolerance in Caenorhabditis elegans. We focused on two newly isolated sinuatol derivatives (1 and 2) and their influence on conserved molecular networks regulating stress response and aging.
METHODS: Following isolation and identification of compounds 1 and 2, phenotypic analyses were conducted to assess toxicity, lifespan, physiology, and stress resistance. Basal metabolism and molecular mechanisms were further examined.
RESULTS: Methanol extract of aerial parts of V. nigrum ssp. abietinum yielded two previously undescribed iridoid glycosides (1 and 2) along with twelve known constituents. Both compounds upregulated sek-1/p38 (MAPK) and sqst-1/p62 (SQSTM1), indicating enhanced autophagy and stress response. Additionally, sgk-1/SGK-1, hsf-1/HSF1, and tcer-1/TCERG1 were consistently overexpressed, suggesting improved oxidative stress defense, heat shock response, and transcriptional regulation. Notably, the selective upregulation of hsp-16.1 and hsp-16.2 upon supplementation with compound 1 suggests a stereospecific interaction with the HSP network, potentially linked to the positional arrangement of the caffeoyl moiety.
CONCLUSION: This study provides the first evidence that iridoid glycosides 1 and 2 from V. nigrum ssp. abietinum promote C. elegans healthspan by enhancing stress response through modulation of genes related to autophagy and inflammation.

Keywords:  Aging; Caenorhabditis elegans; Healthspan; Iridoid glycosides; Stress response; Verbascum nigrum

DOI:  https://doi.org/10.1016/j.phymed.2026.157944
Aging Dis. 2026 Feb 10.

The Effects of Aging and Anti-Aging Dietary Restriction on Brain Glutathione and Thioredoxin Redox Systems.

Leah E Jamerson, Patrick C Bradshaw.

Glutathione (GSH) is a cofactor for several enzymes including glutathione peroxidases (GPXs) that detoxify H2O2 and for glutaredoxins that catalyze protein cysteine deglutathionylation. Aging results in a decreased rate of brain GSH synthesis and an oxidation of brain GSH to glutathione disulfide (GSSG), which increases oxidative damage, but is delayed or reversed by anti-aging dietary restriction (DR). Fasting increases the hepatic synthesis and release of GSH, which is catabolized to its amino acids, possibly increasing their transport to the brain for the re-synthesis of GSH. Brain GSH synthesis is limited by cysteine availability. Some astrocytes may increase GSH synthesis during fasting and DR by increasing metabolic flux through the cysteine and H2S-synthesizing transsulfuration pathway. In contrast to the cytoplasm where the GPX1-GSH pathway for H2O2 detoxification is highly active, the mitochondrial matrix relies largely on peroxiredoxin 3 (PRDX3), which functions together with thioredoxin 2 and thioredoxin reductase 2. In contrast to the cytoplasmic and mitochondrial GSH/GSSG, the ER GSH/GSSG is more oxidized in young organisms and becomes reduced with aging and plays a more fundamental role in buffering protein disulfide bond isomerization than for providing GSH to ER GPXs. Studies addressing the aging and DR-induced redox changes in the cytoplasm, mitochondria, and ER in different neural cell types and brain regions are needed to establish effective therapies for aging-related disorders. This review further covers the brain cell-type and brain region-specific gene expression changes that occur with aging and DR for the major enzymes that maintain the cellular redox state.

DOI: https://doi.org/10.14336/AD.2025.1505
Redox Biol. 2026 Feb 10. pii: S2213-2317(26)00077-7. [Epub ahead of print]91 104079

The autophagy-senescence axis as a threshold model of aging and therapeutic targeting.

Md Entaz Bahar, Jin Seok Hwang, Trang Huyen Lai, Kazi-Marjahan Akter, Rizi Firman Maulidi, Deok Ryong Kim.

  Autophagy and cellular senescence are fundamental stress-response programs that critically shape aging and disease progression, yet their functional relationship has remained paradoxical. Autophagy is traditionally viewed as a cytoprotective process that preserves cellular homeostasis and delays senescence. In contrast, emerging evidence demonstrates that autophagy is also indispensable for the survival and pathological activity of established senescent cells. In this review, we propose a "threshold model" to reconcile these opposing roles and to provide a unified framework linking signal transduction, organelle quality control, and therapeutic intervention. According to this model, autophagy exerts stage-dependent functions governed by stress intensity and disease progression. Below a critical damage threshold, robust autophagic flux suppresses senescence initiation by maintaining mitochondrial integrity, limiting oxidative stress, and preserving proteostasis. Once this threshold is exceeded, autophagy is functionally reprogrammed to sustain the metabolic and biosynthetic demands of senescent cells, including production of the senescence-associated secretory phenotype (SASP). We highlight key signaling nodes that regulate this transition, including mTORC1, AMPK, p53, and p62, as well as spatial and organelle-specific mechanisms such as the TOR-autophagy spatial coupling compartment (TASCC), mitophagy failure, lipophagy blockade, and aberrant nucleophagy. These processes converge on innate immune pathways, notably cGAS-STING and NF-κB signaling, to drive chronic inflammation and tissue dysfunction. Importantly, we extend this mechanistic framework to clinical translation, synthesizing evidence from ongoing trials in cancer, neurodegeneration, metabolic liver disease, and fibrosis. We argue that effective targeting of the autophagy-senescence axis requires precision gerontology, integrating dynamic biomarkers to guide stage-specific interventions-autophagy activation for prevention and autophagy inhibition or senolysis for established disease. This threshold-based perspective provides a rational foundation for next-generation therapeutic strategies targeting aging and age-related disorders.

Keywords:  Autophagy; Cellular stress; Senescence; Targeted senotherapy; Threshold-model

DOI:  https://doi.org/10.1016/j.redox.2026.104079
Sci Adv. 2026 Feb 20. 12(8): eadz3026

Structures of the 26S proteasome in complex with the Hsp70 co-chaperone Bag1 reveal a mechanism for direct substrate transfer.

Moisés Maestro-López, Tat Cheung Cheng, Jimena Muntaner, Margarita Menéndez, Melissa Alonso, Andreas Schweitzer, Masato Ishizaka, Robert J Tomko, Jorge Cuéllar, José María Valpuesta, Eri Sakata.

Coupling between the chaperone and degradation systems, particularly under stress, is essential for eliminating unfolded proteins. The co-chaperone Bag1 links Hsp70 to the 26S proteasome, recruiting Hsp70-bound clients for proteasomal degradation. Here, we present cryo-electron microscopy structures of the Bag1-bound 26S proteasome, revealing unprecedented conformational rearrangements within the 19S regulatory particle. Bag1 binding to the Rpn1 induces a marked reconfiguration of AAA+ adenosine triphosphatase (ATPase) ring, disrupting its canonical spiral staircase and remodeling the central channel architecture. This reconfiguration generates a large cavity above the substrate entry gate of the 20S core particle. The conserved pore-2 loops of ATPases Rpt2 and Rpt5 play critical roles in opening of the 20S gate, enabling substrate entry into proteolytic chamber independently of ubiquitination. These findings suggest a previously unknown mechanism of the proteasomal degradation, by which remodeling the central cavity and 20S gate in the presence of Bag1, possibly bypassing the need for ubiquitination.

DOI: https://doi.org/10.1126/sciadv.adz3026
PLoS Biol. 2026 Feb;24(2): e3003639

Transcriptomic and chromatin accessibility profiling unveils new regulators of heat hormesis in Caenorhabditis elegans.

Hsin-Yun Chang, Sarah E McMurry, Sicheng Ma, Charles L Heinke, Christian A Mansour, Sophia Marie T Schwab, Charles G Danko, Siu Sylvia Lee.

Heat hormesis describes the beneficial adaptations resulting from transient exposure to mild heat stress, which enhances stress resilience and promotes healthy aging. While heat hormesis is widely observed, much remains to be learned about its molecular basis. This study bridges a critical knowledge gap through a comprehensive multiomic analysis, providing key insights into the transcriptomic and chromatin accessibility landscapes throughout a heat hormesis regimen in Caenorhabditis elegans. We uncover highly dynamic, dose-dependent molecular responses to heat stress and reveal that while most initial molecular changes induced by mild stress revert to baseline, key differences emerge in response to subsequent heat shock challenge that likely contribute to physiological benefits. We further demonstrate that heat hormesis extends life span specifically in wild-type animals, but not in germline-less mutants, likely due to transient disruption of germline activities during mild heat exposure, which appears sufficient to trigger pro-longevity mechanisms. This finding points to tissue-specific responses in mediating the physiological outcomes of heat hormesis. Importantly, we identify several highly conserved regulators of heat hormesis that likely orchestrate gene expression to enhance stress resilience. Among these regulators, some (MARS-1/MARS1, SNPC-4/SNAPc, FOS-1/c-Fos) are broadly required for heat-hormesis-induced benefits, whereas others (ELT-2/GATA4, DPY-27/SMC4) are uniquely important in specific genetic backgrounds. This study advances our understanding of stress resilience mechanisms, points to multiple new avenues for future investigations, and provides a molecular framework for promoting healthy aging through strategic mid-life stress management.

DOI: https://doi.org/10.1371/journal.pbio.3003639
Neurochem Res. 2026 Feb 20. 51(2): 80

Chaetoglobosin F Attenuates Amyloid-β-Induced Neurotoxicity in Caenorhabditis elegans by Regulating Autophagy and Oxidative Stress Via the Insulin/IGF-1 and p38 MAPK Pathways.

Xuefei Lu, Kai Xu, Zhenyu Zhou, Gaonan Ding, Yuan Zhang, Yongwen Liang, Jiahui Zhou, Minglu Jia, Yitang Zhang, Li Shen, Hualing Li.

  Alzheimer's disease (AD) is a progressive neurodegenerative disease for which no effective clinical therapies currently exist. The neuroprotective potential of Chaetoglobosin F (CF), a fungal secondary metabolite, was investigated in this study using a Caenorhabditis elegans (C. elegans) model of AD that are transgenic nematodes expressing amyloid-beta (Aβ). Key parameters evaluated included paralysis rate, lifespan, motor and cognitive functions, Aβ plaque aggregation, intracellular reactive oxygen species (ROS), and autophagosome formation. The transcriptional levels of genes were examined by real time PCR. Results showed that treatment with CF significantly delayed paralysis, extended lifespan, and ameliorated Aβ-induced deficits in locomotion and chemotaxis. CF markedly reduced Aβ plaque accumulation, suppressed intracellular ROS levels, and promoted autophagosome formation. Furthermore, CF had potent inhibitory effects on acetylcholinesterase (AChE) activity. These beneficial effects were correlated with the upregulation of crucial genes, including daf-16, skn-1, pmk-1, mtl-1, unc-51, bec-1, lgg-1, sod-1 and sod-3, which confirmed the improving antioxidant defenses and autophagy. Our findings demonstrate that CF confers strong neuroprotection against Aβ-induced toxicity in C. elegans by co-regulating oxidative stress and autophagy through the Insulin/IGF-1 (IIS) and p38 MAPK signaling pathways. These results suggest that CF is a promising natural compound for further investigation as a potential therapeutic agent for AD.

Keywords:   Caenorhabditis elegans ; Alzheimer's disease; Autophagy; Chaetoglobosin F; Oxidative stress

DOI:  https://doi.org/10.1007/s11064-026-04704-y