bims-proreb 2026-03-08 papers

bims-proreb

Biomed News

on Proteostasis and redox biology

Issue of 2026–03–08
eleven papers selected by
Shayan Motiei, Universität des Saarlandes

Protection from thiol reductive stress through an autoinhibitory hypoxia response pathway in Caenorhabditis elegans.
Heat shock proteins (Hsp70 and Hsp90) in neurodegeneration: pathogenic roles and therapeutic potential.
Aedes aegypti Hsp70 has enhanced ATPase and protein protection under oxidative stress.
GCN2 in proteostasis: structural logic, signalling networks and disease.
Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
Functions of J-domain proteins in mitochondrial protein biogenesis.
Proteostasis, disease and the ageing neuron: Compartmental complexity in non-renewing cells.
Escitalopram accelerated aging via impaired IIS/autophagy signaling pathway.
Diversity of GET3 chaperones in tail-anchored protein insertion.
The mechanism of oxidative stress induced by nanoplastics in Caenorhabditis elegans: Integrated analysis of transcriptomics and metabolomics.
A hierarchy of causes of death in senescent C. elegans.

Genetics. 2026 Jan 22. pii: iyag018. [Epub ahead of print]

Protection from thiol reductive stress through an autoinhibitory hypoxia response pathway in Caenorhabditis elegans.

Ravi, Jogender Singh.

  Cellular redox homeostasis depends on a finely tuned balance between oxidizing and reducing conditions, and disturbances in this balance lead to oxidative or reductive stress. While oxidative stress and its pathological outcomes are well studied, the molecular mechanisms underlying cellular responses to reductive stress remain poorly understood. Using Caenorhabditis elegans as a model, we investigate thiol reductive stress induced by dithiothreitol (DTT) and uncover a critical protective role for the hypoxia response pathway. We identify RHY-1, a membrane-associated acyltransferase and known negative regulator of the hypoxia-inducible factor HIF-1, as essential for survival under thiol reductive stress. Notably, rhy-1 is a direct transcriptional target of HIF-1, and overexpression of rhy-1 fully rescues the sensitivity of hif-1 loss-of-function mutants to DTT. We demonstrate that RHY-1 functions in an autoinhibitory feedback loop, where elevated RHY-1 levels suppress activation of the hypoxia response pathway even during reductive stress. Together, our findings establish RHY-1 as both a regulatory and effector component of the hypoxia response pathway that mediates cellular protection against thiol reductive stress.

Keywords:  HIF-1; RHY-1; WormBase; dithiothreitol; redox homeostasis; reductive stress

DOI:  https://doi.org/10.1093/genetics/iyag018
Front Aging Neurosci. 2026 ;18 1711422

Heat shock proteins (Hsp70 and Hsp90) in neurodegeneration: pathogenic roles and therapeutic potential.

Noureddine Ben Khalaf.

  The maintenance of protein homeostasis is essential for neuronal survival and function; however, it progressively declines with age, predisposing the brain to neurodegenerative diseases. Molecular chaperones Hsp70 and Hsp90 are key guardians of proteostasis, pivotally regulating protein folding, refolding, and degradation under both physiological and stress conditions. This review integrates an overview of the structural features, isoforms, and mechanistic interactions of Hsp70 and Hsp90. It highlights how their dysfunction contributes to the pathogenesis of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. We first examine the architecture and ATP-driven chaperone cycles of Hsp70 and Hsp90, their co-chaperone networks, and the feedback regulation by the Heat Shock Factor-1 pathway. We then discuss evidence linking age-related declines in chaperone expression and HSF-1 activity to proteostasis collapse and neuronal vulnerability. The review particularly examines how Hsp70 and Hsp90 differentially influence pathogenic protein aggregation (e.g., tau, α-synuclein, TDP-43, and mutant huntingtin) and how this balance is altered in the aging brain. Regarding therapeutic approaches, we summarize current strategies targeting these chaperones, including small-molecule modulators of Hsp70 and Hsp90, co-chaperone inhibitors, and recombinant chaperone therapy, which has shown to restore proteostasis and cognitive function in experimental models. These emerging interventions underscore the dual nature of Hsp70/Hsp90 systems, acting as both protectors and potential contributors to neurodegeneration, depending on their regulation and interaction context. By linking molecular chaperone biology to aging and translational therapeutics, this review establishes a framework for developing precision approaches that enhance proteostasis capacity, delay age-associated neurodegeneration, and promote healthy brain aging.

Keywords:  alpha-synuclein; heat shock proteins; molecular chaperone; neurodegenerative diseases; proteostasis; tau

DOI:  https://doi.org/10.3389/fnagi.2026.1711422
Int J Biol Macromol. 2026 Feb 26. pii: S0141-8130(26)01017-2. [Epub ahead of print]352 151091

Aedes aegypti Hsp70 has enhanced ATPase and protein protection under oxidative stress.

Bárbara C T A Aciole, Natália G Quel, Larissa M Antonio, Annelize Z B Aragão, Claudia de Lourenço, Julio C Borges, Carlos H I Ramos.

  Aedes aegypti mosquitoes are responsible for transmitting several viral diseases in humans, including Dengue, Zika, Yellow Fever, and Chikungunya. Despite significant efforts to control the mosquito vector and the viruses, the issue has intensified. This is mainly due to the mosquito's successful adaptation to urban environments and its expanding geographic range, driven by rising global temperatures. To effectively combat vector-borne diseases, we need a comprehensive understanding of mosquito physiology and cellular regulatory mechanisms, as these could reveal new molecular targets for intervention. A major cellular threat is environmental stress, which can cause protein misfolding and aggregation, ultimately leading to cell death. To counteract this, cells utilize their Protein Quality Control (PQC) system to maintain proteostasis. A central component of this system is the Hsp70 chaperone family, which is crucial for nascent protein folding, translocation across membranes, refolding of aggregated proteins, targeting proteins for degradation, and providing general stress protection. In this context, we identified, cloned, expressed, and characterized a cytosolic Hsp70 homolog from Aedes aegypti, which we named AaHsp70. The recombinant AaHsp70 protein was obtained in a pure and folded form, functioning as a monomer in solution and exhibiting hallmark features of the Hsp70 family, including ATPase activity and chaperone function. Notably, its ATPase activity was 2.5 to 3.3 times higher than that of human Hsp70s and increased by 90% under oxidative conditions. Furthermore, AaHsp70 successfully protected several proteins from aggregation under redox stress in Aedes larval cell extracts. Among the protected proteins was actin, a crucial cytoskeletal and contractile protein involved in both larval and adult muscle function in insects. Overall, our findings demonstrate that AaHsp70 plays a vital role in maintaining protein homeostasis under stress in mosquito cells. This chaperone may represent a promising molecular target for developing novel strategies to mitigate the spread of Aedes aegypti and the diseases it transmits.

Keywords:  Actin; Aedes aegypti; Chaperone; Oxidative stress; Proteostasis; Stress response

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151091
FEBS J. 2026 Mar 04.

GCN2 in proteostasis: structural logic, signalling networks and disease.

JiaYi Zhu, Stefan J Marciniak.

  Proteostasis is the finely tuned balance of protein synthesis, folding and degradation essential for cellular health. When this equilibrium is disrupted, misfolded proteins accumulate, triggering adaptive stress responses such as the unfolded protein response and the integrated stress response (ISR). Central to the ISR is the kinase GCN2, a sensor of amino acid deprivation and ribosomal stress. Upon activation, GCN2 phosphorylates eIF2α, dampening global translation while selectively enhancing the synthesis of the stress-responsive transcription factors ATF4 and CHOP. ATF4 orchestrates a broad transcriptional programme that supports amino acid metabolism, redox homeostasis, autophagy and proteasomal degradation, which are key processes for restoring proteostasis. Beyond its canonical role, GCN2 interfaces with other regulatory networks modulating mTORC1 to promote autophagic clearance of damaged proteins and organelles, facilitating stress granule formation, and integrating signals from oxidative and endoplasmic reticulum stress to rebalance the proteome. Dysregulated GCN2 activity has been implicated in diverse pathologies including neurodegeneration, cancer and pulmonary vascular disease, positioning it as a promising therapeutic target. In this review, we explore how GCN2 links nutrient sensing to translational control and metabolic adaptation, and how its central role in proteostasis may inform new strategies for treating diseases driven by protein misfolding and stress pathway imbalance.

Keywords:  GCN2; amino acid sensing; integrated stress response; proteostasis; translational control

DOI:  https://doi.org/10.1111/febs.70480
Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2525619123

Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.

Rebecca Cornell, Ava Handley, Roger Pocock.

  The mitochondrial unfolded protein response (UPRmt) is triggered by cells to alleviate proteotoxicity in response to metabolic stress. The ability to anticipate and prime cells against mitochondrial stress, by sensing potentially toxic changes in the external or internal environment, would provide a survival advantage. Yet, whether and how animals anticipate mitochondrial stress remains unclear. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signaling from carbon dioxide-sensing neurons to govern a noncanonical mitochondrial stress response in the intestine. This noncell autonomous stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset metabolic and proteotoxic risks. Thus, environmental sensing by peripheral neurons can preemptively enhance systemic mitochondrial function in response to metabolic uncertainty.

Keywords:  Caenorhabditis elegans; gas-sensing; mitochondrial stress; neuropeptide

DOI:  https://doi.org/10.1073/pnas.2525619123
Protein Sci. 2026 Apr;35(4): e70516

Functions of J-domain proteins in mitochondrial protein biogenesis.

Vitasta Tiku, Georg Bossenz, Janine Kirstein, Thomas Becker.

  Mitochondrial biogenesis and functions depend on the import and assembly of more than 1000 proteins that are made as precursors on cytosolic ribosomes. The majority of these precursor proteins are transported from the ribosome to the translocase of the outer membrane (TOM complex), which constitutes the main entry site for mitochondrial precursors. The transient localization of mitochondrial precursor proteins in the cytosol represents a major burden for cellular proteostasis since these proteins can aggregate and accumulate in different cellular compartments, causing proteotoxic stress. Inside mitochondria, protein translocases sort the precursor proteins into the mitochondrial subcompartments-outer and inner membrane, the intermembrane space and matrix. The imported proteins have to be folded and efficiently assembled into functional protein complexes. Molecular chaperones such as Hsp70 monitor these processes to minimize proteotoxic stress. J-domain proteins stimulate the ATPase activity of Hsp70 and recruit the chaperones to their clients in the biogenesis of mitochondrial proteins. They ensure protein targeting to mitochondria, drive protein import into mitochondria, as well as folding and assembly of mitochondrial proteins. Here, we summarize the emerging view of how J-domain proteins guide mitochondrial precursor proteins from their synthesis in the cytosol until their folding into a mature protein and assembly into protein complexes in mitochondria.

Keywords:  ER‐SURF; Hsp70; J‐domain protein; TOM complex; mitochondria; protein targeting

DOI:  https://doi.org/10.1002/pro.70516
Ageing Res Rev. 2026 Feb 27. pii: S1568-1637(26)00065-6. [Epub ahead of print]118 103073

Proteostasis, disease and the ageing neuron: Compartmental complexity in non-renewing cells.

Rosemary A Coleman, Michaela E Johnson, Anna Konopka, Yee Lian Chew.

  Proteostasis, the maintenance of protein homeostasis, is a critical cellular process for neuronal health that declines with age, contributing to neurodegenerative disease. This review examines the molecular architecture of the proteostasis network, how this is disrupted in ageing neurons, and its impact on neuronal function. We discuss unique challenges posed by the complexity arising from distinct neuronal compartments with distinct functions, as well as neurons' high energy demands, and post-mitotic status. We next detail how proteostasis mechanisms differ across neuronal compartments and neural subtypes, and how these differences influence susceptibility to stress and disease. Finally, we explore how these differences shape selective vulnerability in neurodegenerative diseases. By integrating recent transcriptomic and proteomic insights, this review highlights the need for compartment- and cell-type-specific approaches to mitigate proteostasis collapse in the ageing brain.

Keywords:  Ageing; Axon; Dendrite; Neurodegeneration; Proteostasis

DOI:  https://doi.org/10.1016/j.arr.2026.103073
Geroscience. 2026 Mar 05.

Escitalopram accelerated aging via impaired IIS/autophagy signaling pathway.

Zi-Yi Chen, Cao-Yan Qi, Ji Feng, Kun Xue, Hong-Bo Quan, Jing Zhou, Wu-Zhong Liu, Guo-Dong Lu.

  Escitalopram is one of the most widely prescribed selective serotonin reuptake inhibitors (SSRIs) for treating depression and anxiety disorders in adolescents and pregnant women. While some SSRIs have been reported to extend lifespan, the impact of escitalopram on the aging process remains unclear. Here, we demonstrated that escitalopram administration at juvenile, young, or old adult stages significantly shortens lifespan and impairs healthspan in Caenorhabditis elegans. This pro-aging phenotype was accompanied by increased lipofuscin accumulation and reduced stress resistance. Mechanistically, escitalopram induced mitochondrial dysfunction, characterized by elevated ROS production and diminished membrane potential. Genetic analyses established that these detrimental effects are mediated by the insulin/IGF-1 signaling (IIS) pathway, leading to the subsequent suppression of autophagy. Mutant worms in IIS (daf-2, daf-16, and sod-3) or autophagy-related genes (unc-51, atg-3, and atg-13) abolished the lifespan reduction. Consistently, in human BJ fibroblasts, escitalopram triggered premature cellular senescence, marked by increased SA-β-gal activity and upregulated P53/P21 expression, and impaired cell proliferation, which was mediated by impairment in fusion between autophagosome and lysosome. Collectively, our cross-species study reveals that escitalopram, contrary to some other SSRIs, accelerates aging through impairment of the evolutionarily conserved IIS/autophagy axis, suggesting its potential pro-aging toxicity with long-term use.

Keywords:   Caenorhabditis elegans ; Aging; Autophagy; Escitalopram; Insulin-like growth factor I

DOI:  https://doi.org/10.1007/s11357-026-02190-2
J Exp Bot. 2026 Mar 01. pii: erag084. [Epub ahead of print]

Diversity of GET3 chaperones in tail-anchored protein insertion.

Aron Struss, Christopher Grefen.

  Tail anchored proteins are involved in a broad range of essential cellular processes. Because of their unique membrane topology, dedicated pathways are required for their targeting to the ER. One such pathway is the guided entry of TA proteins (GET) pathway, which has been extensively studied in yeast and is gaining significant importance in plants as well. The key player in this pathway is the dimeric chaperone Get3 (TRC40 in mammals). Unlike in yeast, plants possess multiple paralogs that differ in their subcellular localization and amino acid composition. Despite its important role in protein trafficking, disruption of the GET pathway leads only to minor growth defects that do not affect overall plant development. Further research indicates that alternative pathways may act in parallel to the GET pathway and that Get3 is involved in additional mechanisms beyond its originally anticipated role in protein targeting.

Keywords:  ATPase; GET pathway; TA proteins; chaperone; holdase; membrane insertion; protein targeting

DOI:  https://doi.org/10.1093/jxb/erag084
Comp Biochem Physiol C Toxicol Pharmacol. 2026 Mar 03. pii: S1532-0456(26)00065-7. [Epub ahead of print] 110507

The mechanism of oxidative stress induced by nanoplastics in Caenorhabditis elegans: Integrated analysis of transcriptomics and metabolomics.

Jiayun Ji, Xingyi Kang, Bingqing Wang, Hang Yuan, Zhaoyu Jiang.

  Nanoplastics, as emerging contaminants, have attracted widespread global attention owing to their threats to ecosystems. The Caenorhabditis elegans nematode is regarded as a versatile model organism for disease mechanisms and toxicity mechanisms of various compounds studies. We investigated the toxicome of PS-NPs exposure in C. elegans (exposed to 0, 0.1, 1, 10, 50 and 100 mg/L) by combining transcriptomic and metabolomic analyses with measurements of survival rate, reproductive capacity and antioxidant capacity. The most pronounced oxidative stress responses were observed at 10 mg/L PS-NPs. Integrated omics analysis revealed disturbances in fatty acid metabolism, glutathione metabolism, drug metabolism-other enzymes, and glycine/serine/threonine metabolism upon exposure to 10 mg/L PS-NPs. These co-affected pathways are closely associated with the induction of oxidative stress. Essential genes gst-4 and ugt-33 as well as metabolite as (e)-2,6-dimethyl-2,5-heptadienoic acid are the key regulators of oxidative stress in C. elegans cells. This study used C. elegans as the main model to provide new insights for assessing the risks of PS-NPs exposure in the ecosystem.

Keywords:  Caenorhabditis elegans; Metabolomics; Oxidative stress; Polystyrene nanoplastics; Transcriptomics

DOI:  https://doi.org/10.1016/j.cbpc.2026.110507
NPJ Aging. 2026 Mar 03.

A hierarchy of causes of death in senescent C. elegans.

Hongyuan Wang, Carina C Kern, Chiminh Nguyen Hong, Alis Saez Allende, Jiayi Qiao, Aihan Zhang, Yimu Fan, Marina Ezcurra, David Gems.

Interventions that extend lifespan in animal models could, in principle, decelerate the aging process as a whole. Alternatively, they could act by suppressing one or more individual late-life pathologies that contribute to mortality. Here we show how, in the nematode Caenorhabditis elegans, late-life pathologies can compete in a hierarchical fashion to cause death, such that removal of one cause of death can unmask another. Under standard culture conditions, a major cause of death in elderly C. elegans is infection by their bacterial food source. We report that only when such infection is prevented is lifespan extended by suppression of a second senescent pathology, teratoma-like uterine tumors. Thus, as in mammals, lifespan in wild-type C. elegans can be limited by naturally-occurring neoplasia. By contrast, blocking bacterial infection attenuated the life-shortening effects of vitellogenesis, and did not unmask a life-shortening effect of distal gonad degeneration. Thus, depending on the masking or unmasking of competing causes of mortality in the hierarchy of causes of death, nematode lifespan limitation in different contexts can reflect action of distinct life-limiting senescent pathologies. This underscores how increases in lifespan do not necessarily reflect a reduction in overall aging rate.

DOI: https://doi.org/10.1038/s41514-026-00354-0