bims-proreb 2025-11-30 papers

bims-proreb

Biomed News

on Proteostasis and redox biology

Issue of 2025–11–30
thirty-two papers selected by
Shayan Motiei, Universität des Saarlandes

Distinct responses to non-autonomous UPRER mediated by glutamatergic and octopaminergic neurons.
Proteostasis and pathogenesis: Unraveling the complexity of protein misfolding disorders.
Disruption of the insulin signaling pathway in C. elegans dramatically increases male longevity and enhances reproductive health late in life.
The Role of Hsp72 in Handing Misfolded Proteins Metabolism in Heat-Stressed Cells: Mechanisms and Hypotheses.
Protein misfolding and its dual role in neurodegeneration and cancer progression.
Lysosomal control of proteostasis and reproductive capacity by conserved LMD-3 protein in C. elegans.
NAD+ restores proteostasis through splicing-dependent autophagy.
Impact of bacterial inactivation methods on Caenorhabditis elegans feeding and healthspan.
DAF-16/FOXO maintains genome integrity following genotoxic stress.
Protein misfolding and neurodegeneration: Mechanisms, implications, and therapeutic strategies.
Every step you take: How pathogens hijack host proteostasis from transcription, through translation, to degradation.
piRNAs safeguard splicing and RNA fidelity during heat shock.
FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review).
PHA-4/FoxA controls the function of pharyngeal and extrapharyngeal enteric neurons of C. elegans.
HLH-30/TFEB is necessary for chromatin reorganization and maintenance of cell quiescence during starvation in C. elegans.
Neuronal expressions of Taxi and Adar are crucial in maintaining the lifespan of Drosophila melanogaster.
Probiotic Modulation in Aging: Strain-Specific Geroprotective Effects in Caenorhabditis elegans.
Kinesins in Caenorhabditis elegans neuronal morphogenesis.
Transposon Regulation in the Caenorhabditis elegans Germline and Soma.
Bacterial metabolism of tryptophan causes toxicity in Caenorhabditis elegans that is alleviated by sugar supplementation.
Caenorhabditis Elegans Ortholog of TNF Alpha-Induced Protein 1 is Upregulated by TOL-1 and Exacerbates Amyloid-Beta-Associated Pathology.
Chaperone machinery in neurodegeneration: A spotlight on protein misfolding diseases.
Proteostasis network response to environmental chronic stress: linking survival to protein aggregation in a human neuroblastoma cellular model.
ER-resident proteins are key players in cartilage and bone homeostasis.
Hypoxia-driven perturbations of proteostasis and therapeutic vulnerabilities in cancer.
The NMDA Receptor Antagonist Memantine Modulates Aging and Stress Resilience.
Effects of Royal Jelly Freshness and Concentration on Lifespan, Growth, Motility and Reproduction in Caenorhabditis elegans.
Small heat shock protein HSPB5 uses disorder to bind zinc with high affinity.
An acyltransferase protects Caenorhabditis elegans from thiol reductive stress through an autoinhibitory hypoxia response pathway.
Inhibition of Mitochondrial Complex III Causes Dopaminergic Neurodegeneration by Redox Stress in Caenorhabditis elegans.
Lipid bilayer thinning near a ubiquitin ligase selects ER membrane proteins for degradation.
L-Quebrachitol from Sea Buckthorn Leaves Extends Lifespan by Regulating Antioxidant Activity and Autophagy through AMP-Activated Protein Kinase/SIR-2.1/DAF-16 and IIS Signaling Pathways.

Commun Biol. 2025 Nov 24. 8(1): 1650

Distinct responses to non-autonomous UPRER mediated by glutamatergic and octopaminergic neurons.

Aeowynn J Coakley, Adam J Hruby, Jing Wang, Andrew Bong, Tripti Nair, Carmen M Ramos, Athena Alcala, Daniel Hicks, Maxim Averbukh, Naibedya Dutta, Darius Moaddeli, Camilla Pearson, Cynthia J Siebrand, Mattias de Los Rios Rogers, Arushi Sahay, Sean P Curran, Peter J Mullen, Bérénice A Benayoun, Gilberto Garcia, Ryo Higuchi-Sanabria.

The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism, which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRER by overexpression of the major transcription factor, xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissues to activate UPRER in a non-autonomous fashion. Previous work identified serotonergic, dopaminergic, and tyraminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRER solely in glutamatergic, octopaminergic, and GABAergic neurons in C. elegans and paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways, while more modest changes were detected in GABAergic UPRER activation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress.

DOI: https://doi.org/10.1038/s42003-025-09036-1
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00071-9. [Epub ahead of print]148 299-353

Proteostasis and pathogenesis: Unraveling the complexity of protein misfolding disorders.

Tripti Nair, Ditsa Sarkar, Sumit Murmu, Rahul Singh Rawat, Biplab Singha.

  Within the cellular milieu, protein molecules must fold into precise three-dimensional structures to attain functionality. Protein chains can assume many misfolded states during this critical process. Such errant configurations are unstable and can aggregate into toxic misfolded conformations. In protein misfolding disorders, polypeptides are folded in an aberrant manner, resulting in non-functional and often pathogenic states. Protein folding is fundamental to biological function, and disruption of the process can result in toxic aggregates, such as oligomers and amyloid fibrils, which are implicated in a variety of diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's. Here, we examine the delicate interplay of forces that determine the native conformation of proteins and how perturbations in this balance lead to disease. A critical aspect of our discussion is the cell's proteostasis network, a complex network of molecular chaperones and regulators responsible for regulating protein folding and maintaining the health of the cell. In this chapter, we discuss how intrinsic protein properties, post-translational modifications, and extrinsic environmental factors can destabilize proteins, thereby resulting in their misfolding. Several pathogenic mechanisms will be elucidated, including the progression from a misfolded protein to the development of disease phenotypes. Next, the chapter will present an overview of the current therapeutic approaches to mitigate the diseases caused by protein misfolding. Using the latest findings in clinical and experimental research, we will evaluate the therapeutic landscape, ranging from small-molecule inhibitors to chaperone-based therapies.

Keywords:  Molecular chaperones; Neurodegenerative diseases; Oxidative stress; Post-translational modifications; Protein aggregation; Protein misfolding; Proteostasis; Ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/bs.apcsb.2025.08.013
bioRxiv. 2025 Nov 06. pii: 2025.11.04.686639. [Epub ahead of print]

Disruption of the insulin signaling pathway in C. elegans dramatically increases male longevity and enhances reproductive health late in life.

Rose S Al-Saadi, Hannah B Lewack, Patrick C Phillips.

Males and females are known to have dramatically different health and lifespan trajectories, but the underlying basis for these differences is only now being fully investigated 1 . In the Caenorhabditis elegans nematode model system, most aging studies have been conducted with hermaphrodites, and little is known about male-specific responses to pro-longevity mutations. Several previous studies have used the auxin-inducible degron system to degrade the insulin-like DAF-2/IGF-1 receptor in hermaphrodites, finding that both ubiquitous and tissue-specific degradation can extend lifespan 2-4 . Here we show that ubiquitous degradation of DAF-2 in male C. elegans increases median lifespan by more than 440%, one of the longest lifespan extensions by a single intervention to date. Conversely, degrading DAF-2 in the male germline decreased lifespan, opposite of its effect in hermaphrodites 3 . Using male mating and reproductive success as a meaningful ecological and neurophysiological measure of healthspan, we found that ubiquitous degradation of DAF-2 greatly prolongs reproductive health, likely by prolonging function of the male intromittent organ in the tail. This work highlights the importance of studying sex differences in aging and highlights the utility of using C. elegans males to understand the underlying basis of enhanced lifespan and healthspan.

DOI: https://doi.org/10.1101/2025.11.04.686639
J Cell Biochem. 2025 Nov;126(11): e70075

The Role of Hsp72 in Handing Misfolded Proteins Metabolism in Heat-Stressed Cells: Mechanisms and Hypotheses.

Yue Guo, Haotian Lan, Haoying Wang, Xiaoyu Sun, Benge Zou, Wei Zhang, Yu Wang, Xiaowei Wang, Chunying Li, Shiyong Zhu, Rongfeng Cao, Kaiqiang Fu.

  The accumulation of misfolded proteins within cells, often induced by stress, is a major contributor to cellular dysfunction. Heat shock proteins, which serve as critical chaperone molecules in response to stress-related damage, are essential for maintaining protein homeostasis within cells. In this family of proteins, Heat Shock Protein 72 (Hsp72) stands out for its acute responsiveness to thermal stress. It can swiftly be produced in reaction to the surge of misfolded proteins caused by heat, thus maintaining the equilibrium of intracellular protein metabolism. This analysis explores the function of Hsp72 in maintaining protein homeostasis, focusing on its ability to assist in the refolding of incorrectly folded proteins and to guide their breakdown through the ubiquitin-proteasome and autophagy systems. Furthermore, the potential mechanisms through which cells may eliminate misfolded protein aggregates via the secretory autophagy pathway under heat stress conditions are explored. This study systematically analyzes the various mechanisms by which Hsp72 influences misfolded protein metabolism and discusses the relevance of each pathway in the context of heat stress. Integrating findings from prior laboratory research, it is concluded that Hsp72 plays a pivotal role in regulating misfolded protein metabolism through the secretory autophagy pathway, thereby sustaining intracellular protein homeostasis during heat stress. This investigation expands the functional network of Hsp72 in maintaining protein homeostasis and elucidates the molecular pathways involved in its regulation of misfolded protein metabolism under heat stress, providing a framework for future research on Hsp72's role in cellular recovery from heat stress.

Keywords:  Hsp72; UPS; autophagy; misfolded proteins

DOI:  https://doi.org/10.1002/jcb.70075
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00088-4. [Epub ahead of print]148 355-377

Protein misfolding and its dual role in neurodegeneration and cancer progression.

Rajeshwer Singh Jamwal, Bhawani Sharma, Minerva, Agamya Gupta, Swati Misri, Raju Shankaryan, Ruchi Shah, Rakesh Kumar.

  Protein misfolding is a fundamental biological process with profound implications for human health and disease. Typically, proteins assume precise three-dimensional structures to perform their functions, a process safeguarded by the proteostasis network, which comprises molecular chaperones, the ubiquitin-proteasome system (UPS), and autophagy. However, genetic mutations, oxidative stress, and environmental insults can disrupt folding, leading to the accumulation of non-functional or toxic conformations. In neurodegenerative diseases such as Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral Sclerosis (ALS), chronic misfolding results in toxic protein aggregates like amyloid-β, tau, and α-synuclein. These disrupt synaptic function, induce oxidative and nitrosative stress, and trigger apoptosis, ultimately leading to progressive neuronal loss. Dysregulation of the unfolded protein response (UPR) and weakened proteostasis with aging exacerbate disease pathology. In contrast, cancer cells utilize protein misfolding to enhance their survival and progression. Misfolded oncoproteins, such as mutant p53, not only evade degradation but also acquire oncogenic properties. Tumor cells hijack the UPR and chaperone networks, upregulate heat shock proteins, and manipulate oxidative stress responses to withstand hypoxia, nutrient deprivation, and rapid proliferation. Cancer stem cells (CSCs) further adapt to proteotoxic stress, contributing to tumor heterogeneity, therapy resistance, and immune evasion. The dual role of protein misfolding, driving degeneration in neurons while supporting proliferation in tumors, underscores its centrality in disease biology. Future research should focus on identifying early biomarkers of proteostasis imbalance and exploiting shared molecular pathways for the development of novel therapeutic interventions.

Keywords:  Cancer progression; Molecular chaperones; Neurodegeneration; Protein misfolding; Proteostasis; Ubiquitin–proteasome system (UPS); Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.001
Sci Adv. 2025 Nov 28. 11(48): eadz3192

Lysosomal control of proteostasis and reproductive capacity by conserved LMD-3 protein in C. elegans.

Yile Zhai, Tiantian Wang, Jiangxue Han, Mengxiao Wu, Meixi Gong, Wenfei Li, Zhe Zhang.

Human female fertility declines markedly with age, a pattern mirrored in C. elegans fecundity. This shared vulnerability stems from evolutionarily conserved molecular pathways. A growing body of evidence links impaired proteostasis-the cell's ability to manage its proteins-to this age-related fertility drop in both species, although the underlying mechanisms are not fully understood. Here, we identify that LMD-3, a LysM domain protein, is a critical regulator of proteostasis and reproductive capacity in C. elegans. Deficiency of lmd-3 leads to notable defects in oxidation resistance and constitutively high cellular stress responses. We demonstrate that LMD-3, localized to the lysosome, interacts with vitellogenin and a proton-pumping V-type ATPase via its TLDc domain to regulate lysosomal function and maintain yolk protein homeostasis. We also found that supplementing with vitamin B12 can restore fertility in lmd-3 mutants by reducing oxidative stress and improving lysosomal function. These findings establish a model for studying reproductive health and finding potential therapeutic strategies.

DOI: https://doi.org/10.1126/sciadv.adz3192
Autophagy. 2025 Nov 28.

NAD+ restores proteostasis through splicing-dependent autophagy.

Ruixue Ai, Evandro F Fang.

  Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) is a hallmark of this decline, yet how metabolic restoration enhances autophagic control has remained obscure. Meanwhile, alternative RNA splicing errors accumulate in aging brains, compromising proteostasis. Here, we identify a metabolic - transcriptional mechanism linking NAD+ metabolism to autophagic proteostasis through the NAD+ -EVA1C axis. Cross-species analyses in C. elegans, mice, and human samples reveal that NAD+ supplementation corrects hundreds of age- or Alzheimer-associated splicing errors, notably restoring balanced expression of EVA1C isoforms. Loss of EVA1C impairs the memory and proteostatic benefits of NAD+, underscoring its essential role in neuronal resilience. Mechanistically, NAD+ rebalances EVA1C isoforms that interact with chaperones BAG1 and HSPA/HSP70, reinforcing their network to facilitate chaperone-assisted selective autophagy and proteasomal degradation of misfolded proteins such as MAPT/tau. Thus, NAD+ restoration coordinates RNA splicing fidelity with downstream proteostatic systems, establishing a metabolic - transcriptional checkpoint for neuronal quality control. This finding expands the paradigm of autophagy regulation, positioning metabolic splice-switching as a crucial mechanism to maintain proteostasis and suggesting new strategies to combat aging-related neurodegenerative diseases.

Keywords:  Aging; NAD+ precursors; alzheimer disease; machine learning; rna splicing; tauopathy

DOI:  https://doi.org/10.1080/15548627.2025.2596679
Sci Rep. 2025 Nov 23.

Impact of bacterial inactivation methods on Caenorhabditis elegans feeding and healthspan.

Valérie Thériault, Claudia Miriam Alonzo De la Rosa, Stéphanie Miard, Stefan Taubert, Frédéric Picard.

  Accurate bacterial inactivation methods are essential for nutritional and microbiota studies in Caenorhabditis elegans, to determine whether the observed effects arise from nutrients provided by ingested bacteria or from active symbiotic interactions. However, some inactivation methods alter bacterial palatability, complicating conclusions about their direct impact. We aimed to identify an effective method for inactivating the bacterial strain Escherichia coli OP50, the standard food source for most C. elegans experiments, that preserves normal behavior and physiology in C. elegans. We compared heat inactivation (65 °C for 35 min) with 0.5% paraformaldehyde (PFA) inactivation. Worms fed PFA-inactivated bacteria showed no food aversion, and maintained wild-type pharyngeal pumping levels, fertility rates, and lipid accumulation, closely resembling the behavior and physiology of worms fed alive E. coli OP50. In contrast, heat‑inactivated bacteria elicited strong food avoidance, reduced pumping activity, activation of the mitochondrial unfolded protein response (UPRmt), decreased lipid stores and fertility, and increased survival relative to the other groups. These findings demonstrate that 0.5% PFA inactivation more accurately preserves C. elegans physiological and behavioral traits than heat inactivation, making it a more suitable method for microbiota and nutritional studies.

Keywords:   C. elegans ; Biology; Food behavior; Heat; Inactivation; Paraformaldehyde

DOI:  https://doi.org/10.1038/s41598-025-27444-5
bioRxiv. 2025 Oct 28. pii: 2025.10.27.684284. [Epub ahead of print]

DAF-16/FOXO maintains genome integrity following genotoxic stress.

Umanshi Rautela, Oviya Devendran, Gautam Chandra Sarkar, K R Ranjisha, Rashi Mittal, Anita Goyala, Arnab Mukhopadhyay.

Preserving genomic integrity is crucial for the accurate transmission of genetic information across generations, as well as for preventing precocious ageing. The DNA Damage Response (DDR) safeguards the genome from genotoxic stress through a coordinated system of sensors, relay proteins, and repair mechanisms. Since DNA repair is an energy-intensive activity, the process is tightly regulated and coordinated with various metabolic pathways. The nutrient-sensing insulin/IGF signalling (IIS) pathway has been extensively studied for its role in ageing and lifespan regulation in C. elegans through its downstream FOXO transcription factor DAF-16. However, there is limited understanding of its involvement in maintaining genomic integrity through the regulation of the DDR. In this study, we demonstrate the role of DAF-16/FOXO in preserving genome integrity by activating the expression of DDR repair genes in C. elegans . Activated DAF-16/FOXO directly binds to the promoter of DDR genes under conditions of low IIS, ensuring that their expression is maintained at a higher level, which is crucial for prompt DNA damage repair. Interestingly, we find that DAF-16 functions both cell autonomously as well as non-autonomously to support DNA integrity. We also determine that the DAF-16(d/f) isoform, but not the DAF-16(a) isoform, is essential for maintaining germline genome integrity. Furthermore, DAF-16 activation enhances the DDR primarily through the canonical DDR components and, to a lesser extent, via apoptosis-mediated clearance of damaged cells. Overall, our study highlights a new role for DAF-16/FOXO in the DDR and the preservation of genome integrity.

DOI: https://doi.org/10.1101/2025.10.27.684284
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00070-7. [Epub ahead of print]148 135-177

Protein misfolding and neurodegeneration: Mechanisms, implications, and therapeutic strategies.

Asma Shah, Tharini Karthikeyan, Sheema Hashem, Rakesh Kumar, Ajaz A Bhat, Muzafar A Macha.

  Protein misfolding and aggregation play a pivotal role in the development of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's disease, and other related disorders. Proper protein folding is essential for cellular function, but due to the complexity of the folding process and external factors like genetic mutations, oxidative stress, and aging, misfolding is inevitable. These misfolded proteins often aggregate into toxic forms that disrupt cellular processes, leading to neuronal damage and cognitive decline. This chapter provides a comprehensive overview of molecular mechanisms behind protein misfolding, highlighting how these abnormal structures contribute to neurodegeneration. It also explores the role of the proteostasis network and its therapeutic potential in alleviating these processes. Focusing on multitarget therapeutic strategies, the chapter offers insights into promising approaches for addressing the root causes of neurodegenerative diseases while identifying key research gaps that could shape future treatment developments. By blending current knowledge with emerging therapeutic directions, this chapter provides a comprehensive and engaging perspective on combating the challenges of protein misfolding in neurodegeneration.

Keywords:  Amyloid fibrils; Molecular chaperones; Neurodegenerative disorders; Neuronal toxicity; Protein misfolding; Therapeutic targets; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/bs.apcsb.2025.08.012
Curr Opin Plant Biol. 2025 Nov 22. pii: S1369-5266(25)00140-2. [Epub ahead of print]89 102826

Every step you take: How pathogens hijack host proteostasis from transcription, through translation, to degradation.

Manuel González-Fuente, Margot Raffeiner, Suayib Üstün.

Proteostasis, the regulated balance between protein synthesis and degradation, is crucial for the cellular function and survival. Disruptions in this balance caused by different internal cues and environmental stresses, including pathogen infection, lead to proteotoxicity, which can be highly detrimental or even lethal to the organisms. Pathogens, in their efforts to modulate the host physiology to accommodate their own needs, target and manipulate host proteostasis processes. The extent of pathogen-mediated manipulation of host proteostasis spans every step in the life cycle of a protein: from the transcription and maturation of its coding mRNA, to the protein turnover via the ubiquitin-proteasome system or vacuolar degradation. These diverse sophisticated strategies to manipulate the host proteostasis ultimately lead to the overaccumulation of unfunctional and misfolded proteins, causing proteotoxic stress and facilitating in most cases the pathogen colonization. In turn, plants try to cope with this pathogen-induced proteotoxicity by attenuating translation, promoting chaperon-assisted protein folding and increasing the activity of different proteolytic pathways. Here, we discuss recent advances in understanding the global picture of how pathogens modulate plant proteostasis as well as how plants counter this, which will be crucial for the future development of more tolerant crops to mitigate emerging food security threats.

DOI: https://doi.org/10.1016/j.pbi.2025.102826
bioRxiv. 2025 Oct 28. pii: 2025.10.27.684940. [Epub ahead of print]

piRNAs safeguard splicing and RNA fidelity during heat shock.

Sehee Min, Johnny Cruz-Corchado, Veena Prahlad.

Piwi-interacting RNAs (piRNAs) that silence transposons and other non-self-sequences in the genome, also pervasively target endogenous mRNAs in diverse species, and most germline transcripts in Caenorhabditis elegans 1-10 . The functions of this broad targeting remain unclear. Here, we uncovered a surprising role for the piRNA pathway in regulating the splicing and fidelity of nascent mRNAs induced during stress. Upon heat shock, piRNAs target essential heat-shock protein ( hsp ) RNAs-normally absent but massively upregulated upon stress-and generate abundant sequence-specific secondary RNAs (22G-RNAs) antisense to these transcripts. Instead of enforcing silencing, these 22G-RNAs associate with nascent hsp transcripts and RNA polymerase II at the transcription complex, delaying splicing and preserving a pool of pre-mRNAs for processing during recovery from stress. This role of the piRNA pathway in enforcing splicing delays, extends beyond hsps to alternatively spliced genes and ensures the proper expression of long-intron-containing genes in the genome. In piRNA-deficient prde-1 mutants, splicing is precocious, hsp pre-mRNAs are depleted, expression of long-genes is impaired, transcripts accumulate errors, and consequently, embryos become critically dependent on nonsense-mediated decay (NMD) for survival. Downregulating NMD components in piRNA-deficient animals results in the accumulation of polyubiquitinated proteins and embryonic lethality. Thus, by safeguarding splicing under stress, the piRNA pathway complements NMD as a mechanism of RNA quality control, linking RNA fidelity to genome surveillance.

DOI: https://doi.org/10.1101/2025.10.27.684940
Int J Mol Med. 2026 Jan;pii: 30. [Epub ahead of print]57(1):

FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review).

Zhi Li, Xiaolei Liu, Hesong Zeng.

  Protein homeostasis, or proteostasis, refers to the integrated quality control systems that regulate protein synthesis, folding, post‑translational modification, trafficking and degradation to maintain proteome stability and function. Disruption of these processes, including abnormal synthesis, misfolding or impaired degradation, results in proteostasis collapse and underlies the pathogenesis of cancer, neurodegeneration, cardiovascular disease and metabolic syndromes. Recent studies have highlighted FK506‑binding proteins (FKBPs), a family of immunophilins defined by a conserved peptidyl‑prolyl cis‑trans isomerase domain, as pivotal modulators of proteostasis. By modulating protein folding, stabilizing complexes, regulating endoplasmic reticulum stress and directing selective degradation, FKBPs establish direct links between proteostasis regulation and disease progression. This review presents the first comprehensive synthesis of FKBP‑mediated control of proteostasis across diverse clinical contexts. It analyzed how their structural features confer regulatory potential and elucidate their roles in proteome remodeling in cancer, pathogenic protein aggregation in neurodegenerative disorders, ion channel stabilization in cardiovascular dysfunction and kinase phosphorylation in metabolic regulation. By integrating these diverse actions within a unified proteostasis framework, FKBPs are proposed as versatile regulators and promising therapeutic targets, providing new perspectives on the proteostasis‑disease axis and opportunities for precision intervention across multiple organ systems.

Keywords:  FK506‑binding proteins; cancer; cardiovascular diseases; metabolic dysregulation; neurodegenerative diseases; proteostasis

DOI:  https://doi.org/10.3892/ijmm.2025.5701
bioRxiv. 2025 Nov 10. pii: 2025.08.13.670029. [Epub ahead of print]

PHA-4/FoxA controls the function of pharyngeal and extrapharyngeal enteric neurons of C. elegans.

Zion Walker, Wen Xi Cao, Eduardo Leyva-Diaz, Mayeesa Rahman, Surojit Sural, Michelle A Attner, Oliver Hobert.

FoxA transcription factors pattern gut tissue across animal phylogeny. Beyond their early patterning function, little is known about whether they control the terminal differentiation and/or function of the fully mature enteric nervous system, the intrinsic nervous system of the gut. We show here that the expression and function of the sole C. elegans FoxA homolog, PHA-4, reaches beyond its previously described pioneer factor roles in patterning the foregut. Through the engineering of neuron-specific cis -regulatory alleles, Cre-mediated cell-specific knockouts and degron-mediated, temporally controlled PHA-4/FoxA removal in postmitotic neurons, we found that PHA-4/FoxA is required not only to initiate the terminal differentiation program of foregut-associated enteric neurons, but also to maintain their functional properties throughout the life of the animal. Moreover, we discovered novel sites of expression of PHA-4/FoxA in extrapharyngeal enteric neurons that innervate the hindgut (AVL and DVB), a GABAergic interneuron that controls foregut function during sleep (RIS), and a peptidergic neuron, PVT, which we implicate here in controlling defecation behavior. We show that while PHA-4/FoxA is not required for the developmental specification of AVL, DVB, RIS, and PVT, it is required to enable these neurons to control enteric functions. Taken together, pha-4 is the only transcription factor known to date that is expressed in and required for the proper function of all distinct types of enteric neurons in a nervous system.

DOI: https://doi.org/10.1101/2025.08.13.670029
bioRxiv. 2025 Nov 03. pii: 2025.10.31.685810. [Epub ahead of print]

HLH-30/TFEB is necessary for chromatin reorganization and maintenance of cell quiescence during starvation in C. elegans.

Marta Muñoz-Barrera, Alejandro Mata-Cabana, Almudena Moreno-Rivero, Francine A Piubeli, Beatriz Ren-Barroso, Nada Al-Refaie, Gabriel Gutierrez, Daphne S Cabianca, María Olmedo.

Cellular quiescence is a metabolically active, non-proliferative state critical for tissue maintenance and regenerative capacity, with broad implications for aging and age-related diseases. In Caenorhabditis elegans , L1 developmental arrest upon hatching in the absence of food provides a robust in vivo model to study quiescence. Here, we investigate the roles of the transcription factors HLH-30/TFEB and DAF-16/FOXO during L1 arrest. We show that HLH-30 and DAF-16 collaborate to ensure survival under starvation, with reciprocal regulation of their subcellular localization and transcriptional activity. HLH-30 exerts broad transcriptional control during L1 arrest, modulating genes involved in chromosome organization and cell cycle progression. Profiling of chromatin spatial distribution reveals that HLH-30 is required for fasting-induced 3D chromatin reorganization. Loss of HLH-30 disrupts seam cell cycle arrest and leads to overactivation of the pioneer transcription factor BLMP-1, leading to premature initiation of developmental programs under starvation. Our findings uncover previously unrecognized functions of HLH-30 in genome architecture and quiescence regulation, highlighting conserved mechanisms of transcriptional control during nutrient deprivation with implications for aging and disease.

DOI: https://doi.org/10.1101/2025.10.31.685810
J Genet. 2025 ;pii: 27. [Epub ahead of print]104

Neuronal expressions of Taxi and Adar are crucial in maintaining the lifespan of Drosophila melanogaster.

Upasana Gupta, Vanlalrinchhani Varte, Fathima M Ashraf, Upendra Nongthomba.

Ageing involves deterioration in physiological processes, such as maintenance of neuronal health, muscle, fat bodies, and gut bacteria, which play a crucial role in the progression of ageing. In this study, we show that the expression of Taxi, a transcription factor is required to maintain the lifespan in Drosophila melanogaster. Hypermorphic and hypomorphic alleles of taxi show reduced lifespan. We have identified that pan-neuronal overexpression and knockdown of Taxi lead to a stark reduction in the lifespan. In our previous study, we showed that Taxi negatively regulates Adar. Interestingly, overexpression of Adar significantly rescued the reduction in lifespan caused by taxi overexpression in neurons. Conversely, the knockdown of Adar rescued the defective lifespan caused by taxi knockdown in neurons. We show that enzymatically inactive Adar also rescued the reduced lifespan in flies having a neuronal taxi overexpression background. Our work suggests that, besides the editing activity, Adar may have editing-independent roles implicated in lifespan regulation. Overall, we show that neuronal tissue-specific controlled expression of taxi and its interacting partner Adar is imperative in lifespan maintenance.
Int J Mol Sci. 2025 Nov 20. pii: 11205. [Epub ahead of print]26(22):

Probiotic Modulation in Aging: Strain-Specific Geroprotective Effects in Caenorhabditis elegans.

Barbara Sciandrone, Diletta Francesca Squarzanti, Patrizia Malfa, Maria Elena Regonesi.

  Elderly individuals are more vulnerable to disease due to their increased frailty. Emerging evidence highlights the potential of probiotics as geroprotective agents by maintaining gut health and modulating key physiological processes involved in aging, such as inflammation, cognitive functions, and metabolism. Here, we investigated the geroprotective potential of four probiotic strains (Lacticaseibacillus paracasei LPC1114, Limosilactobacillus reuteri PBS072, Bifidobacterium breve BB077, and Bifidobacterium animalis subsp. lactis BL050) using Caenorhabditis elegans as an aging model. Mid-life healthspan parameters were assessed, including lifespan, motility, ROS levels, lipofuscin accumulation, and cognitive capabilities. The probiotics exhibited strain-specific effects. L. reuteri PBS072 and B. lactis BL050 significantly increased locomotion by 20% and decreased ROS levels by 70% and 30% respectively, suggesting enhanced oxidative stress response and neuromuscular maintenance. B. breve BB077, L. paracasei LPC1114, and L. reuteri PBS072 enhanced associative learning performance, whereas B. lactis BL050 improved chemotactic response. Notably, only L. paracasei LPC1114 and L. reuteri PBS072 extended the maximum lifespan by 4 and 5 days, respectively, an effect mediated by the longevity-related genes skn1, sir2.1, and daf16. Our findings highlight the multifaceted, strain-specific geroprotective properties of probiotics and support their potential as microbiome-based interventions to promote healthy aging.

Keywords:  Caenorhabditis elegans; aging; geroprotector; gut-microbiota; probiotics

DOI:  https://doi.org/10.3390/ijms262211205
Open Biol. 2025 Nov;15(11): 250072

Kinesins in Caenorhabditis elegans neuronal morphogenesis.

Shinsuke Niwa, Kyoko Chiba.

  Neuronal morphogenesis is regulated by intracellular transport and cytoskeletal dynamics. Kinesin superfamily proteins (KIFs), or kinesins, function as molecular motors for intracellular transport and as regulators of the microtubule cytoskeleton, making them essential for neuronal development. Caenorhabditis elegans has been widely used as a model organism to study neuronal morphogenesis. Due to the critical roles of kinesins in neuronal functions, numerous kinesin mutants, including unique gain-of-function mutants and temperature-sensitive mutants, have been identified through forward genetic screens in C. elegans. The availability of whole-genome knockout resources and CRISPR/Cas9 genome editing has further enabled precise genetic analysis, facilitating the modelling of human kinesin-related diseases in C. elegans. In this review, we discuss the functions of C. elegans kinesins in neuronal morphogenesis, focusing on their roles in neuronal transport and cytoskeletal regulations.

Keywords:  Caenorhabditis elegans; axonal transport; biology; kinesin

DOI:  https://doi.org/10.1098/rsob.250072
bioRxiv. 2025 Oct 10. pii: 2025.10.09.681459. [Epub ahead of print]

Transposon Regulation in the Caenorhabditis elegans Germline and Soma.

Cindy Chang, Dong Cao, Daniel J Pagano, Scott Kennedy.

Transposons are parasitic nucleic acids present in most genomes. The ability of transposons to mobilize makes them a source of genetic diversity and a threat to genome integrity. Interestingly, mutations in the C. elegans gene mut-2/rde-3 increases the rate of transposition in the germline, but not in the soma, suggesting that the C. elegans germline and soma employ different strategies to regulate Tc1 transposition. Here, we develop fluorescence reporters for studying DNA transposon regulation in living C. elegans in a tissue-specific manner and we use candidate gene testing and genetic screening approaches to identify factors that regulate Tc1 mobility in the germline and/or the soma of the animal. We find that both cytoplasmic and nuclear components of the RNA interference (RNAi) pathway silence Tc1 in the germline, but not in the soma. We identify a novel pathway involving the C. elegans ortholog of HNRNPC, and a gene we term suppressor of transposon mobilization ( stm ) -1 , which regulates Tc1 primarily in the soma, likely by binding Tc1 RNA and preventing its splicing. Our findings reveal tissue-specific strategies for regulating parasitic nucleic acids and pave the way for future studies exploring how and why different tissues adopt different transposon silencing systems.

DOI: https://doi.org/10.1101/2025.10.09.681459
bioRxiv. 2025 Nov 05. pii: 2025.06.09.658597. [Epub ahead of print]

Bacterial metabolism of tryptophan causes toxicity in Caenorhabditis elegans that is alleviated by sugar supplementation.

Shivani Gahlot, Subodh, Jogender Singh.

Tryptophan is an essential amino acid required not only for protein biosynthesis but also for the production of several physiologically important metabolites, including serotonin, kynurenine, and nicotinamide. Although dietary tryptophan is associated with various health benefits, excessive intake can result in adverse physiological effects. The specific tryptophan- derived metabolites responsible for such toxicity, however, remain incompletely characterized. Here, we investigate the mechanisms underlying tryptophan-induced toxicity in Caenorhabditis elegans . We observe that tryptophan concentrations of 1 mM or higher are highly toxic to C. elegans , blocking egg hatching. Notably, supplementation with various sugars, including glucose, fructose, mannose, galactose, rhamnose, and lactose, alleviates this toxicity. Genetic analyses reveal that host tryptophan metabolism is dispensable for the observed effects. Instead, bacterial metabolism, particularly the conversion of tryptophan to indole, is essential for mediating toxicity. Bacterial strains deficient in indole production abolished tryptophan-induced toxicity, and all sugars that conferred protection also suppressed bacterial indole synthesis. These findings demonstrate that tryptophan toxicity in C. elegans is primarily mediated by bacterial metabolism.

DOI: https://doi.org/10.1101/2025.06.09.658597
Mol Neurobiol. 2025 Nov 22. 63(1): 146

Caenorhabditis Elegans Ortholog of TNF Alpha-Induced Protein 1 is Upregulated by TOL-1 and Exacerbates Amyloid-Beta-Associated Pathology.

Yanmei Su, Donghua Zhang, Yixin Li, Huan Gu, Wenhu Li, Wenhui Zhou, Ninghui Zhao, Xiaowei Huang.

  Neuroinflammation has been recognized as a central pathological mechanism in Alzheimer's disease (AD), modulated by diverse molecular pathways. Among these, the tumor necrosis factor superfamily (TNFSF) pathway serves as a pivotal mediator of inflammatory responses in higher organisms, representing a potential therapeutic target for AD treatment. Notably, TNF alpha-induced protein 1 (TNFAIP1) is significantly upregulated following amyloid-beta1-42 (Aβ1-42) accumulation in the postmortem brains of patients with AD and in transgenic Caenorhabditis elegans models. However, the regulatory mechanism of its ortholog F22E5.6 in C. elegans and its role in Aβ neurotoxicity remain elusive due to the absence of the core TNFSF members in this model. Through systematic screening of TNFSF orthologs, the trf-1 gene that encodes the adapter protein, TNF receptor-associated factor (TRAF), has been identified as a critical regulator in Aβ1-42-induced F22E5.6 overexpression of C. elegans. In this genetic model, the only Toll-like receptor TOL-1 in C. elegans serves as a potential receptor to activate TRF-1 and to transmit this signal to the SRC-2/PMK-3 axis, thereby executing the effects on mitochondrial homeostasis disequilibrium. These findings reveal the regulatory mechanism on Aβ1-42-induced F22E5.6/TNFAIP1 overexpression and its involvement in AD model of C. elegans, providing a clue to resolve the paradox of TNFSF-mediated inflammation in organisms lacking the canonical TNFSF pathway.

Keywords:   Caenorhabditis elegans ; Alzheimer’s disease; Mitochondrial homeostasis; Molecular mechanism of pathogenesis; TNFSF pathway; Toll-like receptor

DOI:  https://doi.org/10.1007/s12035-025-05554-5
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00065-3. [Epub ahead of print]148 455-480

Chaperone machinery in neurodegeneration: A spotlight on protein misfolding diseases.

Abhilasha Sood, Madhumita Dey, Arpit Tyagi, Deepak Kumar Sharma, Arpit Mehrotra.

  Proteins misfolding in neurodegenerative disorders pose a significant challenge to human health and this necessitates a deeper understanding of the fundamental molecular mechanisms. Molecular chaperones are a diverse group of specialized proteins, which are extensively involved in maintaining cellular protein homeostasis and thus preventing aggregation of misfolded proteins. Pathological advancement in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) is characterized by the rampant accretion of misfolded proteins due to chaperonic failure, leading to progressive neuronal dysfunctioning and eventually cell death. Such as in AD, Hsp70 and Hsp90 chaperones are known to interact with β-amyloid and tau proteins, thus preventing their subsequent aggregation with concomitant refolding into native conformations. In PD, chaperones are involved in assisting mitigation of α-Syn misfolding and aggregation, thereby maintaining the normal neuronal functions and their viability. Similarly in HD, chaperones modulate aberrant misfolding of huntingtin protein and its aggregation, thus highlighting prospective therapeutic targets for disease intervention. Nevertheless, further investigating and understanding the explicit roles of chaperones in modulating several protein misfolding diseases holds potential for the development of novel therapeutic approaches. Moreover, targeting such specialized chaperone machinery in restoring protein homeostasis and alleviating subsequent protein aggregation could be considered as a promising approach in managing neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Chaperones; Huntington’s disease; Neurodegeneration; Parkinson’s disease; Protein misfolding diseases

DOI:  https://doi.org/10.1016/bs.apcsb.2025.08.007
Cell Mol Life Sci. 2025 Nov 27. 82(1): 430

Proteostasis network response to environmental chronic stress: linking survival to protein aggregation in a human neuroblastoma cellular model.

Emiliano Montalesi, Daniela Caissutti, Camilla Moliterni, Antonella Ferrante, Rita Pepponi, Tina Garofalo, Maurizio Sorice, Roberta Misasi, Niccolò Candelise.

  Proteins tend to misfold upon stressful events that alter their homeostasis, potentially leading to protein aggregation. A tight regulation of synthesis, folding and degradation, defined as proteostasis network (PN), is required to ensure the functionality of the cell. PN is of utmost importance in post-mitotic cells such as neurons, where protein quality must be preserved for their entire lifetime. Most neurodegenerative disorders are associated with dysregulation of this network. Here, we describe the alteration in key components of the PN during chronic stress and link them with the increase in the amyloid burden and with the aggregation of the protein TDP-43, a major player in Amyotrophic Lateral Sclerosis and other neurodegenerative diseases. Neuroblastoma SH-SY5Y cells were treated with a panel of environmental stressors and analyzed after 24 h and 72 h. Treatments resulted in altered PN functionality, including proteasome impairment, halted protein synthesis, engulfed bulk and selective autophagy, in the absence of overt cell death. Thioflavin staining showed increased amyloid burden throughout treatments, associated with phosphorylated TDP-43 (pTDP-43). Biochemical analyses further revealed the cleavage and increased insolubility of pTDP-43. Our results suggest that TDP-43 is a central player during the integrated stress response to chr onic insults and that increased amyloid burden may reflect the global wellfare of a cellular system, pointing toward the alteration of the PN as the main drive for the onset of sporadic neurodegenerative disorders.

Keywords:  Cell fate; Cellular homeostasis; Prion-like; Protein misfolding; Protein quality control; Protein solubility

DOI:  https://doi.org/10.1007/s00018-025-05884-6
Front Cell Dev Biol. 2025 ;13 1661846

ER-resident proteins are key players in cartilage and bone homeostasis.

Sina Stücker, Yvonne Rellmann, Sandra Schulte, Rita Dreier.

  Hyaline cartilage is essential for bone formation and joint function. It contains a dense extracellular matrix that is produced in the ER of chondrocytes. Therefore, the ER contains a complex machinery of enzymes including chaperones, glycosyltransferases and hydroxylases that control folding, modification and secretion of newly synthesized matrix proteins. Loss or malfunction of ER-resident chaperones and proteins leads to misfolding and accumulation of matrix proteins in the ER. This causes ER stress and disrupts crucial cellular processes including chondrocyte differentiation, signaling and matrix production. During skeletal development, deficiency of ER chaperones disrupts cartilage and bone formation by impairing the folding and maturation of collagens and other matrix proteins, causing chondrodysplasia, pseudoachondroplasia and other skeletal diseases. Loss of ER-resident chaperones also impairs the integrity and stability of the cartilage matrix, promoting its degeneration during osteoarthritis. Due to the complexity of the ER protein processing machinery, the specific roles of ER-resident proteins in cartilage and bone homeostasis largely remain elusive. This review provides an overview of the most common ER-resident proteins and our current understanding of their function in cartilage homeostasis and disease.

Keywords:  ER stress; cartilage; chaperone; endoplasmic reticulum; extracellular matrix; protein folding

DOI:  https://doi.org/10.3389/fcell.2025.1661846
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(25)00130-0. [Epub ahead of print]148 507-528

Hypoxia-driven perturbations of proteostasis and therapeutic vulnerabilities in cancer.

Manvi Sharma, Tushar Singh Barwal, Neha, Yashika, N K Ganguly, Shivani Arora Mittal.

  Solid tumors are characterized by chaotic architecture and abnormal vasculature, which trigger rapid cell proliferation leading to steep oxygen gradients, and render the tumor core highly hypoxic or anoxic. These hypoxic regions within a tumor profoundly drive cancer progression by stabilizing key transcription factors, Hypoxia-Inducible Factors, HIF-1 and HIF-2. In addition to the well-established HIF pathways, hypoxic areas in tumors are being increasingly examined for their capacity to disrupt proteostasis, specifically influencing oxygen-dependent protein folding in the endoplasmic reticulum. Hypoxia acts as a key stressor, leading to the accumulation of misfolded proteins, triggering Unfolded Protein Response as a compensatory mechanism, mediated by the three main ER sensors: PKR-like ER kinase, Inositol-Requiring enzyme 1, and Activating Transcription factor 6. In a healthy cell, UPR typically seeks to induce cell death, reestablishing cellular equilibrium. Cancer cells subvert this response by utilizing it to their advantage, enhancing metabolic flexibility, evading immune surveillance, and establishing resistance. There is growing evidence that these hypoxia-induced misfolded proteins contribute to the progression of tumors by causing genomic instability and dysregulating oncogenic signaling. This chapter details how hypoxia regulates protein misfolding, leading to cancer cell adaptation, and outlines relevant therapeutic targets.

Keywords:  Cancer; ER stress; HIF; Hypoxia; Protein misfolding; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1016/bs.apcsb.2025.11.001
Aging Cell. 2025 Nov 28. e70303

The NMDA Receptor Antagonist Memantine Modulates Aging and Stress Resilience.

Vaida Juozaityte, Chiara Pregnolato, Steffen Abay-Nørgaard, Dylan Matthew Rausch, Rebecca L McIntyre, Zachary Gerhart-Hines, Tune H Pers, Anna Elisabetta Salcini, Christoffer Clemmensen.

Aging is associated with a progressive decline in physiological resilience, often linked to impaired stress responses and metabolic dysfunction. In Caenorhabditis elegans (C. elegans), caloric restriction (CR) and pharmacological interventions are widely used to dissect conserved longevity pathways. Here, we identify the N-methyl-D-aspartate receptor (NMDAR) antagonist memantine as a novel modulator of lifespan and stress tolerance in C. elegans. Memantine, but not ketamine, extends median lifespan and reproductive lifespan, suggesting that the observed effects are not shared with ketamine at the tested concentration. Transcriptomic analysis revealed significant overlap between memantine-treated animals and CR models, particularly eat-2 mutants, implicating shared metabolic and longevity-associated pathways. Functionally, memantine was found to reduce mitochondrial and oxidative stress, while enhancing β-oxidation of fatty acids, and modifying behavioral responses to food cues, delaying food-seeking behavior and increasing locomotion under starvation, without affecting lipid storage. In summary, these findings suggest that memantine promotes stress resilience and healthy aging via metabolic changes that overlap with CR-associated pathways, highlighting its potential as a longevity-modulating intervention.

DOI: https://doi.org/10.1111/acel.70303
Foods. 2025 Nov 10. pii: 3839. [Epub ahead of print]14(22):

Effects of Royal Jelly Freshness and Concentration on Lifespan, Growth, Motility and Reproduction in Caenorhabditis elegans.

Chenhuan Zhang, Yuanhao Deng, Zhenling Luo, Shenyun Liu, Wenhui Tao, Yuhan Zhang, Hongliang Li, Fan Wu.

  Although aging is an irreversible process, the rate of aging can be delayed by a reasonable diet. As a nutrient-dense natural product, royal jelly (RJ) has an enormous potential for applications in medicine and health promotion. However, the exact physiological activity of RJ with varying freshness and concentration has not been fully clarified, and more investigation is needed to determine their precise contributions. Here, fresh RJ (just produced recently) and RJ stored for 2 weeks at -20 °C, 4 °C or 25 °C were tested at concentrations of 100, 50, 25 and 12.5 μg/mL on Caenorhabditis elegans. Fresh RJ, with concentrations of 100 μg/mL, 50 μg/mL and 25 μg/mL, could extend the lifespan of C. elegans by 16.37%, 9.53% and 4.32%, while RJs stored at 4 °C and 25 °C were ineffective. In terms of body length, treatment with fresh RJ significantly enlarged the body size by around 48%. Although RJ stored at 4 °C and 25 °C could also promote nematode growth, its activity diminishes as storage temperature increases. RJs stored at -20 °C and 4 °C with concentrations of 100 μg/mL significantly increased the pumping rate of nematodes by 58% and 50%. But non-fresh RJ or low-concentration RJ (≤25 μg/mL) had no effects on the motility of C. elegans. In addition, fresh RJ could improve the reproductive capacity of C. elegans, with the highest increase reaching approximately 25%. Even when stored at 25 °C, RJ also significantly enhanced the reproductive capacity of C. elegans, increasing it by approximately 14.8%. Moreover, qPCR showed that RJ could significantly affect the expression of multiple genes associated with aging and vitality. Fresh RJ significantly up-regulated bec1 and hsp16.2 3.19- and 2.80-fold, while RJ stored at 25 °C significantly up-regulated sod3 and gpd1 3.80- and 3.40-fold. Our results suggested that the activity of RJ on C. elegans is related to its freshness and concentration, while RJ also contains active components that are independent of freshness. Therefore, it is necessary to explore effective methods for accurately assessing the freshness of RJ.

Keywords:  Caenorhabditis elegans; freshness; longevity; reproductive capacity; royal jelly (RJ)

DOI:  https://doi.org/10.3390/foods14223839
bioRxiv. 2025 Oct 17. pii: 2025.10.17.683119. [Epub ahead of print]

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 mismetalation and protein 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 scale 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/10.1101/2025.10.17.683119
bioRxiv. 2025 Oct 10. pii: 2025.10.09.681334. [Epub ahead of print]

An acyltransferase protects Caenorhabditis elegans from thiol reductive stress through an autoinhibitory hypoxia response pathway.

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. Finally, we show that RHY-1 physically interacts with CYSL-1, a cysteine synthase-like protein and positive regulator of HIF-1, and likely inhibits its function through this interaction. 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.

DOI: https://doi.org/10.1101/2025.10.09.681334
bioRxiv. 2025 Oct 23. pii: 2025.10.21.683798. [Epub ahead of print]

Inhibition of Mitochondrial Complex III Causes Dopaminergic Neurodegeneration by Redox Stress in Caenorhabditis elegans.

Javier Huayta, Joel N Meyer.

Environmental factors including chemical exposures are important contributors to Parkinson's disease (PD). Nearly all well-validated chemicals involved in PD affect mitochondria, and the great majority of those identified inhibit mitochondrial complex I, causing ATP depletion and oxidative stress. We hypothesized that inhibition of mitochondrial complex III would also cause dopaminergic neurodegeneration. Using Caenorhabditis elegans to evaluate the in vivo effects of the complex III-inhibiting pesticides antimycin A and pyraclostrobin, we found that both caused neurodegeneration. Neurodegeneration was specific to the dopamine neurons, and complex III inhibition caused a more-oxidized cellular environment in those neurons. Pharmacological and genetic antioxidant interventions rescued neurodegeneration, but energetic rescue attempts did not. Finally, optogenetic production of superoxide anion specifically at complex III caused dopaminergic neurodegeneration. Thus, redox stress at complex III is sufficient for dopaminergic neurodegeneration, and redox stress following chemical inhibition is necessary for dopaminergic neurodegeneration in vivo in C. elegans.

DOI: https://doi.org/10.1101/2025.10.21.683798
bioRxiv. 2025 Nov 01. pii: 2025.10.31.685944. [Epub ahead of print]

Lipid bilayer thinning near a ubiquitin ligase selects ER membrane proteins for degradation.

Rudolf Pisa, Tom A Rapoport.

Misfolded or unassembled membrane proteins in the endoplasmic reticulum (ER) are polyubiquitinated, translocated into the cytosol, and degraded by the proteasome, a poorly understood process that is conserved in all eukaryotes. Here, we use S. cerevisiae to elucidate how ER membrane proteins are selected for degradation. We show that hydrophilic residues in a trans-membrane (TM) segment cause the TM to partition into a thinned membrane region next to the ubiquitin ligase Hrd1, which then leads to substrate polyubiquitination and degradation. In the case of single-pass membrane proteins, the Hrd1-associated Der1 protein contributes to partitioning and degradation. In contrast, multi-pass proteins require Hrd1 to function on its own. Our results provide a general mechanism by which ER membrane proteins are targeted for degradation.

DOI: https://doi.org/10.1101/2025.10.31.685944
J Agric Food Chem. 2025 Nov 24.

L-Quebrachitol from Sea Buckthorn Leaves Extends Lifespan by Regulating Antioxidant Activity and Autophagy through AMP-Activated Protein Kinase/SIR-2.1/DAF-16 and IIS Signaling Pathways.

Jinmei Zhao, Juan Wei, Yumei Jiang, Jörg Thomas Mörsel, Yury A Zubarev, Yang Bi.

  L-Quebrachitol (QBC), a derivative of L-inositol, exhibits antioxidant and antimetabolic disorder properties; however, its antiaging effects remain unexplored. This study isolated QBC from sea buckthorn leaves using the CaO/resin purification-methanol precipitation method. The structure was confirmed using nuclear magnetic resonance (NMR), X-ray diffraction (XRD), ultraperformance liquid chromatography-mass spectrometry (UPLC-MS), and fourier transform infrared spectroscopy (FTIR). QBC was found to extend the lifespan of Caenorhabditis elegans (with an optimal dose of 50 μg/mL), reduce lipofuscin accumulation, and enhance stress resistance, motility, and mitochondrial health. Further studies have found that QBC activates the AMP-activated protein kinase (AMPK) signaling pathway via dietary restriction and mitochondrial uncoupling. This then upregulates the key transcription factors DAF-16, SKN-1, and HSF-1 within the SIR-2.1 and insulin/insulin-like growth factor signaling (IIS) pathways. The activation of these transcription factors helps to maintain protein homeostasis and enhances nematode resistance. In addition, QBC demonstrated significant autophagy induction, dependent on the regulation of AMPK and DAF-16. In conclusion, this study provides the first insight into the antiaging activity of QBC and its potential mechanisms. By activating the AMPK/SIR-2.1/DAF-16 and IIS signaling pathways, QBC regulates the antioxidant system and the autophagy response, thereby effectively delaying the aging process in C. elegans.

Keywords:  AMP-activated protein kinase; Caenorhabditis elegans; L-quebrachitol; insulin/insulin-like growth factor signaling; lifespan; mitochondrial autophagy

DOI:  https://doi.org/10.1021/acs.jafc.5c05084