bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–03–23
eighteen papers selected by
Jessica Rosarda, Uniformed Services University
  1. Pharmacological landscape of endoplasmic reticulum stress: Uncovering therapeutic avenues for metabolic diseases.
  2. TOR and heat shock response pathways regulate peroxisome biogenesis during proteotoxic stress.
  3. Phosphorylation of eIF2α suppresses the impairment of GSH/NADPH homeostasis and mitigates the activation of cell death pathways, including ferroptosis, during ER stress.
  4. DR5 disulfide bonding functions as a sensor and effector of protein folding stress.
  5. Proteostasis regulation of GABAA receptors in neuronal function and disease.
  6. Role of Assemblysomes in Cellular Stress Responses.
  7. Dynamic regulation of murine RNA Polymerase III transcription during heat shock stress.
  8. Nonvesicular cholesterol transport in physiology.
  9. Innate immune and endoplasmic reticulum unfolded protein response pathways protect Caenorhabditis elegans against chloroquine toxicity.
  10. Kinetic modelling reveals the presence of multistability in normal and stressful conditions in translational initiation mechanism.
  11. License to drive: Receptor-mediated ER exit of proteins and lipids.
  12. Proteasome dynamics in response to metabolic changes.
  13. ER O-glycosylation in synovial fibroblasts drives cartilage degradation.
  14. Deep indel mutagenesis reveals the impact of amino acid insertions and deletions on protein stability and function.
  15. Mesencephalic astrocyte-derived neurotrophic factor upregulates CHOP and ATF6 in the rat retina with retinitis pigmentosa.
  16. A cysteine-less and ultra-fast split intein rationally engineered from being aggregation-prone to highly efficient in protein trans-splicing.
  17. Mitoregulin, a tiny protein at the crossroads of mitochondrial functioning, stress, and disease.
  18. Chemical Probes for Studying the Eukaryotic Translation Initiation Factor 4E (eIF4E)-Regulated Translatome in Cancer.
  1. Eur J Pharmacol. 2025 Mar 13. pii: S0014-2999(25)00263-8. [Epub ahead of print]998 177509
    Pharmacological landscape of endoplasmic reticulum stress: Uncovering therapeutic avenues for metabolic diseases.
    Ghallab Alotaibi, Abdullah Alkhammash.
      The endoplasmic reticulum (ER) plays a fundamental role in maintaining cellular homeostasis by ensuring proper protein folding, lipid metabolism, and calcium regulation. However, disruptions to ER function, known as ER stress, activate the unfolded protein response (UPR) to restore balance. Chronic or unresolved ER stress contributes to metabolic dysfunctions, including insulin resistance, non-alcoholic fatty liver disease (NAFLD), and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Recent studies have also highlighted the importance of mitochondria-ER contact sites (MERCs) and ER-associated inflammation in disease progression. This review explores the current pharmacological landscape targeting ER stress, focusing on therapeutic strategies for rare metabolic and neurodegenerative diseases. It examines small molecules such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA), repurposed drugs like 17-AAG (17-N-allylamino-17demethoxygeldanamycin (tanespimycin)) and berberine, and phytochemicals such as resveratrol and hesperidin. Additionally, it discusses emerging therapeutic areas, including soluble epoxide hydrolase (sEH) inhibitors for metabolic disorders and MERCs modulation for neurological diseases. The review emphasizes challenges in translating these therapies to clinical applications, such as toxicity, off-target effects, limited bioavailability, and the lack of large-scale randomized controlled trials (RCTs). It also highlights the potential of personalized medicine approaches and pharmacogenomics in optimizing ER stress-targeting therapies.
    Keywords:  Endoplasmic reticulum (ER) stress; Mitochondria-ER contact sites (MERCs); Protein folding disorders; Tauroursodeoxycholic acid (TUDCA); Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177509
  2. bioRxiv. 2025 Jan 02. pii: 2024.12.31.630809. [Epub ahead of print]
    TOR and heat shock response pathways regulate peroxisome biogenesis during proteotoxic stress.
    Nandini Shukla, Maxwell L Neal, Jean-Claude Farré, Fred D Mast, Linh Truong, Theresa Simon, Leslie R Miller, John D Aitchison, Suresh Subramani.
      Peroxisomes are versatile organelles mediating energy homeostasis and redox balance. While peroxisome dysfunction is linked to numerous diseases, the molecular mechanisms and signaling pathways regulating peroxisomes during cellular stress remain elusive. Using yeast, we show that perturbations disrupting protein homeostasis including loss of ER or cytosolic chaperone function, impairments in ER protein translocation, blocking ER N-glycosylation, or reductive stress, cause peroxisome proliferation. This proliferation is driven by increased de novo biogenesis from the ER as well as increased fission of pre-existing peroxisomes, rather than impaired pexophagy. Notably, peroxisome biogenesis is essential for cellular recovery from proteotoxic stress. Through comprehensive testing of major signaling pathways, we determine this response to be mediated by activation of the heat shock response and inhibition of Target of Rapamycin (TOR) signaling. Finally, the effects of proteotoxic stress and TOR inhibition on peroxisomes are also captured in human fibroblasts. Overall, our findings reveal a critical and conserved role of peroxisomes in cellular response to proteotoxic stress.
    DOI:  https://doi.org/10.1101/2024.12.31.630809
  3. Mol Cells. 2025 Mar 13. pii: S1016-8478(25)00034-2. [Epub ahead of print] 100210
    Phosphorylation of eIF2α suppresses the impairment of GSH/NADPH homeostasis and mitigates the activation of cell death pathways, including ferroptosis, during ER stress.
    Hien Thi Le, Yong Hwan Kim, Mi-Jeong Kim, Seung Hwa Hyun, Hyeeun Kim, Su Wol Chung, Yeonsoo Joe, Hun Taeg Chung, Dong-Myung Shin, Sung Hoon Back.
      eIF2α phosphorylation helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. This study aims to elucidate the transcriptional regulation of glutathione (GSH) and NADPH homeostasis through eIF2α phosphorylation and its impact on cell death during ER stress. eIF2α phosphorylation-deficient (A/A) cells exhibited decreased expression of multiple genes involved in GSH synthesis and NADPH production, leading to an exacerbated depletion of both cellular and mitochondrial GSH, as well as mitochondrial NADPH, during ER stress. Impaired GSH homeostasis resulted from deficient expression of ATF4 and/or its dependent factor, Nrf2, which are key transcription factors in the antioxidant response during ER stress. In contrast, the exacerbation of NADPH depletion may primarily be attributed to the dysregulated expression of mitochondrial serine-driven one-carbon metabolism pathway genes, which are regulated by an unidentified eIF2α phosphorylation-dependent mechanism during ER stress. Moreover, the eIF2α phosphorylation-ATF4 axis was responsible for upregulation of ferroptosis-inhibiting genes and downregulation of ferroptosis-activating genes upon ER stress. Therefore, ER stress strongly induced ferroptosis of A/A cells, which was significantly inhibited by treatments with cell-permeable GSH and the ferroptosis inhibitor ferrostatin-1 (Fer-1). ATF4 overexpression suppressed impairment of GSH homeostasis in A/A cells during ER stress by promoting expression of downstream target genes. Consequently, ATF4 overexpression mitigated ferroptosis as well as apoptosis of A/A cells during ER stress. Our findings underscore the importance of eIF2α phosphorylation in maintaining GSH/NADPH homeostasis and inhibiting ferroptosis through ATF4 and unidentified eIF2α phosphorylation-dependent target(s)-mediated transcriptional reprogramming during ER stress.
    Keywords:  ATF4; ER stress; Ferroptosis; Glutathione; Nrf2; eIF2α phosphorylation
    DOI:  https://doi.org/10.1016/j.mocell.2025.100210
  4. Mol Cancer Res. 2024 Mar 19.
    DR5 disulfide bonding functions as a sensor and effector of protein folding stress.
    Mary E Law, Zaafir M Dulloo, Samantha R Eggleston, Gregory P Takacs, Grace M Alexandrow, Young Il Lee, Mengxiong Wang, Brian Hardy, Hanyu Su, Bianca Forsyth, Parag Das, Pran K Datta, Chi-Wu Chiang, Abhisheak Sharma, Siva Rama Raju Kanumuri, Olga A Guryanova, Jeffrey K Harrison, Boaz Tirosh, Ronald K Castellano, Brian K Law.
      New agents are needed that selectively kill cancer cells without harming normal tissues. The TRAIL ligand and its receptors, DR5 and DR4, exhibit cancer-selective toxicity. TRAIL analogs or agonistic antibodies targeting these receptors are available but have not yet received FDA approval for cancer therapy. Small molecules for activating DR5 or DR4 independently of protein ligands may activate TRAIL receptors as a monotherapy or potentiate the efficacy of TRAIL analogs and agonistic antibodies. Previously described Disulfide bond Disrupting Agents (DDAs) activate DR5 by altering its disulfide bonding through inhibition of the Protein Disulfide Isomerases (PDIs) ERp44, AGR2, and PDIA1. Work presented here extends these findings by showing that disruption of single DR5 disulfide bonds causes high-level DR5 expression, disulfide-mediated clustering, and activation of Caspase 8-Caspase 3 mediated pro-apoptotic signaling. Recognition of the extracellular domain of DR5 by various antibodies is strongly influenced by the pattern of DR5 disulfide bonding, which has important implications for the use of agonistic DR5 antibodies for cancer therapy and as research tools. Importantly, other ER stressors, including Thapsigargin and Tunicamycin also alter DR5 disulfide bonding in various cancer cell lines and in some instances, DR5 mis-disulfide bonding is potentiated by overriding the Integrated Stress Response (ISR) with inhibitors of the PERK kinase or the ISR inhibitor ISRIB. These observations indicate that the pattern of DR5 disulfide bonding functions as a sensor of ER stress and serves as an effector of proteotoxic stress by driving extrinsic apoptosis independently of extracellular ligands. Implications: Extreme endoplasmic reticulum stress triggers triage of transmembrane receptor production, whereby mitogenic receptors are downregulated and death receptors are simultaneously elevated.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-24-0756
  5. Biomed Pharmacother. 2025 Mar 19. pii: S0753-3322(25)00186-6. [Epub ahead of print]186 117992
    Proteostasis regulation of GABAA receptors in neuronal function and disease.
    Xi Chen, Ya-Juan Wang, Ting-Wei Mu.
      The γ-aminobutyric acid type A receptors (GABAARs) are ligand-gated anion channels that mediate fast inhibitory neurotransmission in the mammalian central nervous system. GABAARs form heteropentameric assemblies comprising two α1, two β2, and one γ2 subunits as the most common subtype in mammalian brains. Proteostasis regulation of GABAARs involves subunit folding within the endoplasmic reticulum, assembling into heteropentamers, receptor trafficking to the cell surface, and degradation of terminally misfolded subunits. As GABAARs are surface proteins, their trafficking to the plasma membrane is critical for proper receptor function. Thus, variants in the genes encoding GABAARs that disrupt proteostasis result in various neurodevelopmental disorders, ranging from intellectual disability to idiopathic generalized epilepsy. This review summarizes recent progress about how the proteostasis network regulates protein folding, assembly, degradation, trafficking, and synaptic clustering of GABAARs. Additionally, emerging pharmacological approaches that restore proteostasis of pathogenic GABAAR variants are presented, providing a promising strategy to treat related neurological diseases.
    Keywords:  4-phenylbutyric acid (PubChem CID: 4775); AA147 (PubChem CID: 882909); AA263 (PubChem CID: 135509553); BIX (PubChem CID: 16656807); Dihydroergocristine (PubChem CID: 107715); Dinoprost (PubChem CID: 5280363); Epilepsy; GABA(A) receptors; Hispidulin (PubChem CID: 5281628); Pharmacological Chaperones; Proteostasis; Proteostasis regulators; SAHA (PubChem CID: 5311); TP003 (PubChem CID: 10001434); Variants; Verapamil (PubChem CID: 2520)
    DOI:  https://doi.org/10.1016/j.biopha.2025.117992
  6. Wiley Interdiscip Rev RNA. 2025 Mar-Apr;16(2):16(2): e70009
    Role of Assemblysomes in Cellular Stress Responses.
    Bence György Gombás, Orsolya Németh-Szatmári, Bence Nagy-Mikó, Zoltán Villányi.
      Assemblysomes are recently discovered intracellular RNA-protein complexes that play important roles in cellular stress response, regulation of gene expression, and also in co-translational protein assembly. In this review, a wide spectrum overview of assemblysomes is provided, including their discovery, mechanism of action, characteristics, and potential applications in several fields. Assemblysomes are distinct liquid-liquid phase-separated condensates; they have certain unique properties differentiating them from other cellular granules. They are composed of ribosome-nascent protein chain complexes and are resistant to cycloheximide and EDTA. The discovery and observation of intracellular condensates, like assemblysomes, have further expanded our knowledge of cellular stress response mechanisms, particularly in DNA repair processes and defense against proteotoxicity. Ribosome profiling experiments and next-generation sequencing of cDNA libraries extracted from EDTA-resistant pellets-of ultracentrifuged cell lysates-have shed light on the composition and dynamics of assemblysomes, revealing their role as repositories for pre-made stress-responsive ribosome-nascent chain complexes. This review gives an exploration of assemblysomes' potential clinical applications from multiple aspects, including their usefulness as diagnostic biomarkers for chemotherapy resistance and their implications in cancer therapy. In addition, in this overview, we raise some theoretical ideas of industrial and agricultural applications connected to these membraneless organelles. However, we see several challenges. On one hand, we need to understand the complexity of assemblysomes' multiple functions and regulations; on the other hand, it is essential to bridge the gap between fundamental research and practical applications. Overall, assemblysome research can be perceived as a promising upcomer in the improvement of biomedical settings as well as those connected to agricultural and industrial aspects.
    Keywords:  1,6‐hexanediol; NCAs; assemblysomes; phase separation; translation regulation
    DOI:  https://doi.org/10.1002/wrna.70009
  7. Genetics. 2025 Mar 18. pii: iyaf042. [Epub ahead of print]
    Dynamic regulation of murine RNA Polymerase III transcription during heat shock stress.
    Thomas F Nguyen, James Z J Kwan, Jennifer E Mitchell, Jieying H Cui, Sheila S Teves.
      Cells respond to many different types of stresses by overhauling gene expression patterns, both at the transcriptional and translational level. Under heat stress, global transcription and translation are inhibited, while the expression of chaperone proteins are preferentially favored. As the direct link between mRNA transcription and protein translation, tRNA expression is intricately regulated during the stress response. Despite extensive research into the heat shock response (HSR), the regulation of tRNA expression by RNA Polymerase III (Pol III) transcription has yet to be fully elucidated in mammalian cells. Here, we examine the regulation of Pol III transcription during different stages of heat shock stress in mouse embryonic stem cells (mESCs). We observe that Pol III transcription is downregulated after 30 minutes of heat shock, followed by an overall increase in transcription after 60 minutes of heat shock. This effect is more evident in tRNAs, though other Pol III gene targets are also similarly affected. Notably, we show that the downregulation at 30 minutes of heat shock is independent of HSF1, the master transcription factor of the HSR, but that the subsequent increase in expression at 60 minutes requires HSF1. Taken together, these results demonstrate an adaptive RNA Pol III response to heat stress, and an intricate relationship between the canonical HSR and tRNA expression.
    Keywords:  heat shock; mouse embryonic stem cells; transcription; transfer RNA
    DOI:  https://doi.org/10.1093/genetics/iyaf042
  8. J Clin Invest. 2025 Mar 17. pii: e188127. [Epub ahead of print]135(6):
    Nonvesicular cholesterol transport in physiology.
    Alessandra Ferrari, Peter Tontonoz.
      In mammalian cells cholesterol can be synthesized endogenously or obtained exogenously through lipoprotein uptake. Plasma membrane (PM) is the primary intracellular destination for both sources of cholesterol, and maintaining appropriate membrane cholesterol levels is critical for cellular viability. The endoplasmic reticulum (ER) acts as a cellular cholesterol sensor, regulating synthesis in response to cellular needs and determining the metabolic fates of cholesterol. Upon reaching the ER, cholesterol can be esterified to facilitate its incorporation into lipoproteins and lipid droplets or converted into other molecules such as bile acids and oxysterols. In recent years, it has become clear that the intracellular redistribution of lipids, including cholesterol, is critical for the regulation of various biological processes. This Review highlights physiology and mechanisms of nonvesicular (protein-mediated) intracellular cholesterol trafficking, with a focus on the role of Aster proteins in PM to ER cholesterol transport.
    DOI:  https://doi.org/10.1172/JCI188127
  9. J Biosci. 2025 ;pii: 15. [Epub ahead of print]50
    Innate immune and endoplasmic reticulum unfolded protein response pathways protect Caenorhabditis elegans against chloroquine toxicity.
    Rajneesh Rao, Jogender Singh.
      Chloroquine (CQ) is a 4-aminoquinoline that has historically been used as an anti-malarial drug. It has also been used to treat several autoimmune diseases, cancers, and viral infections. Most of the effects of CQ are mediated through its ability to accumulate in acidic vacuoles and increase their pH. However, at high doses, CQ is known to have various toxic effects, including ocular, retinal, neuromuscular, renal, and cardiac toxicities. The host responses involved in counteracting CQ toxicity remain poorly characterized. Here, using the Caenorhabditis elegans model, we characterize the host pathways that protect against CQ toxicity. Transcriptomics studies reveal that CQ exposure results in the upregulation of innate immune response and endoplasmic reticulum (ER) unfolded protein response (UPR) pathways. An analysis of multiple immune pathway mutants shows that different immune pathways defend against CQ toxicity. Intriguingly, some of these pathways, which converge to defend against pathogenic bacteria, operate independently to protect against CQ toxicity. Finally, we demonstrate that the ER-UPR pathways also play a crucial role in counteracting CQ toxicity.
  10. PLoS One. 2025 ;20(3): e0319280
    Kinetic modelling reveals the presence of multistability in normal and stressful conditions in translational initiation mechanism.
    Guturu L Harika, Krishnamachari Sriram.
      Protein synthesis involves translation initiation, elongation, termination, and ribosome recycling, and each step is controlled intricately by many signaling proteins. Translation initiation can be compactly categorized into two mechanisms: primary and secondary. The primary mechanism involves the recruitment of three important eukaryotic initiation factors, eIF2-GDP, eIF5, and eIF2B, and their interactions, followed by the GDP-GTP exchange by eIF2B to form an active dimer eIF2-GTP. The dimer binds with Met-tRNA to form a robust ternary complex (TC). The secondary mechanism closely mirrors the primary reaction mechanism, except that the interactions of eIF2B and eIF5 happen with the TC to form complexes. These interactions happen with high fidelity and precision, failing which fail-safe mechanisms are invoked instantaneously to delay the initiation process. In this work, we build a mathematical model to unravel how the transition between translation initiation and termination occurs at the initiation stage based on the elementary mechanisms we built from the network assembled from experimental observations. We focus only on the dynamics of primary and secondary mechanisms involved in the translation initiation process under normal and integrated stress response (ISR) conditions that act as a fail-safe mechanism by through phosphorylation-dephosphorylation (PdP) reactions. Since the network is huge and has many unknown kinetic parameters, we perform structural analysis using chemical reaction network theory (CRNT) and find hidden positive feedback loops that regulate the initiation mechanism. We apply bifurcation theory to show that the model exhibits ultrasensitivity and bistability under normal conditions, while under ISR, it exhibits both bistability and tristability for the choice of kinetic parameters. We attribute bistability to translation initiation and termination and tristability in ISR to translation recovery and attenuation. We conclude that the translation initiation process is a highly regulated process guided by the threshold and switching mechanisms to make quick decisions on the translation initiation, termination, recovery or attenuation under different conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0319280
  11. Curr Opin Cell Biol. 2025 Mar 20. pii: S0955-0674(25)00039-0. [Epub ahead of print]94 102501
    License to drive: Receptor-mediated ER exit of proteins and lipids.
    Xiao Wang, Tiantian Li, Yusong Guo, Xiao-Wei Chen.
      The secretory pathway, which begins at the endoplasmic reticulum (ER) through the COPII complex, is responsible for transporting proteins and lipid carriers to various destined cellular compartments or extracellular space. The fundamental mechanism by which the COPII operates is evolutionarily conserved. Nevertheless, the vast diversity of mammalian cargos poses significant challenges to the secretory pathway, especially considering the intricate physiology in vivo. Particularly, certain physiologically essential cargos, including procollagen and lipoproteins, appear to be oversized for these canonical carriers, implying the need for additional sophisticated regulation at the onset step so-called ER exit. Emerging evidence highlights the critical role of cargo receptors in selective sorting for ER export, illuminating the complex biology of the trafficking dynamics, which holds broad implications for human health and diseases.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102501
  12. Front Cell Dev Biol. 2025 ;13 1523382
    Proteasome dynamics in response to metabolic changes.
    Cordula Enenkel, Oliver P Ernst.
      Proteasomes, essential protease complexes in protein homeostasis, adapt to metabolic changes through intracellular movements. As the executive arm of the ubiquitin-proteasome system, they selectively degrade poly-ubiquitinated proteins in an ATP-dependent process. The primary proteasome configuration involved in this degradation is the 26S proteasome, which is composed of a proteolytically active core particle flanked by two regulatory particles. In metabolically active cells, such as proliferating yeast and mammalian cancer cells, 26S proteasomes are predominantly nuclear and actively engaged in protein degradation. However, during nutrient deprivation or stress-induced quiescence, proteasome localization changes. In quiescent yeast, proteasomes initially accumulate at the nuclear envelope. During prolonged quiescence with decreased ATP levels, proteasomes exit the nucleus and are sequestered into cytoplasmic membraneless organelles, so-called proteasome storage granules (PSGs). In mammalian cells, starvation and stress trigger formation of membraneless organelles containing proteasomes and poly-ubiquitinated substrates. The proteasome condensates are motile, reversible, and contribute to stress resistance and improved fitness during aging. Proteasome condensation may involve liquid-liquid phase separation, a mechanism underlying the assembly of membraneless organelles.
    Keywords:  metabolic regulation of proteasome localization; proteasome condensates in membraneless organelles; proteasome storage granules; protein homeostasis (proteostasis); ubiquitin 26S-proteasome system
    DOI:  https://doi.org/10.3389/fcell.2025.1523382
  13. Nat Commun. 2025 Mar 14. 16(1): 2535
    ER O-glycosylation in synovial fibroblasts drives cartilage degradation.
    Le Son Tran, Joanne Chia, Xavier Le Guezennec, Keit Min Tham, Anh Tuan Nguyen, Virginie Sandrin, Way Cherng Chen, Tan Tong Leng, Sreedharan Sechachalam, Khai Pang Leong, Frederic A Bard.
      How arthritic synovial fibroblasts (SFs) activate cartilage ECM degradation remains unclear. GALNT enzymes initiate O-glycosylation in the Golgi; when relocated to the ER, their activity stimulates ECM degradation. Here, we show that in human rheumatoid and osteoarthritic synovial SFs, GALNTs are relocated to the ER. In an RA mouse model, GALNTs relocation occurs shortly before arthritis symptoms and abates as the animal recovers. An ER GALNTs inhibitor prevents cartilage ECM degradation in vitro and expression of this chimeric protein in SFs results in the protection of cartilage. One of the ER targets of GALNTs is the resident protein Calnexin, which is exported to the cell surface of arthritic SFs. Calnexin participates in matrix degradation by reducing ECM disulfide bonds. Anti-Calnexin antibodies block ECM degradation and protect animals from RA. In sum, ER O-glycosylation is a key switch in arthritic SFs and glycosylated surface Calnexin could be a therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-025-57401-9
  14. Nat Commun. 2025 Mar 17. 16(1): 2617
    Deep indel mutagenesis reveals the impact of amino acid insertions and deletions on protein stability and function.
    Magdalena Topolska, Antoni Beltran, Ben Lehner.
      Amino acid insertions and deletions (indels) are an abundant class of genetic variants. However, compared to substitutions, the effects of indels on protein stability are not well understood. To better understand indels here we analyse new and existing large-scale deep indel mutagenesis (DIM) of structurally diverse proteins. The effects of indels on protein stability vary extensively among and within proteins and are not well predicted by existing computational methods. To address this shortcoming we present INDELi, a series of models that combine experimental or predicted substitution effects and secondary structure information to provide good prediction of the effects of indels on both protein stability and pathogenicity. Moreover, quantifying the effects of indels on protein-protein interactions suggests that insertions can be an important class of gain-of-function variants. Our results provide an overview of the impact of indels on proteins and a method to predict their effects genome-wide.
    DOI:  https://doi.org/10.1038/s41467-025-57510-5
  15. Ophthalmic Genet. 2025 Mar 20. 1-9
    Mesencephalic astrocyte-derived neurotrophic factor upregulates CHOP and ATF6 in the rat retina with retinitis pigmentosa.
    Zhenya Gao, Hongge Hu, Yanming Huang, Fang Yu, Bin Lou.
       PURPOSE: In the current work, we investigated the potential protective function of MANF against the degeneration of RP in S334ter-3 rats and the mechanism underlying these effects.
    METHODS: The left eye of rat was injected with MANF, and the right eye injected PBS as a control. The levels of those ER stress associated proteins were determined by western blot analysis.
    RESULTS: First, those ER stress associated proteins were detected in S334ter-3 rats. Among these proteins, a decrease in the expression of PERK was only showed from PD 6 to PD 12. Surprisingly, a dramatic increase of ATF6 was induced by injection MANF. Then, the expression of ATF6 protein declined rapidly to the control eye. Furthermore, a remarkable increase in the expression of CHOP was examined at 6 h, which peaked at 12 h and maintained the level until 48 h. At the same time, CHOP was detected in Müller cells but not in photoreceptor; nevertheless, photoreceptor survival clearly improved. The increasing expressions of CHOP and ATF6 in SD rats were similar to the changes in S33ter-3 rats after injection MANF.
    CONCLUSIONS: These results indicate that MANF may play an important role in protecting photoreceptor degeneration in RP.
    Keywords:  ATF6; CHOP; ER stress; MANF; S334ter-3
    DOI:  https://doi.org/10.1080/13816810.2025.2482610
  16. Nat Commun. 2025 Mar 19. 16(1): 2723
    A cysteine-less and ultra-fast split intein rationally engineered from being aggregation-prone to highly efficient in protein trans-splicing.
    Christoph Humberg, Zahide Yilmaz, Katharina Fitzian, Wolfgang Dörner, Daniel Kümmel, Henning D Mootz.
      Split inteins catalyze protein trans-splicing by ligating their extein sequences while undergoing self-excision, enabling diverse protein modification applications. However, many purified split intein precursors exhibit partial or no splicing activity for unknown reasons. The Aes123 PolB1 intein, a representative of the rare cysteine-less split inteins, is of particular interest due to its resistance to oxidative conditions and orthogonality to thiol chemistries. In this work, we identify β-sheet-dominated aggregation of its N-terminal intein fragment as the origin of its low (~30%) splicing efficiency. Using computational, biochemical, and biophysical analyses, we characterize the fully active monomeric fraction and pinpoint aggregation-prone regions. Supported by a crystal structure, we design stably monomeric mutants with nearly complete splicing activity. The optimized CLm intein (Cysteine-Less and monomeric) retains the wild-type's ultra-fast reaction rate and serves as an efficient, thiol-independent protein modification tool. We find that other benchmark split inteins show similar precursor aggregation, suggesting that this general phenomenon arises from the intrinsic challenge to maintain the precursor in a partially disordered state while promoting stable folding upon fragment association.
    DOI:  https://doi.org/10.1038/s41467-025-57596-x
  17. Front Cell Dev Biol. 2025 ;13 1545359
    Mitoregulin, a tiny protein at the crossroads of mitochondrial functioning, stress, and disease.
    Petr Sergiev, Olga Averina, Julia Golubeva, Mikhail Vyssokikh, Olga Dontsova.
      Mitoregulin (Mtln) is a small mitochondrial protein that was only recently identified. Despite this, a substantial number of studies on its function have already been published. Although sometimes contradictory, these studies have revealed the localization of Mtln, its protein and lipid partners, and its role in lipid homeostasis, energy metabolism, oxidative stress, and other aspects of mitochondrial functioning. Moreover, research using knockout and transgenic mouse models has revealed the important role of Mtln in mammalian physiology. Metabolic changes, along with muscle, kidney, and fat-related phenotypes, have been linked to Mtln dysfunction. In this review, we summarize a comprehensive set of published data on Mtln. While controversies remain, we seek to offer a unified view of its functions, spanning molecular mechanisms to organism-level effects.
    Keywords:  Mtln; cardiolipin; membrane; mitochondria; respiration; small peptide
    DOI:  https://doi.org/10.3389/fcell.2025.1545359
  18. ACS Pharmacol Transl Sci. 2025 Mar 14. 8(3): 621-635
    Chemical Probes for Studying the Eukaryotic Translation Initiation Factor 4E (eIF4E)-Regulated Translatome in Cancer.
    Rachel L O'Rourke, Amanda L Garner.
      The dysregulation of translation is a hallmark of cancer that enables rapid changes in the cell proteome to shape oncogenic phenotypes that promote tumor survival. The predominant signaling pathways leading to dysregulation of translational control in cancer are the PI3K-AKT-mTORC1, RAS-RAF-MAPK, and MYC pathways, which all converge on eukaryotic translation initiation factor 4E (eIF4E), an RNA-binding protein that binds to the m7GpppX cap structure at the 5' end of mRNAs to initiate cap-dependent translation. eIF4E is the rate-limiting factor of translation initiation, and its overexpression is known to drive oncogenic transformation, progression, and chemoresistance across many cancers, establishing it as an attractive therapeutic target. Over the last several decades, significant efforts have been made to inhibit eIF4E through the development of mechanistically distinct small-molecule inhibitors that both directly and indirectly act on eIF4E to prevent cap-dependent translation initiation. These inhibitors can serve as powerful chemical tools to improve our understanding of the mechanisms of cap-dependent translation in cancer and to ultimately predict specific cancers that may benefit from eIF4E-targeted therapeutics. This review discusses the progress made in the development of different classes of small-molecule eIF4E inhibitors, the challenges that remain, and their potential as chemical probes to elucidate the complexities of cap-dependent translation in cancer.
    DOI:  https://doi.org/10.1021/acsptsci.4c00674
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