bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–05–25
eleven papers selected by
Jessica Rosarda, Uniformed Services University
  1. Pharmacological Regulation of Heat Shock Response via Aptamer-Antidote Couple.
  2. N-glycan-dependent protein maturation and quality control in the ER.
  3. Selective removal of astrocytic PERK protects against glymphatic impairment and decreases toxic aggregation of β-amyloid and tau.
  4. Induction of the ISR by AB5 subtilase cytotoxin drives type-I IFN expression in pDCs via STING activation.
  5. Inhibition of IRE1α Alleviates Renal Fibrosis and Downregulates M1 Macrophage Activation via the p38 MAPK Pathway.
  6. Stepwise ATP translocation into the endoplasmic reticulum by human SLC35B1.
  7. Cell cycle regulation by the ribotoxic stress response.
  8. Analysis of translational regulation using polysome profiling and puromycin incorporation.
  9. How Do Mitochondria Manage Competing Biochemical Metabolic Processes Under Stress?
  10. Problematic issues of ATP synthesis in vivo.
  11. De novo serine biosynthesis is protective in mitochondrial disease.
  1. ACS Chem Neurosci. 2025 May 19.
    Pharmacological Regulation of Heat Shock Response via Aptamer-Antidote Couple.
    Jaskirat Kaur, Ipsita Roy.
      Heat shock factor 1 (HSF1) orchestrates the cellular heat shock response (HSR) by binding to heat shock elements (HSEs) in the promoters of genes encoding heat shock proteins (HSPs). In a nonstressed state, HSF1 exists in a dormant complex with HSP90 and other chaperones. Upon cellular stress or upon inhibition of HSP90, HSF1 dissociates from the complex and activates the expression of HSPs to mitigate protein misfolding and aggregation. This study explores the potential of RNA aptamers selected against HSP90 to modulate HSF1 activity, with a role in Huntington's disease model characterized by protein aggregation. Selected aptamers disrupted the HSP90-HSF1 interaction, enhancing the binding of HSF1 with HSEs. This upregulated heat shock response (HSR) and reduced aggregation of Q74-huntingtin in Neuro 2a cells with improved cell survival. Designed antidote sequences could reverse the effect of the aptamers on the HSF1-HSE interaction, allowing for fine-tuning of HSR. Chronic activation of stress response pathways is deleterious for cellular fitness. Our findings suggest that coupling an antidote with an aptamer offers a novel therapeutic strategy to regulate cellular proteostasis under disease conditions.
    Keywords:  Heat shock proteins; heat shock response; protein aggregation; proteostasis network
    DOI:  https://doi.org/10.1021/acschemneuro.4c00865
  2. Nat Rev Mol Cell Biol. 2025 May 19.
    N-glycan-dependent protein maturation and quality control in the ER.
    Kevin P Guay, Wen-Chuan Chou, Nathan P Canniff, Kylie B Paul, Daniel N Hebert.
      The vast majority of proteins that traverse the mammalian secretory pathway become N-glycosylated in the endoplasmic reticulum (ER). The bulky glycan protein modifications, which are conserved in fungi and humans, act as maturation and quality-control tags. In this Review, we discuss findings published in the past decade that have rapidly expanded our understanding of the transfer and processing of N-glycans, as well as their role in protein maturation, quality control and trafficking in the ER, facilitated by structural insights into the addition of N-glycans by the oligosaccharyltransferases A and B (OST-A and OST-B). These findings suggest that N-glycans serve as reporters of the folding status of secretory proteins as they traverse the ER, enabling the lectin chaperones to guide their maturation. We also explore how the emergence of co-translational glycosylation and the expansion of the glycoproteostasis network in metazoans has expanded the role of N-glycans in early protein-maturation events and quality control.
    DOI:  https://doi.org/10.1038/s41580-025-00855-y
  3. Neuron. 2025 May 19. pii: S0896-6273(25)00310-1. [Epub ahead of print]
    Selective removal of astrocytic PERK protects against glymphatic impairment and decreases toxic aggregation of β-amyloid and tau.
    Kai Chen, Yosuke M Morizawa, Tal Nuriel, Osama Al-Dalahmah, Zhongcong Xie, Guang Yang.
      Dysfunction of the glymphatic system, a brain-wide waste clearance network, is strongly linked to Alzheimer's disease (AD) and the accumulation of β-amyloid (Aβ) and tau proteins. Here, we identify an astrocytic signaling pathway that can be targeted to preserve glymphatic function and mitigate neurotoxic protein buildup. Analysis of astrocytes from both human AD brains and two transgenic mouse models (5XFAD and PS19) reveals robust activation of the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK)-α subunit of eukaryotic initiation factor 2 (eIF2α) branch of the unfolded protein response. Chronic PERK activation suppresses astrocytic protein synthesis and, through casein kinase 2 (CK2)-dependent mechanisms, disrupts the perivascular localization of aquaporin-4 (AQP4), a water channel essential for glymphatic flow. Importantly, astrocyte-specific PERK deletion or pharmacological inhibition restores AQP4 localization, enhances glymphatic clearance, reduces Aβ and tau pathology, and improves cognitive performance in mice. These findings highlight the critical role of the astrocytic PERK-CK2-AQP4 axis in glymphatic dysfunction and AD pathogenesis, positioning this pathway as a promising therapeutic target.
    Keywords:  AD; AQP4; CK2; PERK; astrocyte; glymphatic function; protein synthesis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.neuron.2025.04.027
  4. Proc Natl Acad Sci U S A. 2025 May 27. 122(21): e2421258122
    Induction of the ISR by AB5 subtilase cytotoxin drives type-I IFN expression in pDCs via STING activation.
    Daniela Barros, Beatriz H Ferreira, Paulina Garcia-Gonzalez, Francesco Carbone, Marine Luka, Fátima Leite-Pinheiro, Mariana D Machado, Theopisti Nikolaou, Angelo Pilotti, Eliot Goguet, Paulo Antas, Andreia Mendes, Lichen Zhang, Marina Cresci, Lou Galliot, Julien P Gigan, Marisa Reverendo, Bing Su, Miwako Narita, Adrienne W Paton, James C Paton, Stéphane Rocchi, Frédéric Rieux-Laucat, Rafael J Argüello, Béatrice Nal, Yinming Liang, Mickaël Ménager, Evelina Gatti, Catarina R Almeida, Philippe Pierre.
      We demonstrate that exposure to the AB5 subtilase cytotoxin (SubAB) induces the unfolded protein response (UPR) in human peripheral blood mononuclear cells, concomitant with a proinflammatory response across distinct cell subsets. Notably, SubAB selectively induces type-I interferon (IFN) expression in plasmacytoid dendritic cells, acting synergistically with Toll-like receptor 7 stimulation. The induction of type-I IFN in response to SubAB relies on stimulator of interferon genes (STING) activation, coupled with protein synthesis inhibition mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) and phosphorylation of the eukaryotic translation initiation factor 2 subunit-alpha. By impeding mRNA translation through the integrated stress response, SubAB precipitates the downregulation of the negative innate signaling feedback regulator Tax1-binding protein 1. This downregulation is necessary to unleash TANK-binding kinase 1 signaling associated with STING activation. These findings shed light on how UPR-inducing conditions may regulate the immune system during infection or pathogenesis.
    Keywords:  innate immunity; pDC; subtilase cytotoxin; unfolded protein stress response
    DOI:  https://doi.org/10.1073/pnas.2421258122
  5. Immunology. 2025 May 22.
    Inhibition of IRE1α Alleviates Renal Fibrosis and Downregulates M1 Macrophage Activation via the p38 MAPK Pathway.
    Zichan Guo, Yuting Shen, Xiaxia Yu, Yun Song, Jiyang Zheng, Yuen Zeng, Yazhen Wang, Zhaoyue Fu, Yongli Hou, Dingwen Shi, Liangjian Han, Juan Li, Lihua Chen.
      The enhanced M1 macrophage activation and proportion significantly promote the progression of renal fibrosis in the unilateral ureteral obstruction (UUO) model, while the underlying mechanisms need to be further studied. Here, we examined whether or not endoplasmic reticulum (ER) stress contributed to M1 macrophage activation and the mechanisms in this process. In the UUO mouse model, the proportion of M1 macrophages could be significantly increased in the early renal fibrosis, with the ER stress activated. The inhibitor of ER stress (4-PBA) significantly suppressed the activation of M1 macrophages and alleviated the renal fibrosis in the UUO mouse model. Furthermore, the renal fibrosis could be relieved after the administration of IRE1α inhibitor (4μ8C), with the downregulation of ER stress and M1 macrophage activation. Mechanistically, ER stress-enhanced activation of M1 macrophages was regulated through the IRE1α/XBP1s-p38 MAPK pathway. IRE1α-deficient macrophages could alleviate the renal fibrosis in the UUO mouse model. Thus, our findings suggest that the ER stress pathway regulates M1 macrophage activation in the UUO model, which provides a novel therapeutic approach for renal fibrosis.
    Keywords:  IRE1α; M1 macrophage; endoplasmic reticulum stress; p38 MAPK; renal fibrosis
    DOI:  https://doi.org/10.1111/imm.13949
  6. Nature. 2025 May 21.
    Stepwise ATP translocation into the endoplasmic reticulum by human SLC35B1.
    Ashutosh Gulati, Do-Hwan Ahn, Albert Suades, Yurie Hult, Gernot Wolf, So Iwata, Giulio Superti-Furga, Norimichi Nomura, David Drew.
      ATP generated in the mitochondria is exported by an ADP/ATP carrier of the SLC25 family1. The endoplasmic reticulum (ER) cannot synthesize ATP but must import cytoplasmic ATP to energize protein folding, quality control and trafficking2,3. It was recently proposed that a member of the nucleotide sugar transporter family, termed SLC35B1 (also known as AXER), is not a nucleotide sugar transporter but a long-sought-after ER importer of ATP4. Here we report that human SLC35B1 does not bind nucleotide sugars but indeed executes strict ATP/ADP exchange with uptake kinetics consistent with the import of ATP into crude ER microsomes. A CRISPR-Cas9 cell-line knockout demonstrated that SLC35B1 clusters with the most essential SLC transporters for cell growth, consistent with its proposed physiological function. We have further determined seven cryogenic electron microscopy structures of human SLC35B1 in complex with an Fv fragment and either bound to an ATP analogue or ADP in all major conformations of the transport cycle. We observed that nucleotides were vertically repositioned up to approximately 6.5 Å during translocation while retaining key interactions with a flexible substrate-binding site. We conclude that SLC35B1 operates by a stepwise ATP translocation mechanism, which is a previously undescribed model for substrate translocation by an SLC transporter.
    DOI:  https://doi.org/10.1038/s41586-025-09069-w
  7. Trends Cell Biol. 2025 May 15. pii: S0962-8924(25)00106-0. [Epub ahead of print]
    Cell cycle regulation by the ribotoxic stress response.
    Connor D McKenney, Sergi Regot.
      Cells must sense and respond to numerous stimuli to maintain their function. Stress-activated protein kinases (SAPKs) are part of an integrated network that responds to these stimuli and have critical roles in determining cell behavior. Over the past 5 years, ribosomes and the ribotoxic stress response (RSR) have unexpectedly emerged as critical regulators of the SAPK network and drivers of global cell fate changes. In particular, RSR-SAPK signaling has potent effects on cellular proliferation, with important implications for senescence and cancer. In this review, we discuss cell cycle regulation by the SAPK p38, with a particular focus on how ribotoxic stress affects key cell cycle transitions.
    Keywords:  RSR; SAPK; ZAK; cell cycle; ribotoxic stress
    DOI:  https://doi.org/10.1016/j.tcb.2025.04.005
  8. Methods Enzymol. 2025 ;pii: S0076-6879(25)00042-4. [Epub ahead of print]715 211-230
    Analysis of translational regulation using polysome profiling and puromycin incorporation.
    Quinton W Wood, Teresa L Mastracci.
      Translation is the process of decoding an mRNA transcript to permit the synthesis of a protein. This process occurs in three steps: initiation, elongation, and termination. Each step of translation is regulated by translation factors. By regulating translation, the quantity and quality of proteins can be controlled. When translation becomes dysfunctional, disease can ensue, making translational regulation an important avenue of research. Polysome profiling and puromycin incorporation are experimental techniques used in concert to analyze the translational state of cells or tissues. Polysome profiling evaluates the state of translation by quantifying mRNAs based on the abundance of associated ribosomes. Puromycin incorporation measures the amount of newly synthesized protein. Together these methodologies can decipher stark and subtle changes in the rate and efficiency of translation, and provide the opportunity to dissect alterations to the translation of specific transcripts.
    Keywords:  Polysome Profiling; Puromycin Incorporation; Translation regulation; mRNA translation
    DOI:  https://doi.org/10.1016/bs.mie.2025.01.035
  9. Curr Protein Pept Sci. 2025 May 16.
    How Do Mitochondria Manage Competing Biochemical Metabolic Processes Under Stress?
    Drew Hindrer, Tyler Stark, Selman Aydogdu, Cade Ward, Mohamed Eldeeb.
      
    Keywords:  Mitochondrial fission; mitochondrial fusion; mitochondrial quality control.; mitochondrial stress; molecular metabolism; redox reactions
    DOI:  https://doi.org/10.2174/0113892037381885250506091434
  10. Biosystems. 2025 May 19. pii: S0303-2647(25)00103-0. [Epub ahead of print] 105493
    Problematic issues of ATP synthesis in vivo.
    Viktor V Ivanishchev.
      The work is devoted to description of processes that provide fundamental conditions for ATP synthesis in vivo. The work presents information on the basis of which a general fundamental picture of formation of electrochemical gradient on the mitochondrial (or chloroplast) membrane and its use for ATP-synthase operation is described. An attempt was made to explain the order of appearance of electrical and chemical gradients, as well as the feedback between electrical and chemical components of the driving force in mitochondria and chloroplasts based on Nath's two-ion theory. The results of the analysis allowed us to conclude that a series of sequential events (which are separated in time and space) is necessary for ATP synthesis in vivo, namely: formation of electrical potential, formation of chemical potential, their use for ATP synthase operation. The electrical component is formed due to light energy (chloroplast) or metabolite-associated processes (mitochondria) by pumping of H+ by the electron transport chain. Formation of chemical gradients occur only upon collapse of the electrical gradient by counterion translocation. As a result of their interaction, a driving force (plus change in the conformation of membrane components) is formed on the membrane, which makes ATP-synthase work. The reasons for significant differences in the values of the chemical and electrical components of the gradient on the membranes of mitochondria and chloroplasts are shown (explained). Analysis of the active transport of metabolites from the mitochondria allows us to conclude that it is possible to "break" the concentration flow of Krebs cycle metabolites into mitochondria in vivo, which can be maintained by cytoplasmic malate.
    Keywords:  ATP synthesis; chloroplast; electrochemical gradient; electron transport chain; metabolites; mitochondria
    DOI:  https://doi.org/10.1016/j.biosystems.2025.105493
  11. Cell Rep. 2025 May 15. pii: S2211-1247(25)00481-4. [Epub ahead of print]44(5): 115710
    De novo serine biosynthesis is protective in mitochondrial disease.
    Christopher B Jackson, Anastasiia Marmyleva, Geoffray Monteuuis, Ryan Awadhpersad, Takayuki Mito, Nicola Zamboni, Takashi Tatsuta, Amy E Vincent, Liya Wang, Nahid A Khan, Thomas Langer, Christopher J Carroll, Anu Suomalainen.
      The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.
    Keywords:  CP: Metabolism; de novo serine synthesis; mitochondrial disease; mitochondrial integrated stress response; mitochondrial translation; tissue specificity; treatment
    DOI:  https://doi.org/10.1016/j.celrep.2025.115710
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