bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–07–27
seven papers selected by
Jessica Rosarda, Uniformed Services University
  1. PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.
  2. Arrest Peptide Profiling resolves co-translational folding pathways and chaperone interactions in vivo.
  3. Silencing stress: Structural insights into ISR termination by the SIFI ubiquitin ligase.
  4. Gangliosides and cholesterol, two major components of the membrane lipid rafts, as news regulatory partners for Stress Granules assembly.
  5. Fluorescence-activated particle sorting for condensate purification.
  6. Self-driving microscopy detects the onset of protein aggregation and enables intelligent Brillouin imaging.
  7. Regulatory interaction between metabolite transporters coordinates glucose and exometabolite fluxes to drive bioenergetics.
  1. J Biol Chem. 2025 Jul 21. pii: S0021-9258(25)02354-3. [Epub ahead of print] 110504
    PERK and IRE1α promote exosome secretion via blocking lysosomal degradation of multiple vesicular body.
    Shixin Zhou, Zihan Zhou, Si Chen, Ming Wang, Likun Wang.
      The unfolded protein response (UPR) initiated under endoplasmic reticulum (ER) stress can not only maintain the ER homeostasis, but also modulate the secretion of proteins and lipids that transmit ER stress signals among cells. Exosomes are multivesicular body (MVB)-derived extracellular vesicles, constituting the unconventional protein secretion pathway. Whether and how the secretion of exosomes is regulated by the UPR remains largely unknown. Here, we reported that ER stress induces exosome secretion in an UPR-dependent way. Activation of PERK and IRE1α, two of the UPR branches, represses the acidification and catabolic activity of lysosomes. This blocked MVB-lysosome fusion, re-directing MVBs from lysosomal degradation to plasma membrane fusion, resulting in exosome release. Calcium-mediated activation of PERK, in the absence of ER stress, is sufficient to suppress lysosomal degradation and augment exosome secretion, partly through its downstream factor ATF4. Our study revealed a function of PERK and IRE1α in modulating lysosome activity and dictating the fate of MVBs, facilitating cell-cell communication via exosomes.
    Keywords:  IRE1α; PERK; extracellular vesicle; lysosome; unfolded protein response
    DOI:  https://doi.org/10.1016/j.jbc.2025.110504
  2. Nat Commun. 2025 Jul 24. 16(1): 6833
    Arrest Peptide Profiling resolves co-translational folding pathways and chaperone interactions in vivo.
    Xiuqi Chen, Vincent J Hilser, Christian M Kaiser.
      Cytosolic proteins begin to fold co-translationally as soon as they emerge from the ribosome during translation. These early co-translational steps are crucial for overall folding and are guided by an intricate network of interactions with molecular chaperones. Because cellular co-translational folding is challenging to detect, its timing and progression remain largely elusive. To quantitatively define co-translational folding in live cells, we developed a high-throughput method that we term "Arrest Peptide Profiling" (AP Profiling). Combining AP Profiling with single-molecule experiments, we delineate co-translational folding for a set of GTPase domains with similar structures, defining how topology shapes folding pathways. Genetic ablation of nascent chain-binding chaperones results in discrete and localized folding changes, highlighting how functional redundancy among chaperones is achieved by distinct engagement with the nascent protein. Our work provides a window into cellular folding pathways of structurally intricate proteins and paves the way for systematic studies of nascent protein folding at exceptional resolution and throughput.
    DOI:  https://doi.org/10.1038/s41467-025-61398-6
  3. Cell Chem Biol. 2025 Jul 17. pii: S2451-9456(25)00202-8. [Epub ahead of print]32(7): 905-907
    Silencing stress: Structural insights into ISR termination by the SIFI ubiquitin ligase.
    Zeba Rizvi, Gabriel C Lander.
      The E3 ligase complex SIFI silences the integrated stress response (ISR) by targeting stress-induced proteins for degradation. In the May 6th issue of Nature, Yang et al.1 revealed how this megadalton complex recognizes diverse substrates and coordinates ubiquitin chain formation. Their insights into the ISR shutdown mechanism suggest new avenues for modulating stress responses in neurodegenerative disease.
    DOI:  https://doi.org/10.1016/j.chembiol.2025.06.007
  4. Cell Stress Chaperones. 2025 Jul 19. pii: S1355-8145(25)00038-0. [Epub ahead of print] 100093
    Gangliosides and cholesterol, two major components of the membrane lipid rafts, as news regulatory partners for Stress Granules assembly.
    Anaïs Aulas, Coralie Di Scala.
      Stress granules are cytoplasmic inclusions with cyto-protective functions assembling in response to stress. They are now accepted to be part of the pathological mechanism in several diseases, from cancer to neurodegenerative disorders. However, the field is still struggling to find common regulators of their assembly and function. In this study, we describe a mechanism involving lipid rafts (gangliosides and cholesterol),in the regulation of stress granules formation. This study reports that membrane lipid composition is able to regulate the formation of stress granules potentially unraveling several disease mechanisms.
    Keywords:  Stress Granules; cholesterol; gangliosides; lipid rafts; stress; translation
    DOI:  https://doi.org/10.1016/j.cstres.2025.100093
  5. Nat Protoc. 2025 Jul 18.
    Fluorescence-activated particle sorting for condensate purification.
    Annie Munier Godebert, Dominique Weil, Adham Safieddine.
      Condensates are receiving increasing attention because of their ability to organize subcellular space. In eukaryotes, nuclear condensates include nucleoli and paraspeckles, and cytoplasmic ones include P-bodies (PBs) and stress granules. One approach to investigate condensate biology is through analyzing their protein and RNA content. However, purifying condensates remains a challenge because of their densities being similar to various other organelles, and the absence of protein markers accumulating exclusively in them. These limitations, combined with the generally low number of condensates per cell, necessitate new approaches to tackle their purification. Here, we present a protocol describing fluorescence-activated particle sorting (FAPS) for purifying condensates. In brief, FAPS involves fluorescently labeling condensates to identify and isolate them from other cellular components via sorting. In this Protocol, we focus on PB purification, quality control and downstream characterization of PB protein and RNA contents. Although originally developed to purify PBs from human cell lines, FAPS can be adapted to various condensates across model organisms. The procedure requires knowledge in basic cell culture, molecular biology and flow cytometry and access to a fluorescence-activated cell sorter with sufficient sensitivity. It requires ~25-30 d, including a hands-on period of 15 d, to complete. In summary, FAPS allows the characterization of the content of diverse condensates across cell types and organisms.
    DOI:  https://doi.org/10.1038/s41596-025-01216-x
  6. Nat Commun. 2025 Jul 24. 16(1): 6699
    Self-driving microscopy detects the onset of protein aggregation and enables intelligent Brillouin imaging.
    Khalid A Ibrahim, Camille Cathala, Carlo Bevilacqua, Lely Feletti, Robert Prevedel, Hilal A Lashuel, Aleksandra Radenovic.
      The process of protein aggregation, central to neurodegenerative diseases like Huntington's, is challenging to study due to its unpredictable nature and relatively rapid kinetics. Understanding its biomechanics is crucial for unraveling its role in disease progression and cellular toxicity. Brillouin microscopy offers unique advantages for studying biomechanical properties, yet is limited by slow imaging speed, complicating its use for rapid and dynamic processes like protein aggregation. To overcome these limitations, we developed a self-driving microscope that uses deep learning to predict the onset of aggregation from a single fluorescence image of soluble protein, achieving 91% accuracy. The system triggers optimized multimodal imaging when aggregation is imminent, enabling intelligent Brillouin microscopy of this dynamic biomechanical process. Furthermore, we demonstrate that by detecting mature aggregates in real time using brightfield images and a neural network, Brillouin microscopy can be used to study their biomechanical properties without the need for fluorescence labeling, minimizing phototoxicity and preserving sample health. This autonomous microscopy approach advances the study of aggregation kinetics and biomechanics in living cells, offering a powerful tool for investigating the role of protein misfolding and aggregation in neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-025-60912-0
  7. Nat Commun. 2025 Jul 24. 16(1): 6819
    Regulatory interaction between metabolite transporters coordinates glucose and exometabolite fluxes to drive bioenergetics.
    Noa Yehoshua, Ahlam Khamaysi, Liana Shimshilashvili, Aharon Keshet, Mahmoud Taha, Moran Fremder, Hadar Eini-Rider, Ehud Ohana.
      The composition of tricarboxylic acid cycle metabolites in the external environment of cells determines vital physiological functions, including nutrient and mineral absorption, inflammation, and cellular energy management. Here, we study how the transport of external metabolites into the cells functions as an independent metabolic pathway that controls cellular energy. We show that liver cells orchestrate simultaneous fluxes of glucose and the omnipotent metabolite citrate across the cell membrane, acting as a first line metabolic pathway that responds to nutrient availability. Using functional mapping and gene silencing, we delineate the underlying molecular mechanism showing that the liver citrate transporter (NaCT) interacts with glucose transporters (Glut) and the anion transporters. The interaction is mediated by a specific region of the NaCT protein to reciprocally regulate the transport functions. Our findings describe an independent mechanism that coordinates external metabolites and glucose balance, thus driving key energy management processes in response to nutrient availability in the liver.
    DOI:  https://doi.org/10.1038/s41467-025-62103-3
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