bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–07–20
fourteen papers selected by
Jessica Rosarda, Uniformed Services University
  1. The endoplasmic reticulum proteostasis network and bone disease.
  2. Dissecting Branch-Specific Unfolded Protein Response Activation in Drug-Tolerant BRAF-Mutant Melanoma using Data-Independent Acquisition Mass Spectrometry.
  3. Optogenetics-enabled discovery of integrated stress response modulators.
  4. Nuclear and cytosolic J-domain proteins provide synergistic control of Hsf1 at distinct phases of the heat shock response.
  5. Emerging roles for integrated stress response signaling in homeostasis.
  6. Stress testing reveals selective vulnerabilities in protein homeostasis.
  7. Chaperone saturation mediates translation and protein folding efficiency.
  8. Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.
  9. Scouring the human Hsp70 network uncovers diverse chaperone safeguards buffering TDP-43 toxicity.
  10. Chronic integrated stress response causes dysregulated cholesterol synthesis in white matter disease.
  11. Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
  12. Heat-Induced Phosphatidylserine Changes Drive HSPA1A's Plasma Membrane Localization.
  13. NRF2 regulates lipid droplet dynamics to prevent lipotoxicity.
  14. ER tethering and active transport govern condensate diffusion during hyperosmotic stress.
  1. Trends Mol Med. 2025 Jul 10. pii: S1471-4914(25)00145-5. [Epub ahead of print]
    The endoplasmic reticulum proteostasis network and bone disease.
    Hesso Farhan, Muhammad Zahoor, Josephine T Tauer, Wolfgang Högler.
      Bone homeostasis relies on the coordinated activity of osteoblasts and osteoclasts that balances bone formation and resorption, and of osteocytes for biomechanical sensing and hormone secretion. A key factor in the function of these cells is proteostasis, where the endoplasmic reticulum (ER) oversees protein synthesis, quality control, folding, and the secretion of proteins such as collagen type I. Emerging research links ER proteostasis defects to skeletal disorders caused by impaired bone development and mass. We explore the mechanisms of ER proteostasis, including the unfolded protein response (UPR), and discuss how genetic, metabolic, and environmental factors disrupt these pathways and contribute to bone pathology. We also highlight the need for further mechanistic insights which could pave the way for novel therapies that target ER-Golgi traffic and inhibit ER stress in bone diseases.
    Keywords:  COPII; endoplasmic reticulum; osteogenesis imperfecta; proteostasis; skeletal dysplasia; unfolded protein response
    DOI:  https://doi.org/10.1016/j.molmed.2025.06.005
  2. Mol Cell Proteomics. 2025 Jul 14. pii: S1535-9476(25)00135-5. [Epub ahead of print] 101036
    Dissecting Branch-Specific Unfolded Protein Response Activation in Drug-Tolerant BRAF-Mutant Melanoma using Data-Independent Acquisition Mass Spectrometry.
    Lea A Barny, Jake N Hermanson, Sarah K Garcia, Philip E Stauffer, Lars Plate.
      Cells rely on the Unfolded Protein Response (UPR) to maintain ER protein homeostasis (proteostasis) when faced with elevated levels of misfolded and aggregated proteins. The UPR is comprised of three main branches-ATF6, IRE1, and PERK-that coordinate the synthesis of proteins involved in folding, trafficking, and degradation of nascent proteins to restore ER function. Dysregulation of the UPR is linked to numerous diseases, including neurodegenerative disorders, cancer, and diabetes. Despite its importance, identifying UPR targets has been challenging due to their heterogeneous induction, which varies by cell type and tissue. Additionally, defining the magnitude and range of UPR-regulated genes is difficult because of intricate temporal regulation, feedback between UPR branches, and extensive cross-talk with other stress-signaling pathways. To comprehensively identify UPR-regulated proteins and determine their branch specificity, we developed a data-independent acquisition (DIA) liquid-chromatography mass spectrometry (LC-MS) pipeline. Our optimized workflow improved identifications of low-abundant UPR proteins and leveraged an automated SP3-based protocol on the Biomek i5 liquid handler for label-free peptide preparation. Using engineered stable cell lines that enable selective pharmacological activation of each UPR branch without triggering global UPR activation, we identified branch-specific UPR proteomic targets. These targets were subsequently applied to investigate proteomic changes in multiple BRAF-mutant melanoma cell lines treated with a BRAF inhibitor (PLX4720, i.e., vemurafenib). Our findings revealed differential regulation of the XBP1s branch of the UPR in the BRAF-mutant melanoma cell lines after PLX4720 treatment, likely due to calcium activation, suggesting that the UPR plays a role as a non-genetic mechanism of drug tolerance in melanoma. In conclusion, the validated branch-specific UPR proteomic targets identified in this study provide a robust framework for investigating this pathway across different cell types, drug treatments, and disease conditions in a high-throughput manner.
    Keywords:  Activating Transcription Factor 6; Data-Independent Acquisition (DIA); Inositol requiring enzyme 1; Protein Kinase R-like ER Kinase; Proteomics automation; Unfolded Protein Response
    DOI:  https://doi.org/10.1016/j.mcpro.2025.101036
  3. Cell. 2025 Jul 03. pii: S0092-8674(25)00690-7. [Epub ahead of print]
    Optogenetics-enabled discovery of integrated stress response modulators.
    Felix Wong, Alicia Li, Satotaka Omori, Ryan S Lach, Jose Nunez, Yunke Ren, Sean P Brown, Vipul Singhal, Brent R Lyda, Taivan Batjargal, Ethan Dickson, Jose Roberto Rodrigues Reyes, Juan Manual Uruena Vargas, Shalaka Wahane, Hahn Kim, James J Collins, Maxwell Z Wilson.
      The integrated stress response (ISR) is a conserved stress response that maintains homeostasis in eukaryotic cells. Modulating the ISR holds therapeutic potential for diseases including viral infection, cancer, and neurodegeneration, but few known compounds can do so without toxicity. Here, we present an optogenetic platform for the discovery of compounds that selectively modulate the ISR. Optogenetic clustering of PKR induces ISR-mediated cell death, enabling the high-throughput screening of 370,830 compounds. We identify compounds that potentiate cell death without cytotoxicity across diverse cell types and stressors. Mechanistic studies reveal that these compounds upregulate activating transcription factor 4 (ATF4), sensitizing cells to stress and apoptosis, and identify GCN2 as a molecular target. Additionally, these compounds exhibit antiviral activity, and one compound reduced viral titers in a mouse model of herpesvirus infection. Structure-activity and toxicology studies highlight opportunities to optimize therapeutic efficacy. This work demonstrates an optogenetic approach to drug discovery and introduces ISR potentiators with therapeutic potential.
    Keywords:  antiviral; drug discovery; endoplasmic reticulum stress; integrated stress response; optogenetics; phenotypic screening; proteostasis; small molecules; synthetic biology; unfolded protein response
    DOI:  https://doi.org/10.1016/j.cell.2025.06.024
  4. bioRxiv. 2025 Jul 08. pii: 2025.04.14.648540. [Epub ahead of print]
    Nuclear and cytosolic J-domain proteins provide synergistic control of Hsf1 at distinct phases of the heat shock response.
    Carmen Ruger-Herreros, Lucia Svoboda, Gurranna Male, Aseem Shrivastava, Markus Höpfler, Jiri Koubek, Günter Kramer, Fabian den Brave, Axel Mogk, David S Gross, Bernd Bukau.
      The heat shock response (HSR) is the major defense mechanism against proteotoxic stress in the cytosol and nucleus of eukaryotic cells. Initiation and attenuation of the response are mediated by stress-dependent regulation of heat shock transcription factors (HSFs). Saccharomyces cerevisiae encodes a single HSF (Hsf1), facilitating the analysis of HSR regulation. Hsf1 is repressed by Hsp70 chaperones under non-stress conditions, and becomes activated under proteotoxic stress, directly linking protein damage and its repair to the HSR. J-domain proteins (JDPs) are essential for targeting of Hsp70s to their substrates, yet the specific JDP(s) regulating Hsf1 and connecting protein damage to HSR activation remain unclear. Here we show that the yeast nuclear JDP Apj1 primarily controls the attenuation phase of the HSR by promoting Hsf1's displacement from heat shock elements in target DNA. In apj1Δ cells, HSR attenuation is significantly impaired. Additionally, yeast cells lacking both Apj1 and the major JDP Ydj1 exhibit increased HSR activation even in non-stress conditions, indicating their distinct regulatory roles. Apj1's role in both nuclear protein quality control and Hsf1 regulation underscores its role in directly linking nuclear proteostasis to HSR regulation. Together these findings establish the nucleus as key stress-sensing signaling hub.
    DOI:  https://doi.org/10.1101/2025.04.14.648540
  5. FEBS J. 2025 Jul 14.
    Emerging roles for integrated stress response signaling in homeostasis.
    Shyama Nandakumar, Lydia Grmai, Deepika Vasudevan.
      Across phyla, organisms have evolved signaling mechanisms to cope with cell-intrinsic and -extrinsic stressors. The integrated stress response (ISR) is a prime example of such a mechanism and has well-defined roles from yeast to humans in dealing with stress burdens imposed by nutrient deprivation, protein misfolding, infectious agents, and oxidative stress. As with many fundamental cellular processes, the complexity of ISR signaling increases with evolutionary complexity. While single-celled organisms have been reported to utilize ISR signaling in the context of stress, multicellular organisms also rely on ISR signaling components for a number of homeostatic functions. The role of ISR signaling in the absence of obvious stressors is less well-studied, though useful insights into this can be extrapolated from prior studies using loss-of-function mutants in model organisms. This review summarizes the known (and inferred) homeostatic roles for ISR signaling components and speculates on cellular functions and principles that might require stress-adaptive mechanisms such as ISR signaling to maintain homeostasis.
    Keywords:  ATF4; ISR; homeostasis; stress
    DOI:  https://doi.org/10.1111/febs.70166
  6. bioRxiv. 2025 Jun 16. pii: 2025.06.11.659168. [Epub ahead of print]
    Stress testing reveals selective vulnerabilities in protein homeostasis.
    Berent Aldikacti, Hidayet Putun, Vishal Sarsani, Rilee Zeinert, Patrick Flaherty, Peter Chien.
      Protein quality control (PQC) systems are essential for cellular resilience to proteotoxic stress. Despite intensive study for decades, functional redundancies in the system obscure the contributions of the collectively important individual genes. Here, we leverage transposon sequencing across bacteria strains lacking key chaperones and proteases to reveal hidden determinants of stress response in protein homeostasis. By profiling fitness under multiple proteotoxic stresses, we uncover stress-specific vulnerabilities and reveal how major players of PQC mask correlations between transcriptomic responses and gene fitness. As an illustration of unexpected connections, we identify a heat-specific synthetic lethality between the disaggregase ClpB and DNA Polymerase I (PolA) mediated by persistent aggregation of the RecA recombinase and toxic persistence of the heat shock regulon. Our findings reveal that stress-induced aggregation is not broadly toxic. Rather, it becomes lethal in specific genetic or environmental contexts due to the depletion of components only needed in those specific circumstances. This work presents a framework to reveal normally hidden fragility in stress responses using gene fitness scores adaptable to a variety of systems.
    DOI:  https://doi.org/10.1101/2025.06.11.659168
  7. bioRxiv. 2025 Jun 28. pii: 2025.06.25.661590. [Epub ahead of print]
    Chaperone saturation mediates translation and protein folding efficiency.
    Andrew T Martens, Vincent J Hilser.
      Whether the emergence of a nascent protein from the ribosome and the formation of structural elements are synchronized has been a longstanding question (Chaney and Clark, 2015; Deane and Saunders, 2011; Levinthal, 1968; Marin, 2008; Sauna and Kimchi-Sarfaty, 2011; Spencer and Barral, 2012; Tsai et al., 2008; Zhang and Ignatova, 2011). Paradoxically, kinetically efficient translation can induce mis-folding and aggregation despite the presence of molecular chaperones (Siller et al., 2010; Spencer et al., 2012), which in Escherichia coli are induced by unfolded protein (Parsell and Sauer, 1989) via σ 32 (Craig and Gross, 1991). The molecular mechanisms mediating translation efficiency and protein folding efficiency remain poorly understood. Using ribosome profiling (Ingolia et al., 2009) and protein quantitation, we show that synonymous changes to Firefly Luciferase ( Luc ) mRNA have a direct effect on its translation efficiency. These changes alone cause up to a 70-fold difference in Luc protein levels. However, increased Luc protein is met with at most a ∼2-fold increase in chaperone levels, revealing that the σ 32 transcriptional response has saturable properties. This response is found to be poised near its midpoint (where it is most sensitive to perturbation) when Luc mRNA has an intermediate translation efficiency. These results suggest not only that chaperone saturation limits the ability of cells to maintain protein folding homeostasis when challenged with highly efficient translation, but that translation efficiency and protein folding efficiency evolved for mutual sensitivity.
    DOI:  https://doi.org/10.1101/2025.06.25.661590
  8. bioRxiv. 2025 Jun 26. pii: 2025.06.23.660251. [Epub ahead of print]
    Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells.
    Prerona Bora, Mashiat Zaman, Samantha Oviedo, Sergei Kutseikin, Nicole Madrazo, Prakhyat Mathur, Meera Pannikkat, Sophia Krasny, Alan Chu, Kristen A Johnson, Danielle A Grotjahn, Timothy E Shutt, R Luke Wiseman.
      Pathogenic variants in the mitochondrial outer membrane GTPase MFN2 cause the peripheral neuropathy Charcot-Marie-Tooth Type 2A (CMT2A). These mutations disrupt MFN2-dependent regulation of diverse aspects of mitochondrial biology including organelle morphology, motility, mitochondrial-endoplasmic reticulum (ER) contacts (MERCs), and respiratory chain activity. However, no therapies currently exist to mitigate the mitochondrial dysfunction linked to genetic deficiencies in MFN2. Herein, we performed a drug repurposing screen to identify compounds that selectively activate the integrated stress response (ISR) - the predominant stress-responsive signaling pathway responsible for regulating mitochondrial morphology and function. This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. We show that treatment with these compounds promotes adaptive, ISR-dependent remodeling of mitochondrial morphology and protects mitochondria against genetic and chemical insults. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2 -deficient cells. These results demonstrate the potential for pharmacologic HRI activation as a viable strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency.
    DOI:  https://doi.org/10.1101/2025.06.23.660251
  9. bioRxiv. 2025 May 10. pii: 2025.05.10.653282. [Epub ahead of print]
    Scouring the human Hsp70 network uncovers diverse chaperone safeguards buffering TDP-43 toxicity.
    Edward M Barbieri, Miriam Linsenmeier, Katherine R Whiteman, Yan Cheng, Sylvanne Braganza, Katie E Copley, Paola Miranda-Castrodad, Brennen Lewis, Kevin Villafañe, Defne A Amado, Beverly L Davidson, James Shorter.
      Cytoplasmic aggregation and concomitant dysfunction of the prion-like, RNA-binding protein TDP-43 underpin several fatal neurodegenerative diseases, including amyotrophic lateral sclerosis. To elucidate endogenous defenses, we systematically scoured the entire human Hsp70 network for buffers of TDP-43 toxicity. We identify 30 J-domain proteins (2 DNAJAs, 10 DNAJBs, 18 DNAJCs), 6 Hsp70s, and 5 nucleotide-exchange factors that mitigate TDP-43 toxicity. Specific chaperones reduce TDP-43 aggregate burden and detoxify diverse synthetic or disease-linked TDP-43 variants. Sequence-activity mapping unveiled unexpected, modular mechanisms of chaperone-mediated protection. Typically, DNAJBs collaborate with Hsp70 to suppress TDP-43 toxicity, whereas DNAJCs act independently. In human cells, specific chaperones increase TDP-43 solubility and enhance viability under proteotoxic stress. Strikingly, spliceosome-associated DNAJC8 and DNAJC17 retain TDP-43 in the nucleus and promote liquid-phase behavior. Thus, we disambiguate a diverse chaperone arsenal embedded in the human proteostasis network that counters TDP-43 toxicity and illuminate mechanistic gateways for therapeutic intervention in TDP-43 proteinopathies.
    DOI:  https://doi.org/10.1101/2025.05.10.653282
  10. JCI Insight. 2025 Jul 15. pii: e188459. [Epub ahead of print]
    Chronic integrated stress response causes dysregulated cholesterol synthesis in white matter disease.
    Karin Lin, Nina Ly, Rejani B Kunjamma, Ngoc Vu, Bryan King, Holly M Robb, Eric G Mohler, Janani Sridar, Qi Hao, José Zavala-Solorio, Chunlian Zhang, Varahram Shahryari, Nick van Bruggen, Caitlin F Connelly, Bryson D Bennett, James J Lee, Carmela Sidrauski.
      Maladaptive integrated stress response (ISR) activation is observed in human diseases of the brain. Genetic mutations of eIF2B, a critical mediator of protein synthesis, cause chronic pathway activation resulting in a leukodystrophy but the precise mechanism is unknown. We generated N208Y eIF2Bα mice and found that this metabolite binding mutation leads to destabilization of eIF2Bα, a systemic ISR, and neonatal lethality. 2BAct, an eIF2B activator, rescued lethality and significantly extended the lifespan of this severe model, underscoring its therapeutic potential in pediatric disease. Continuous treatment was required for survival, as withdrawal led to ISR induction in all tissues and rapid deterioration, thereby providing a model to assess the impact of the ISR in vivo by tuning drug availability. Single nuclei RNA-sequencing of the CNS identified astrocytes, oligodendrocytes, and ependymal cells as the cell types most susceptible to eIF2B dysfunction and revealed dysfunctional maturation of oligodendrocytes. Moreover, ISR activation decreased cholesterol biosynthesis, a process critical for myelin formation and maintenance. As such, persistent ISR engagement may contribute to pathology in other demyelinating diseases.
    Keywords:  Cell biology; Cholesterol; Demyelinating disorders; Metabolism; Mouse models; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.188459
  11. bioRxiv. 2025 Jun 18. pii: 2025.06.18.660458. [Epub ahead of print]
    Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
    Rebecca Cornell, Ava Handley, Roger Pocock.
      Animals integrate environmental and internal cues to maintain homeostasis and health. The mitochondrial stress response is an essential cytoprotective mechanism, and priming its activation provides a survival advantage. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signalling from carbon dioxide sensing neurons to govern a non-canonical mitochondrial stress response in the intestine. This stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. GCY-9 loss disrupts pathogen avoidance, leading to indiscriminate feeding. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset risks associated with this behaviour. Thus, environmental sensing by peripheral neurons can pre-emptively enhance systemic mitochondrial function in response to metabolic uncertainty.
    One-Sentence Summary: Protecting mitochondria by integrating environmental signals.
    DOI:  https://doi.org/10.1101/2025.06.18.660458
  12. Cell Stress Chaperones. 2025 Jul 11. pii: S1355-8145(25)00037-9. [Epub ahead of print] 100092
    Heat-Induced Phosphatidylserine Changes Drive HSPA1A's Plasma Membrane Localization.
    Jensen Low, Rachel Altman, Allen Badolian, Azalea Blythe Cuaresma, Carolina Briseño, Uri Keshet, Oliver Fiehn, Robert V Stahelin, Nikolas Nikolaidis.
      HSPA1A is a molecular chaperone crucial in cell survival. In addition to its cytosolic functions, HSPA1A translocates to heat-shocked and cancer cells' plasma membrane (PM). In cancer, PM-localized HSPA1A (mHSPA1A) is associated with increased tumor aggressiveness and therapeutic resistance, suggesting that preventing its membrane localization could have therapeutic value. This translocation depends on HSPA1A's interaction with PM phospholipids, including phosphatidylserine (PS). Although PS binding regulates HSPA1A's membrane localization, the exact trigger for this movement remains unclear. Given that lipid modifications are a cancer hallmark, we hypothesized that PS is a crucial lipid driving HSPA1A translocation and that heat-induced changes in PS levels trigger HSPA1A's PM localization in response to heat stress. We tested this hypothesis using pharmacological inhibition and RNA interference (RNAi) targeting PS synthesis, combined with confocal microscopy, lipidomics, and western blotting. Lipidomic analysis and PS-specific biosensors confirmed a heat shock-induced PS increase, peaking immediately post-stress. Inhibition of PS synthesis with fendiline and RNAi significantly reduced HSPA1A's PM localization, while depletion of cholesterol or fatty acids had minimal effects, confirming specificity for PS. Further experiments showed that PS saturation and elongation changes did not significantly impact HSPA1A's PM localization, indicating that the total PS increase, rather than specific PS species, is the critical factor. These findings reshape current models of HSPA1A trafficking, demonstrating that PS is a crucial regulator of HSPA1A's membrane translocation during the heat shock response. This work offers new insights into lipid-regulated protein trafficking and highlights the importance of PS in controlling cellular responses to stress.
    Keywords:  Chaperone trafficking; Lipidomics; Membrane lipid remodeling; Protein-lipid interactions; Stress response
    DOI:  https://doi.org/10.1016/j.cstres.2025.100092
  13. iScience. 2025 Jul 18. 28(7): 112925
    NRF2 regulates lipid droplet dynamics to prevent lipotoxicity.
    Christopher T Prevost, William B Gansereit, David F Kashatus.
      Lipid droplets (LDs) are dynamic organelles comprising a neutral lipid core encapsulated by a phospholipid monolayer. LD structure and function are influenced by a variety of intrinsic and extrinsic signals, and cells alter LD content and distribution to adapt to their environment. Here, we show that LD content increases in response to stabilization of the transcription factor NRF2 under conditions of lipotoxic stress. Notably, NRF2 activity leads to increased expression of the G0S2, a protein that inhibits ATGL, the enzyme responsible for degradation of triacylglycerol and the release of fatty acids from LDs. Importantly, stabilization of NRF2 in the absence of stress is sufficient to increase LD content, and inhibition of ATGL partially rescues the impact of NRF2 deletion on stress-induced ferroptosis. These data support a model in which stress-induced NRF2 stabilization protects cells against lipotoxicity in part through the sequestration of fatty acids in lipid droplets.
    Keywords:  Biochemistry; Biological sciences; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112925
  14. bioRxiv. 2025 Jun 17. pii: 2025.06.13.659610. [Epub ahead of print]
    ER tethering and active transport govern condensate diffusion during hyperosmotic stress.
    Bisal Halder, Guoming Gao, Armin Ahnoud, Shelby Stakenas, Emily R Sumrall, Nils G Walter.
       Background: Hyperosmotic shock and the resulting cell volume compression are commonly experienced by organs such as the kidneys, causing rapid formation of hyperosmotic phase separation (HOPS) condensates in the cytoplasm and nucleoplasm. Although the tight relationship between hyperosmotic shock and condensation has been characterized, the dynamics of biomolecular condensates in hyperosmotically compressed cells and their regulatory mechanisms remain largely unknown.
    Results: We used live-cell single-particle tracking (SPT) across different time scales to systematically characterize the dynamics of HOPS condensates formed by model protein mRNA decapping enzyme 1A (DCP1A). We found that HOPS condensates predominantly exhibited sub-diffusion rather than free diffusion, whereas some (∼2%) exhibited short super-diffusion. Using tools measuring spatial accessibility inside cells and fluorescence labels for specific cellular organelles, we further revealed the origins of sub-diffusion and super-diffusion as endoplasmic reticulum (ER) attachment and coupling to microtubule-dependent active transport, respectively. Further, we reconstructed an accessibility map of the hyperosmotically compressed cell from trajectories of genetically encoded multimeric nanoparticles (GEMs), revealing that the cytoplasm of a compressed cell remains highly accessible without significant local corrals.
    Conclusions: In contrast to prior portrayals of the cytosolic space as static and constrained, our data suggest that the cytosol of a hyperosmotically compressed cell remains dynamic and accessible. Meanwhile, hyperosmotic and potentially other condensates can be spatially organized through docking to membrane structures, with intermittent episodes of long-range transport. These insights broaden our understanding of the physical environment within cells under hyperosmotic shock and provide a model for spatiotemporal organization of condensates via docking or coupling to existing cellular structures and processes.
    DOI:  https://doi.org/10.1101/2025.06.13.659610
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