bims-ginsta Biomed News
on Genome instability
Issue of 2025–06–29
33 papers selected by
Jinrong Hu, National University of Singapore
  1. Eomes directs the formation of spatially and functionally diverse extraembryonic hematovascular tissues.
  2. Epiblast-derived CX3CR1+ progenitors generate cardiovascular cells during cardiogenesis.
  3. Mechanosensitive PIEZO2 channels shape coronary artery development.
  4. Spatiotemporal orchestration of mitosis by cyclin-dependent kinase.
  5. Single-cell and spatiotemporal profile of ovulation in the mouse ovary.
  6. PLK-1 suppresses centrosome maturation and microtubule polymerization to ensure faithful oocyte meiosis.
  7. Apical size reduction by macropinocytosis alleviates tissue crowding.
  8. Mechanical cues polarize ADIP protein complexes to control vertebrate morphogenesis and wound healing.
  9. The DNA replication checkpoint limits Okazaki fragment accumulation to protect and restart stalled forks.
  10. Maturation of human cardiac organoids enables complex disease modeling and drug discovery.
  11. WIP1 mutations suppress DNA damage triggered bypass of the mitotic timer.
  12. A host organelle integrates stolen chloroplasts for animal photosynthesis.
  13. Automorphy as a self-organizing DPP-dependent process that translates patterns into mechanical programs during Drosophila embryogenesis.
  14. Hallmarks of stem cell aging.
  15. AIMP3 maintains cardiac homeostasis by regulating the editing activity of methionyl-tRNA synthetase.
  16. Hoxb genes determine the timing of cell ingression by regulating cell surface fluctuations during zebrafish gastrulation.
  17. A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics.
  18. A Dock8-dependent mechanosensitive central actin pool maintains T cell shape and protects nucleus during migration.
  19. Age-dependent accumulation of mitochondrial tRNA mutations in mouse kidneys linked to mitochondrial kidney diseases.
  20. Autophagy-targeted NBR1-p62/SQSTM1 complexes promote breast cancer metastasis by sequestering ITCH.
  21. The PURB-HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation.
  22. Mouse radial spoke 3 is a metabolic and regulatory hub in cilia.
  23. Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22.
  24. Systematic profiling reveals betaine as an exercise mimetic for geroprotection.
  25. RNA codon expansion via programmable pseudouridine editing and decoding.
  26. Self-organization of sinusoidal vessels in pluripotent stem cell-derived human liver bud organoids.
  27. Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD.
  28. Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation.
  29. PEX14 condensates recruit receptor and cargo pairs for peroxisomal protein import.
  30. Podocyte YAP and TAZ hyperactivation drives glomerular epithelial proliferative diseases in mice and humans.
  31. Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.
  32. External strain on the plasma membrane is relayed to the endoplasmic reticulum by membrane contact sites and alters cellular energetics.
  33. Sequestration of ribosome biogenesis factors in HSV-1 nuclear aggregates revealed by spatially resolved thermal profiling.
  1. Dev Cell. 2025 Jun 20. pii: S1534-5807(25)00333-8. [Epub ahead of print]
    Eomes directs the formation of spatially and functionally diverse extraembryonic hematovascular tissues.
    Bart Theeuwes, Luke T G Harland, Alexandra M Bisia, Ita Costello, Mai-Linh N Ton, Tim Lohoff, Stephen J Clark, Ricard Argelaguet, Nicola K Wilson, Wolf Reik, Elizabeth K Bikoff, Elizabeth J Robertson, Berthold Göttgens.
      During mouse gastrulation, extraembryonic mesoderm (ExEM) contributes to the extraembryonic yolk sac (YS) and allantois, both of which are essential for successful gestation. Although the genetic networks coordinating intra-embryonic mesodermal subtype specification are well studied, ExEM diversification remains poorly understood. Here, we identify that embryoid body (EB) in vitro differentiation generates distinct lineages of mesodermal cells, matching YS and allantois development. Combining in vitro and in vivo mouse models, we discover that Eomesodermin (Eomes) controls the formation of YS-fated ExEM but is dispensable for allantois formation. Furthermore, simultaneous disruption of Eomes and T impedes the specification of any YS or allantois mesoderm, indicating compensatory roles for T during allantois formation upon Eomes depletion. Our study highlights previously unrecognized functional and mechanistic diversity in ExEM diversification and endothelial development and introduces a tractable EB model to dissect the signaling pathways and transcriptional networks driving the formation of key extraembryonic tissues.
    Keywords:  Eomes; allantois; embryogenesis; embryonic stem cell models; endothelial development; extraembryonic mesoderm; scRNA + ATAC-seq; scRNA-seq; single-cell analysis; yolk sac
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.001
  2. EMBO J. 2025 Jun 23.
    Epiblast-derived CX3CR1+ progenitors generate cardiovascular cells during cardiogenesis.
    Kyuwon Cho, Mark Andrade, S Khodayari Khodayari, Christine Lee, Seongho Bae, Sangsung Kim, Jin Eyun Kim, Young-Sup Yoon.
      CX3CR1+ cells generate tissue macrophages in the developing heart and play cardioprotective roles in response to ischemic injuries in the adult heart. However, the origin and fate of CX3CR1+ cells during cardiogenesis remain unclear. Here, we performed genetic lineage tracing of CX3CR1+ cells and their progeny (termed Cx3cr1 lineage cells) in the mouse and demonstrated that they emerge from a subset of epiblast cells at embryonic day E6.5 and contribute to the parietal endoderm cells at E7.0. At E8.0-9.5 of development, Cx3cr1 lineage cells produced cardiomyocytes and endothelial cells via both de novo differentiation and fusion with pre-existing cardiomyocytes or endothelial cells, respectively. Cx3cr1 lineage cells persisted in the adult heart, comprising ~13% of cardiomyocytes and ~31% of endothelial cells. Additionally, CX3CR1+ cells differentiated from mouse embryonic stem cells generated cardiomyocytes, endothelial cells, and macrophages in vitro, ex vivo, and in vivo. Single-cell RNA sequencing revealed that Cx3cr1+ cells represent an intermediate cell population transitioning from embryonic stem cells to mesoderm. Taken together, embryonic CX3CR1+ cells constitute a multipotent epiblast-derived progenitor population that contributes not only to the formation of macrophages, but also of cardiomyocytes and endothelial cells.
    Keywords:  CX3CR1; Cardiogenesis; Cardiomyocyte; Endothelial Cells; Genetic Lineage Tracing
    DOI:  https://doi.org/10.1038/s44318-025-00488-z
  3. Nat Cardiovasc Res. 2025 Jun 27.
    Mechanosensitive PIEZO2 channels shape coronary artery development.
    Mireia Pampols-Perez, Carina Fürst, Oscar Sánchez-Carranza, Elena Cano, Jonathan Alexis Garcia-Contreras, Lisa Mais, Wenhan Luo, Sandra Raimundo, Eric L Lindberg, Martin Taube, Arnd Heuser, Anje Sporbert, Dagmar Kainmueller, Miguel O Bernabeu, Norbert Hübner, Holger Gerhardt, Gary R Lewin, Annette Hammes.
      Coronary arteries develop under constant mechanical stress. However, the role of mechanosensitive ion channels in this process remains poorly understood. Here we show that the ion channel PIEZO2, which responds to mechanical stimuli, is expressed in specific coronary endothelial cell populations during a critical phase of coronary vasculature remodeling. These Piezo2+ coronary endothelial cells show distinct transcriptional profiles and have mechanically activated ionic currents. Strikingly, PIEZO2 loss-of-function mouse embryos and mice with human pathogenic variants of PIEZO2 show abnormal coronary vessel development and cardiac left ventricular hyperplasia. We conclude that an optimal balance of PIEZO2 channel function contributes to proper coronary vessel formation, structural integrity and remodeling, and is likely to support normal cardiac function. Our study highlights the importance of mechanical cues in cardiovascular development and suggests that defects in this mechanosensing pathway may contribute to congenital heart conditions.
    DOI:  https://doi.org/10.1038/s44161-025-00677-3
  4. Nature. 2025 Jun 25.
    Spatiotemporal orchestration of mitosis by cyclin-dependent kinase.
    Nitin Kapadia, Paul Nurse.
      Mitotic onset is a critical transition for eukaryotic cell proliferation. The commonly held view of mitotic control is that the master regulator, cyclin-dependent kinase (CDK), is first activated in the cytoplasm, at the centrosome, initiating mitosis1-3. Bistability in CDK activation ensures that the transition is irreversible, but how this unfolds in a spatially compartmentalized cell is unknown4-8. Here, using fission yeast, we show that CDK is first activated in the nucleus, and that the bistable responses differ markedly between the nucleus and the cytoplasm, with a stronger response in the nucleus driving mitotic signal propagation from there to the cytoplasm. Abolishing cyclin-CDK localization to the centrosome led to activation occurring only in the nucleus, spatially uncoupling the nucleus and cytoplasm mitotically, suggesting that centrosomal cyclin-CDK acts as a 'signal relayer'. We propose that the key mitotic regulatory system operates in the nucleus in proximity to DNA, which enables incomplete DNA replication and DNA damage to be effectively monitored to preserve genome integrity and to integrate ploidy within the CDK control network. This spatiotemporal regulatory framework establishes core principles for control of the onset of mitosis and highlights that the CDK control system operates within distinct regulatory domains in the nucleus and cytoplasm.
    DOI:  https://doi.org/10.1038/s41586-025-09172-y
  5. PLoS Biol. 2025 Jun;23(6): e3003193
    Single-cell and spatiotemporal profile of ovulation in the mouse ovary.
    Ruixu Huang, Caroline E Kratka, Jeffrey Pea, Cai McCann, Jack Nelson, John P Bryan, Luhan T Zhou, Daniela D Russo, Emily J Zaniker-Gomez, Achla H Gandhi, Alex K Shalek, Brian Cleary, Samouil L Farhi, Francesca E Duncan, Brittany A Goods.
      Ovulation is a spatiotemporally coordinated process that involves several tightly controlled events, including oocyte meiotic maturation, cumulus expansion, follicle wall rupture and repair, and ovarian stroma remodeling. To date, no studies have detailed the precise window of ovulation at single-cell resolution. Here, we performed parallel single-cell RNA-seq and spatial transcriptomics on paired mouse ovaries across an ovulation time course to map the spatiotemporal profile of ovarian cell types. We show that major ovarian cell types exhibit time-dependent transcriptional states enriched for distinct functions and have specific localization profiles within the ovary. We also identified gene markers for ovulation-dependent cell states and validated these using orthogonal methods. Finally, we performed cell-cell interaction analyses to identify ligand-receptor pairs that may drive ovulation, revealing previously unappreciated interactions. Taken together, our data provides a rich and comprehensive resource of murine ovulation that can be mined for discovery by the scientific community.
    DOI:  https://doi.org/10.1371/journal.pbio.3003193
  6. J Cell Biol. 2025 Sep 01. pii: e202503080. [Epub ahead of print]224(9):
    PLK-1 suppresses centrosome maturation and microtubule polymerization to ensure faithful oocyte meiosis.
    Juhi G Narula, Sarah M Wignall.
      Sexual reproduction relies on meiosis, a specialized cell division program that produces haploid gametes. Oocytes of most organisms lack centrosomes, and therefore chromosome segregation is mediated by acentrosomal spindles. Here, we explore the role of Polo-like kinase 1 (PLK-1) in Caenorhabditiselegans oocytes, revealing mechanisms that ensure the fidelity of this unique form of cell division. Previously, PLK-1 was shown to be required for nuclear envelope breakdown and chromosome segregation in oocytes. We now find that PLK-1 is also required for establishing and maintaining acentrosomal spindle organization and for preventing excess microtubule polymerization in these cells. Additionally, our studies revealed an unexpected new role for this essential kinase. While PLK-1 is known to be required for centrosome maturation during mitosis, we found that either removal of PLK-1 from oocytes or inhibition of its kinase activity caused premature recruitment of pericentriolar material to the sperm-provided centrioles following fertilization. Thus, PLK-1 suppresses centrosome maturation during oocyte meiosis, which is opposite to its role in mitosis. Taken together, our work identifies PLK-1 as a key player that promotes faithful acentrosomal meiosis in oocytes and demonstrates that its catalytic activity is required for carrying out these important roles.
    DOI:  https://doi.org/10.1083/jcb.202503080
  7. Nat Commun. 2025 Jun 23. 16(1): 5338
    Apical size reduction by macropinocytosis alleviates tissue crowding.
    Enzo Bresteau, Eve E Suva, Christopher Revell, Osama A Hassan, Aline Grata, Jennifer Sheridan, Jennifer Mitchell, Constadina Arvanitis, Farida Korobova, Sarah Woolner, Oliver E Jensen, Brian Mitchell.
      Tissue crowding represents a critical challenge to epithelial tissues, which often respond via the irreversible process of live cell extrusion. We report that apical size reduction via macropinocytosis serves as a malleable and less destructive form of tissue remodeling that can alleviate the need for cell loss. We find that macropinocytosis is triggered by tissue crowding via mechanosensory signaling, leading to substantial internalization of apical membrane. This drives a reduction in apical surface which alleviates crowding. We report that this mechanism regulates the long-term organization of the developing epithelium and controls the timing of proliferation-induced cell extrusion. Additionally, we observe a wave of macropinocytosis in response to acute external compression. In both scenarios, inhibiting macropinocytosis induces a dramatic increase in cell extrusion suggesting cooperation between cell extrusion and macropinocytosis in response to both developmental and external compression. Our findings implicate macropinocytosis as an important regulator of dynamic epithelial remodeling.
    DOI:  https://doi.org/10.1038/s41467-025-60724-2
  8. Curr Biol. 2025 Jun 20. pii: S0960-9822(25)00685-2. [Epub ahead of print]
    Mechanical cues polarize ADIP protein complexes to control vertebrate morphogenesis and wound healing.
    Chih-Wen Chu, Satheeja Santhi Velayudhan, Jakob H Schauser, Sapna Krishnakumar, Stephanie Yang, Keiji Itoh, Dominique Alfandari, Ala Trusina, Sergei Y Sokol.
      Planar cell polarity (PCP) is a phenomenon of coordinated cell orientation in many epithelia and is required for early morphogenetic events, such as vertebrate gastrulation or neural tube closure, that place embryonic tissues in their proper locations. Known PCP complexes segregate to opposite edges of each cell due to regulatory feedback interactions; however, whether and how PCP is connected to the tension-sensing machinery has been elusive. Here, we observed dynamic polarization of afadin- and α-actinin-interacting protein (ADIP) in the epithelia adjacent to the involuting marginal zone and the folding neural plate of Xenopus embryos, suggesting that it is controlled by mechanical cues. Supporting this hypothesis, ADIP puncta relocated in response to the pulling forces of neighboring ectoderm cells undergoing apical constriction. Moreover, ADIP puncta rapidly polarized in embryos subjected to stretching and during embryonic wound healing. ADIP formed a mechanosensitive complex with the PCP protein Diversin that was distinct from known core PCP complexes and required for wound repair. We propose that mechanically controlled planar polarization of the ADIP-Diversin complex guides cell behaviors in normal morphogenesis and during wound healing.
    Keywords:  Ankrd6; Diversin; Msd1; SSX2IP; actomyosin; apical constriction; mechanotransduction; neuroectoderm; planar cell polarity; tension sensor
    DOI:  https://doi.org/10.1016/j.cub.2025.05.069
  9. Mol Cell. 2025 Jun 24. pii: S1097-2765(25)00501-5. [Epub ahead of print]
    The DNA replication checkpoint limits Okazaki fragment accumulation to protect and restart stalled forks.
    Berta Canal, Agostina P Bertolin, Giselle C Lee, Lucy S Drury, Masashi Minamino, John F X Diffley.
      Understanding how DNA replication forks stall and restart and how the DNA replication checkpoint prevents irreversible fork collapse in molecular detail are crucial for understanding how cells maintain stable genomes and how they prevent the genetic instability that drives cancer. Here, we describe the reconstitution of fork stalling and restart with purified budding yeast proteins. After nucleotide depletion, leading-strand DNA synthesis quickly stops but CMG helicase continues to unwind, and Okazaki fragments continue to initiate on the lagging strand. Incomplete Okazaki fragments sequester PCNA, RFC, and DNA polymerases δ and ε, which prevents normal DNA synthesis restart and exposes nascent DNA to nuclease attack. The DNA replication checkpoint restrains fork progression, which limits this sequestration, protecting stalled forks from collapse and ensuring restart.
    Keywords:  DNA polymerase α; DNA polymerase δ; DNA polymerase ε; DNA replication checkpoint; DNA replication fork stabilization; Okazaki fragments; PCNA; RFC; RPA exhaustion; replication fork collapse
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.001
  10. Nat Cardiovasc Res. 2025 Jun 25.
    Maturation of human cardiac organoids enables complex disease modeling and drug discovery.
    Mark W Pocock, Janice D Reid, Harley R Robinson, Natalie Charitakis, James R Krycer, Simon R Foster, Rebecca L Fitzsimmons, Mary Lor, Lynn A C Devilée, Christopher A P Batho, Natasha Tuano, Sara E Howden, Katerina Vlahos, Kevin I Watt, Adam T Piers, Kaitlyn Bibby, James W McNamara, Rebecca Sutton, Valerii Iaprintsev, Jacob Mathew, Holly K Voges, Patrick R J Fortuna, Sebastian Bass-Stringer, Celine Vivien, James Rae, Robert G Parton, Anthony B Firulli, Leszek Lisowski, Hannah Huckstep, Sean J Humphrey, Sean Lal, Igor E Konstantinov, Robert G Weintraub, David A Elliott, Mirana Ramialison, Enzo R Porrello, Richard J Mills, James E Hudson.
      Maturation of human pluripotent stem (hPS) cell-derived cardiomyocytes is critical for their use as a model system. Here we mimic human heart maturation pathways in the setting of hPS cell-derived cardiac organoids (hCOs). Specifically, transient activation of 5' AMP-activated protein kinase and estrogen-related receptor enhanced cardiomyocyte maturation, inducing expression of mature sarcomeric and oxidative phosphorylation proteins, and increasing metabolic capacity. hCOs generated using the directed maturation protocol (DM-hCOs) recapitulate cardiac drug responses and, when derived from calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) mutant hPS cells exhibit a pro-arrhythmia phenotype. These DM-hCOs also comprise multiple cell types, which we characterize and benchmark to the human heart. Modeling of cardiomyopathy caused by a desmoplakin (DSP) mutation resulted in fibrosis and cardiac dysfunction and led to identifying the bromodomain and extra-terminal inhibitor INCB054329 as a drug mitigating the desmoplakin-related functional defect. These findings establish DM-hCOs as a versatile platform for applications in cardiac biology, disease and drug screening.
    DOI:  https://doi.org/10.1038/s44161-025-00669-3
  11. EMBO J. 2025 Jun 23.
    WIP1 mutations suppress DNA damage triggered bypass of the mitotic timer.
    Tomoaki Sobajima, Luke J Fulcher, Caleb Batley, Susanna J Alsop, Jonah Veakins, Francis A Barr.
      Prolonged mitosis results in the destruction of MDM2, initiating a p53-dependent G1 cell-cycle arrest in the absence of DNA damage. Here, we investigate how DNA damage earlier in the cell cycle affects this mitotic-timer response. We find that G2-DNA damage triggers highly penetrant bypass of mitosis and of the mitotic timer, generating tetraploid cells arrested in G1. Collapse of G2 to G1 after DNA damage is initiated by p21-mediated CDK2 inhibition and rendered irreversible by the destruction of G2/M-cyclins A and B. This behaviour is altered in cells with cancer-associated mutations in the p53-phosphatase WIP1 (PPM1D), which increase the threshold for DNA-damage signalling, enabling DNA-damaged G2 cells to enter mitosis with elevated levels of MDM2, thereby suppressing mitotic-timer-dependent G1 cell-cycle arrest. Importantly, neither WIP1 mutations nor knockout prevent p53-dependent G1-arrest in response to prolonged mitosis in the absence of DNA damage. Prolonged mitosis and G2-DNA damage thus promote p53-dependent G1 cell-cycle exit through discrete routes with differential requirements for WIP1 and genotoxic stress.
    Keywords:  Cell Cycle; Cell Cycle Checkpoints; DNA Damage; Mitosis
    DOI:  https://doi.org/10.1038/s44318-025-00495-0
  12. Cell. 2025 Jun 21. pii: S0092-8674(25)00637-3. [Epub ahead of print]
    A host organelle integrates stolen chloroplasts for animal photosynthesis.
    Corey A H Allard, Angus B Thies, Rishav Mitra, Patric M Vaelli, Olivia D Leto, Brittany L Walsh, Elise M J Laetz, Martin Tresguerres, Amy S Y Lee, Nicholas W Bellono.
      Eukaryotic life evolved over a billion years ago when ancient cells engulfed and integrated prokaryotes to become modern mitochondria and chloroplasts. Sacoglossan "solar-powered" sea slugs possess the ability to acquire organelles within a single lifetime by selectively retaining consumed chloroplasts that remain photosynthetically active for nearly a year. The mechanism for this "animal photosynthesis" remains unknown. Here, we discovered that foreign chloroplasts are housed within novel, host-derived organelles we term "kleptosomes." Kleptosomes use ATP-sensitive ion channels to maintain a luminal environment that supports chloroplast photosynthesis and longevity. Upon slug starvation, kleptosomes digest stored chloroplasts for additional nutrients, thereby serving as a food source. We leveraged this discovery to find that organellar retention and digestion of photosynthetic cargo has convergently evolved in other photosynthetic animals, including corals and anemones. Thus, our study reveals mechanisms underlying the long-term acquisition and evolutionary incorporation of intracellular symbionts into organelles that support complex cellular function.
    Keywords:  cell biology; endosymbiosis; evolution; kleptoplasty; organellar ion channels; photosynthetic animal
    DOI:  https://doi.org/10.1016/j.cell.2025.06.003
  13. Sci Adv. 2025 Jun 27. 11(26): eadv0311
    Automorphy as a self-organizing DPP-dependent process that translates patterns into mechanical programs during Drosophila embryogenesis.
    Baptiste Tesson, Stéphane A Vincent.
      Morphogens provide developing tissues with positional information to ensure coherent morphogenesis. Bone morphogenetic proteins (BMPs) initially form a gradient to pattern the dorsal domains of the Drosophila embryo. Here, we show that the BMP homolog decapentaplegic (DPP) endows dorsal domains with specific mechanical programs to organize morphogenesis. These domains self-organize using high local DPP activities, a process we call automorphy. Automorphy is key to inducing specific morphological changes while being faithful to the initial positional information. The BMP morphogen therefore uses a series of automorphic events to translate each position into physical potentials that later produce a contractile amnioserosa and a dorsal epidermis displaying plasticity. Plasticity allows cell elongation in wild-type embryos, and perturbations of cellular patterns reveal its crucial role in adapting to mechanical constraints. We propose that gradient formation and automorphy constitute complementary processes that allow BMPs to act as a morphogen in the Drosophila embryo.
    DOI:  https://doi.org/10.1126/sciadv.adv0311
  14. Cell Stem Cell. 2025 Jun 17. pii: S1934-5909(25)00226-7. [Epub ahead of print]
    Hallmarks of stem cell aging.
    Thomas A Rando, Anne Brunet, Margaret A Goodell.
      As organisms age, somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. Although stem cells are relatively shielded from some cellular aging mechanisms compared with their differentiated progeny, they remain vulnerable to both intrinsic and extrinsic stressors. In this review, we delineate five cardinal features that characterize aged stem cells and examine how these alterations underlie functional decline across well-studied stem cell compartments. These hallmarks not only provide insight into the aging process but also serve as promising targets for therapeutic strategies aimed at rejuvenating stem cell function and extending tissue health span.
    Keywords:  aging; differentiation; hematopoietic stem cells; heterogeneity; muscle stem cells; neural stem cells; quiescence; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2025.06.004
  15. Nat Cardiovasc Res. 2025 Jun 25.
    AIMP3 maintains cardiac homeostasis by regulating the editing activity of methionyl-tRNA synthetase.
    Anindhya S Das, Charles P Rabolli, Colton R Martens, Han-Kai Jiang, Yingshen Zhang, Aubree A Zimmer, Kevin Lin, Kedryn K Baskin, Juan D Alfonzo, Federica Accornero.
      In mammals, nine aminoacyl tRNA synthetases (ARSs) and three auxiliary proteins (ARS-interacting multifunctional proteins 1-3 (AIMP1-3)) form the multisynthetase complex (MSC), a molecular hub that provides a subset of aminoacylated tRNAs to the ribosome and partakes in translation-independent signaling. Knowledge of the role of AIMPs in organ physiology is currently limited. AIMP3 (also known as EEF1E1) was proposed to anchor methionyl tRNA synthetase (MetRS) in the complex and regulate protein synthesis through translation initiation and elongation. Here we show that a cardiomyocyte-specific conditional knockout of AIMP3 in mice leads to lethal cardiomyopathy. MetRS localization, aminoacylation efficiency and global protein synthesis were unaffected in our model, suggesting an alternative mechanism for the pathology. We found that AIMP3 is essential for homocysteine editing by MetRS, a reaction that is necessary for the maintenance of translation fidelity. Homocysteine accumulation induced reactive oxygen species production, protein aggregation, mitochondrial dysfunction, autophagy and ultimately cell death.
    DOI:  https://doi.org/10.1038/s44161-025-00670-w
  16. Development. 2025 Jun 15. pii: dev204261. [Epub ahead of print]152(12):
    Hoxb genes determine the timing of cell ingression by regulating cell surface fluctuations during zebrafish gastrulation.
    Yuuta Moriyama, Toshiyuki Mitsui, Carl-Philipp Heisenberg.
      During embryonic development, cell behaviors need to be tightly regulated in time and space. Yet how the temporal and spatial regulations of cell behaviors are interconnected during embryonic development remains elusive. To address this, we turned to zebrafish gastrulation, the process whereby dynamic cell behaviors generate the three principal germ layers of the early embryo. Here, we show that Hoxb cluster genes are expressed in a temporally collinear manner at the blastoderm margin, where mesodermal and endodermal (mesendoderm) progenitor cells are specified and ingress to form mesendoderm/hypoblast. Functional analysis shows that these Hoxb genes regulate the timing of cell ingression: under- or overexpression of Hoxb genes perturb the timing of mesendoderm cell ingression and, consequently, the positioning of these cells along the forming anterior-posterior body axis after gastrulation. Finally, we found that Hoxb genes control the timing of mesendoderm ingression by regulating cellular bleb formation and cell surface fluctuations in the ingressing cells. Collectively, our findings suggest that Hoxb genes interconnect the temporal and spatial pattern of cell behaviors during zebrafish gastrulation by controlling cell surface fluctuations.
    Keywords:  Bleb; Cell surface fluctuation; Gastrulation; Hox
    DOI:  https://doi.org/10.1242/dev.204261
  17. Nat Med. 2025 Jun 27.
    A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics.
    N Furer, N Rappoport, O Milman, S Tavor, A Lifshitz, A Bercovich, O Ben-Kiki, A Danin, M Kedmi, Z Shipony, D Lipson, E Meiri, G Yanai, S Shapira, N Arber, S Berdichevsky, J Tyner, S Joshi, D Landau, S Ganesan, N Dusaj, P Chamely, N Kaushansky, N Chapal-Ilani, R Shamir, A Tanay, L Shlush.
      With aging, deviation of human blood counts from their normal range accompanies the transition from health to disease. Hematopoietic stem and progenitor cells (HSPCs) deliver life-long multi-lineage output, but their variation across healthy humans with aging, and their diagnostic utility, haven't been characterized in depth thus far. To address this, we introduced an HSPC reference model using single-cell RNA profiling of circulating CD34+ HSPCs from 148 healthy age- and sex-diverse individuals. We characterized physiological circulating HSPC composition, showed that age-related myeloid bias is predominant in older men and defined age-related transcriptional signatures in lymphoid progenitors. We further demonstrated the potential of this resource to facilitate the diagnosis of myelodysplastic syndrome (MDS) from peripheral blood without bone marrow sampling, defining classes of patients with MDS and abnormal lymphocyte, basophil or granulocyte progenitor frequencies. Our resource provides insights into HSPC reference ranges across the lifespan and has the potential to facilitate the clinical applications of single-cell genomics in hematology.
    DOI:  https://doi.org/10.1038/s41591-025-03716-5
  18. Sci Immunol. 2025 Jun 26. eadt9239
    A Dock8-dependent mechanosensitive central actin pool maintains T cell shape and protects nucleus during migration.
    Connie Shen, Aysha Cerf, Jérémy Postat, Aanya Bhagrath, Mauricio Merino, Angela Mingarelli, Grace Barnes, Dhanesh Patel, Dakota Rogers, Vincent M Luo, Afnan Abu-Thuraia, Caitlin Schneider, Daniela F Quail, Abhinav Sharma, Woong-Kyung Suh, Allen Ehrlicher, Jean-François Côté, Judith N Mandl.
      Immune cells navigate through complex tissue architectures by extensive cellular deformation, low adhesion, and high cell velocities. Loss-of-function mutations in Dedicator of Cytokinesis 8 (Dock8) are associated with immunodeficiency as immune cells becoming entangled during migration through dense environments, but their migration on two-dimensional surfaces remains entirely intact. Here we investigated the specific cytoskeletal defect of Dock8-deficient activated T cells and describe a central pool of F-actin in wild-type murine and human T cells that is absent in Dock8 knockout T cells. The appearance of the central actin pool is mechanoresponsive and emerges only when cells are very confined. We identified mammalian sterile 20-like (Mst1) as a necessary component in this mechanosensitive pathway in addition to Dock8, allowing for cell shape integrity and survival during migration through complex environments. Our work shows that loss of the central actin pool results in greater nuclear deformation, accrual of DNA damage, and premature cell senescence.
    DOI:  https://doi.org/10.1126/sciimmunol.adt9239
  19. Nat Aging. 2025 Jun 27.
    Age-dependent accumulation of mitochondrial tRNA mutations in mouse kidneys linked to mitochondrial kidney diseases.
    Leping Zhang, Zhe Xu, Jia Jing, Guoshi Chai, Guanglei Xie, Yanfei Ru, Qunyu Lv, Xiang Zuo, Qian Zhang, Jiatong Chen, He Jin, Ning Liu, Minghua Kong, Bin Shen, Mingxi Liu, Lei Jiang, Xi Wang, Yanxiao Zhang, Min Jiang.
      Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are key drivers of mitochondrial diseases, yet their tissue-specific and cell-specific accumulation patterns during aging and the mechanistic links to pathology remain poorly understood. In this study, we employed DddA-derived cytosine base editor technology to generate three mouse models harboring distinct pathogenic mitochondrial tRNA mutations. These mutations exhibited age-dependent accumulation in the kidneys, leading to severe kidney defects that well recapitulate human mitochondrial kidney disease. Mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq) revealed unique heteroplasmy dynamics across different kidney cell types: podocytes exhibited a positive selection for mutant mtDNA, whereas tubular epithelial cells displayed neutral drift of mutations during aging. Integrative analyses combining mtscATAC-seq, single-cell RNA sequencing and spatially enhanced resolution omics sequencing further identified molecular changes in high-mutant defective cells, including increased AP-1 family transcription factor activity, tubular epithelial cell proliferation and immune activation, which contribute to disease progression. Our study underscores the importance of kidney function monitoring in patients with mitochondrial disease, particularly in older adults, and establishes robust preclinical models to facilitate the development of therapeutic strategies.
    DOI:  https://doi.org/10.1038/s43587-025-00909-y
  20. Nat Cell Biol. 2025 Jun 27.
    Autophagy-targeted NBR1-p62/SQSTM1 complexes promote breast cancer metastasis by sequestering ITCH.
    Gourish Mondal, Hugo Gonzalez, Timothy Marsh, Andrew M Leidal, Ariadne Vlahakis, Pravin R Phadatare, Sofı́a Bustamante Eguiguren, Michael Bruck, Akul Naik, Mark Jesus M Magbanua, Laura A Huppert, Arun P Wiita, Jeroen P Roose, Jennifer M Rosenbluth, Jayanta Debnath.
      Autophagy deficiency in breast cancer promotes metastasis through the accumulation of the autophagy cargo receptor NBR1. Here we show that autophagy normally suppresses breast cancer metastasis by enabling the clearance of NBR1-p62/SQSTM1 complexes that instruct p63-mediated pro-metastatic basal differentiation programmes. When autophagy is inhibited, the autophagy cargo receptors NBR1 and p62/SQSTM1 accumulate within biomolecular condensates in cells, which drives basal differentiation in both mouse and human breast cancer models. Mechanistically, these NBR1-p62/SQSTM1 complexes sequester ITCH, a ubiquitin ligase that degrades and negatively regulates p63 in breast cancer cells, thereby stabilizing and activating p63. Accordingly, mutant forms of NBR1 unable to sequester ITCH into NBR1-p62/SQSTM1 complexes do not promote basal differentiation and metastasis in vivo. Overall, our findings illuminate how proteostatic defects arising in the setting of therapeutic autophagy inhibition modulate epithelial lineage fidelity and metastatic progression.
    DOI:  https://doi.org/10.1038/s41556-025-01689-8
  21. Nat Struct Mol Biol. 2025 Jun 25.
    The PURB-HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation.
    Zhangchuan Xia, Ning Kon, Zhenyi Su, Jingjie Yi, Xu Hua, Hui Zhou, Zhiguo Zhang, Wei Gu.
      p53 executes its diverse functions through different transcriptional targets but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify purine-rich element binding protein B (PURB), a dual DNA/RNA-binding protein, which acts as a transcriptional corepressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers, and its knockdown induces p53-dependent activation of p21 but has no effect on other major promoters such as PUMA and MDM2. In contrast to other p53 corepressors, PURB can recognize a unique DNA element at the p21 promoter, with the loss of this element not affecting p53-mediated transactivation but abrogating the ability of p53 to recruit PURB to the p21 promoter for repression. Mechanistically, PURB requires its sequence-specific binding with long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) to exert its repressive role. In turn, HOTAIR interacts directly with EZH2 and, bridged by the PURB-HOTAIR complex, p53 can recruit the EZH2 histone methyltransferase to target promoters for transcriptional repression. Further analysis of p53 targets reveals several promoters that may serve as targets for PURB binding, suggesting that this mechanism of PURB-dependent promoter-specific regulation may not be limited to p21. These data establish a mode of lncRNA-mediated regulation of p53 transcription in a sequence-specific manner and reveal a previously unanticipated mechanism for acetylation-mediated promoter-specific regulation through a cis-regulatory element recognized by the PURB-HOTAIR complex.
    DOI:  https://doi.org/10.1038/s41594-025-01597-3
  22. Nat Struct Mol Biol. 2025 Jun 27.
    Mouse radial spoke 3 is a metabolic and regulatory hub in cilia.
    Yanhe Zhao, Kangkang Song, Amirrasoul Tavakoli, Long Gui, Angeles Fernandez-Gonzalez, Song Zhang, Petras P Dzeja, S Alex Mitsialis, Xuewu Zhang, Daniela Nicastro.
      Cilia are microtubule-based organelles that have important roles in cell sensing, signaling and motility. Recent studies have revealed the atomic structures of many multicomponent ciliary complexes, elucidating their mechanisms of action. However, little is known about the structure, proteome and function of full-length radial spoke 3 (RS3), a conserved complex that transmits mechanochemical signals to coordinate ciliary motility. Here, we combined single-particle cryo-electron microscopy, cryo-electron tomography, proteomic analysis and computational modeling to determine the three-dimensional structure and atomic model of RS3 from mouse respiratory cilia. We reveal all RS3 components, including regulatory and metabolic enzymes such as a protein kinase A subunit, adenylate kinases (AKs) and malate dehydrogenases. Furthermore, we confirm RS3 loss in AK7-deficient mice, which exhibit motility defects. Our findings identify RS3 as an important regulatory and metabolic hub that maintains sufficient adenosine triphosphate for sustained ciliary beating, providing insights into the etiology of ciliopathies.
    DOI:  https://doi.org/10.1038/s41594-025-01594-6
  23. Cell Chem Biol. 2025 Jun 13. pii: S2451-9456(25)00173-4. [Epub ahead of print]
    Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22.
    Wenjun Fan, Hester Liu, Gregory C Stachelek, Asma Begum, Catherine E Davis, Tony E Dorado, Glen Ernst, William C Reinhold, Busra Ozbek, Qizhi Zheng, Angelo M De Marzo, N V Rajeshkumar, James C Barrow, Marikki Laiho.
      Ribosome biosynthesis is a cancer vulnerability targeted by inhibiting RNA polymerase I (Pol I) transcription. We developed specific Pol I inhibitors that activate a ribotoxic stress pathway to uncover drivers of sensitivity. Integrating multi-omics and drug response data from a large cancer cell panel, we found that RPL22 frameshift mutations confer Pol I inhibitor sensitivity. Mechanistically, RPL22 interacts directly with 28S rRNA and mRNA splice junctions, acting as a splicing regulator. RPL22 deficiency, intensified by 28S rRNA sequestration, promotes splicing of its paralog RPL22L1 and the p53 negative regulator MDM4. Both chemical and genetic inhibition of rRNA synthesis broadly remodel mRNA splicing controlling hundreds of targets. Notably, RPL22-dependent alternative splicing is reversed by Pol I inhibition, revealing a non-canonical ribotoxic stress-initiated tumor suppressive pathway. This study uncovers a robust mechanism linking rRNA synthesis activity to splicing, coordinated by the ribosomal protein RPL22.
    Keywords:  MDM4; RPL22; RPL22L1; cancer; nucleolus; rRNA synthesis; ribosome biogenesis; small-molecule; splicing; therapeutics
    DOI:  https://doi.org/10.1016/j.chembiol.2025.05.012
  24. Cell. 2025 Jun 25. pii: S0092-8674(25)00635-X. [Epub ahead of print]
    Systematic profiling reveals betaine as an exercise mimetic for geroprotection.
    Lingling Geng, Jiale Ping, Ruochen Wu, Haoteng Yan, Hui Zhang, Yuan Zhuang, Taixin Ning, Jun Wang, Chuqian Liang, Jiachen Zhang, Qingqing Chu, Jing Zhang, Yifan Wen, Yaobin Jing, Shuhui Sun, Qin Qiao, Qian Zhao, Qianzhao Ji, Shuai Ma, Yusheng Cai, Yandong Zheng, Zhiran Zou, Zhiqing Diao, Mingheng Li, Hao Zhang, Jianli Hu, Liangzheng Fu, Wang Kang, Ruijun Bai, Hongkai Zhao, Sheng Zhang, Yingjie Ding, Jinghui Lei, Wei Wang, Yun Ji, Bo Gou, Guoqiang Sun, Jian Yin, Pengze Yan, Hao Li, Zehua Wang, Shikun Ma, Zunpeng Liu, Hezhen Shan, Qiaoran Wang, Tianling Cao, Shanshan Yang, Cui Wang, Ping Yang, Yanling Fan, Yanxia Ye, Jinghao Hu, Mengmeng Jiang, Ye Wang, Kan Liu, Yujing Li, Yuanxiang Li, Jingyi Li, Weimin Ci, Zi-Bing Jin, Xiaobing Fu, Xu Zhang, Guoguang Zhao, Juan Carlos Izpisua Belmonte, Si Wang, Moshi Song, Weiqi Zhang, Jing Qu, Guang-Hui Liu.
      Exercise has well-established health benefits, yet its molecular underpinnings remain incompletely understood. We conducted an integrated multi-omics analysis to compare the effects of acute vs. long-term exercise in healthy males. Acute exercise induced transient responses, whereas repeated exercise triggered adaptive changes, notably reducing cellular senescence and inflammation and enhancing betaine metabolism. Exercise-driven betaine enrichment, partly mediated by renal biosynthesis, exerts geroprotective effects and rescues age-related health decline in mice. Betaine binds to and inhibits TANK-binding kinase 1 (TBK1), retarding the kinetics of aging. These findings systematically elucidate the molecular benefits of exercise and position betaine as an exercise mimetic for healthy aging.
    Keywords:  ETS1; TBK1; aging; betaine; exercise; exercise immunology; exercise metabolism; inflammation; kidney; senescence
    DOI:  https://doi.org/10.1016/j.cell.2025.06.001
  25. Nature. 2025 Jun 25.
    RNA codon expansion via programmable pseudouridine editing and decoding.
    Jiangle Liu, Xueqing Yan, Hao Wu, Ziqin Ji, Ye Shan, Xinyan Wang, Yunfan Ran, Yichen Ma, Caitao Li, Yuchao Zhu, Ruichu Gu, Han Wen, Chengqi Yi, Peng R Chen.
      The incorporation of non-canonical amino acids (ncAAs) enables customized chemistry to tailor protein functions1-3. Genetic code expansion offers a general approach for ncAA encoding by reassigning stop codons as the 'blank' codon; however, it is not completely orthogonal to translation termination for cellular transcripts. Here, to generate more bona fide blank codons, we developed an RNA codon-expansion (RCE) strategy that introduces and decodes bioorthogonally assignable pseudouridine (Ψ) codons (ΨGA, ΨAA or ΨAG) on specified mRNA transcripts to incorporate ncAAs in mammalian cells. The RCE strategy comprises a programmable guide RNA4, an engineered decoder tRNA, and aminoacyl-tRNA synthetase. We first developed the RCE(ΨGA) system, which incorporates functional ncAAs into proteins via the ΨGA codon, demonstrating a higher translatome-wide and proteomic specificity compared with the genetic code expansion system. We further expanded our strategy to produce the RCE(ΨAA) and RCE(ΨAG) systems, with all three Ψ codon:(Ψ codon)-tRNAPyl pairs exhibiting mutual orthogonality. Moreover, we demonstrated that the RCE system cooperates compatibly with the genetic code expansion strategy for dual ncAA encoding. In sum, the RCE method utilized Ψ as a post-transcriptional 'letter' to encode and decode RNA codons in specific mRNA transcripts, opening a new route for genetic alphabet expansion and site-specific ncAA incorporation in eukaryotic cells.
    DOI:  https://doi.org/10.1038/s41586-025-09165-x
  26. Nat Biomed Eng. 2025 Jun 25.
    Self-organization of sinusoidal vessels in pluripotent stem cell-derived human liver bud organoids.
    Norikazu Saiki, Yasunori Nio, Yosuke Yoneyama, Shuntaro Kawamura, Kentaro Iwasawa, Eri Kawakami, Kohei Araki, Junko Fukumura, Tsuyoshi Sakairi, Tamaki Kono, Rio Ohmura, Masaru Koido, Masaaki Funata, Wendy L Thompson, Pamela Cruz-Encarnacion, Ya-Wen Chen, Takanori Takebe.
      The induction of tissue-specific vessels in in vitro living tissue systems remains challenging. Here, we directly differentiated human pluripotent stem cells into CD32b+ putative liver sinusoidal progenitors by dictating developmental pathways. By devising an inverted multilayered air-liquid interface culture, hepatic endoderm, septum mesenchyme, arterial and sinusoidal quadruple progenitors self-organize to generate and sustain hepatocyte-like cells neighboured by divergent endothelial subsets composed of CD32blowCD31high, LYVE1+STAB1+CD32bhighCD31lowTHBD-vWF- and LYVE1-THBD+vWF+ cells. WNT2 mediates sinusoidal-to-hepatic intercellular crosstalk potentiating hepatocyte differentiation and branched endothelial network formation. Intravital imaging reveals the iPS-cell-derived putative liver sinusoidal endothelial progenitor develops fully perfused human vessels with functional sinusoid-like features. Organoid-derived hepatocyte- and sinusoid-derived coagulation factors enable correction of in vitro clotting time with Factor V-, VIII-, IX- and XI-deficient plasma, and rescues the severe bleeding phenotype in haemophilia A mice on transplantation. Advanced organoid vascularization technology allows for interrogating key insights governing organ-specific vessel development, paving the way for coagulation disorder therapeutics.
    DOI:  https://doi.org/10.1038/s41551-025-01416-6
  27. Nat Metab. 2025 Jun 26.
    Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD.
    Wesley Huang, Yuezhong Zhang, Nupur K Das, Sumeet Solanki, Chesta Jain, Marwa O El-Derany, Imhoi Koo, Hannah N Bell, Noora Aabed, Rashi Singhal, Cristina Castillo, Kathryn Buscher, Yinzhi Ying, James Dimitroff, Ankit Sharma, Jiaqi Shi, Simon P Hogan, Michael K Dame, Peter D R Higgins, Justin A Colacino, Tae Gyu Oh, Jason R Spence, Andrew D Patterson, Andrew S Greenberg, Joel K Greenson, Asma Nusrat, Yatrik M Shah.
      Increased reactive oxygen species (ROS) levels are a hallmark of inflammatory bowel disease (IBD) and constitute a major mechanism of epithelial cell death. Approaches to broadly inhibit ROS have had limited efficacy in treating IBD. Here we show that lipid peroxidation contributes to the pathophysiology of IBD by promoting ferroptosis, an iron-dependent form of programmed cell death. Mechanistically, we provide evidence of heterocellular crosstalk between intestinal fibroblasts and epithelial cells. In IBD tissues and mouse models of chronic colitis, acyl-CoA synthetase long-chain family 4 (ACSL4) is overexpressed in fibroblasts. ACSL4 in fibroblasts reprograms lipid metabolism and mediates intestinal epithelial cell sensitivity to ferroptosis. In mouse models, overexpressing ACSL4 in fibroblasts results in increased intestinal epithelial ferroptosis and worsened colitis, while pharmacological inhibition or deletion of fibroblast ACSL4 ameliorates colitis. Our work provides a targeted approach to therapeutic antioxidant treatments for IBD.
    DOI:  https://doi.org/10.1038/s42255-025-01313-x
  28. Mol Cell. 2025 Jun 20. pii: S1097-2765(25)00472-1. [Epub ahead of print]
    Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation.
    Jiemin Nah, Sreya Mahendran, Baptiste Kerouanton, Liang Cui, Daniella H Hock, Alfredo Cabrera-Orefice, Kyle Dunlap, David Robinson, Desmond W H Tung, Sze Huey Leong, Kiat-Yi Tan, Sonia P Chothani, Jingjing Sun, Agnieszka Dziegowska, Grazyna Leszczynska, Owen J L Rackham, Ilka Wittig, Peter Dedon, Gregory S Ducker, David A Stroud, Lena Ho.
      Mitochondrial small open reading frame (ORF)-encoded microproteins (SEPs) are key regulators and components of the electron transport chain (ETC). Although ETC complex I assembly is tightly coupled to nutrient availability, including serine, the coordinating mechanism remains unknown. A genome-wide CRISPR screen targeting SEPs revealed that deletion of the LINC00493-encoded microprotein SMIM26 sensitizes cells to one-carbon restriction. SMIM26 interacts with mitochondrial serine transporters SFXN1/2 and the mitoribosome, forming a functional triad that facilitates translation of the complex I subunit mt-ND5. SMIM26 loss impairs serine import, reduces folate intermediates, and disrupts key mitochondrial tRNA modifications (τm5U and τm5s²U), resulting in ND5 translation failure and complex I deficiency. SMIM26 deletion is embryonic lethal in mice and impedes tumor growth in a xenograft model of folate-dependent acute myeloid leukemia. These findings define SMIM26 as a critical integrator of one-carbon flux and complex I biogenesis and establish a paradigm for localized mitochondrial translation through transporter-ribosome interactions.
    Keywords:  complex I; electron transport chain; micropeptides; mitochondria; mitochondrial translation; one-carbon pathway; oxidative phosphorylation; small ORF-encoded peptides
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.033
  29. Nat Struct Mol Biol. 2025 Jun 24.
    PEX14 condensates recruit receptor and cargo pairs for peroxisomal protein import.
    Jianguo Wu, Shupei Lv, Peng Xu, Suyu Yue, Min Zhuang.
      Peroxisomal proteins are imported into peroxisomes as folded proteins bound to the receptor peroxisomal biogenesis factor 5 (PEX5) through a biomolecular condensate mainly formed by the tyrosine-glycine (YG) repeats in PEX13. PEX14, another essential component of the translocon complex, contributes to this process by interacting with PEX5 and PEX13 through its N-terminal domain. Clinical data suggest that the human PEX14 (hPEX14) C-terminal domain (CTD) is crucial for peroxisomal protein import. Here we analyze the overall structure of the hPEX14 tetramer and demonstrate that hPEX14 CTD undergoes phase separation in vitro. Replacing hPEX14 CTD with other polypeptides capable of forming condensates partially restores peroxisomal protein import. We found that electrostatic interactions and the specific sequence of the CTD are essential for peroxisomal import. hPEX14 and hPEX13 form immiscible condensates and hPEX14 condensates recruit cargoes containing peroxisome-targeting signal 1 (PTS1) or PTS2 in a PEX5-dependent manner. Overall, our study proposes that PEX14 condensates recruit the receptor-cargo complexes for subsequent partitioning into the PEX13 YG phase.
    DOI:  https://doi.org/10.1038/s41594-025-01601-w
  30. Sci Transl Med. 2025 Jun 25. 17(804): eadq3852
    Podocyte YAP and TAZ hyperactivation drives glomerular epithelial proliferative diseases in mice and humans.
    Xiaolin He, Estefania Rodriguez Ballestas, Li Zeng, Tianzhou Zhang, Caitriona M McEvoy, Paraish S Misra, Victoria Ki, Arnold Apostol, Jenny S Wong, Kristin Meliambro, Justina Ray, Marina De Cos, Maria Elena Melica, Paola Romagnani, Ye Feng, Adriana Krizova, Ira How, Ivy A Rosales, Robert B Colvin, John Cijiang He, Kirk N Campbell, Darren A Yuen.
      Kidney diseases characterized by glomerular epithelial cell proliferation are rare but often devastating, frequently leading to progressive scarring and renal failure. Ranging from autoimmune-induced crescentic glomerulonephritis to HIV infection-induced collapsing glomerulopathy, these diseases are triggered by a wide variety of insults and have generally been thought of as different entities. Here, using immunostaining and spatial transcriptomics, we profiled human kidney biopsies collected from patients with two of these diseases, collapsing glomerulopathy and antineutrophil cytoplasmic antibody (ANCA) vasculitis-induced crescentic glomerulonephritis, to identify common disease-causing molecules. Although triggered by different insults, we identified abnormal hyperactivation of the transcription cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in podocytes as a potential common driver of these diseases. To test this hypothesis, we genetically activated podocyte YAP and TAZ in cultured human cells and in mice by deleting the YAP and TAZ inhibitory large tumor suppressor kinases (LATSs). LATS deficiency in mouse podocytes induced a phenotypic transition in vitro, characterized by a highly distorted structure and an increase in matrix gene expression, mimicking many features of the podocytopathy seen in diseases characterized by glomerular epithelial proliferation. In mice, LATS-deficient podocytes orchestrated a profibrotic and pro-proliferative response in surrounding glomerular cells, a characteristic phenomenon of glomerular epithelial proliferative diseases. This response was attenuated when we also deleted podocyte YAP or TAZ in these mice. Together, our findings point to podocyte YAP-TAZ hyperactivation as a previously unrecognized and unifying driver of glomerular epithelial proliferative diseases.
    DOI:  https://doi.org/10.1126/scitranslmed.adq3852
  31. J Cell Biol. 2025 Aug 04. pii: e202409103. [Epub ahead of print]224(8):
    Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.
    Bobby White, Zhenyi Wang, Matthew Dean, Johanna Michl, Natalia Nieora, Sarah Flannery, Iolanda Vendrell, Roman Fischer, Alzbeta Hulikova, Pawel Swietach.
      Hypoxia-inducible factors (HIFs) mediate cellular responses to low oxygen, notably enhanced fermentation that acidifies poorly perfused tissues and may eventually become more damaging than adaptive. How pH feeds back on hypoxic signaling is unclear but critical to investigate because acidosis and hypoxia are mechanistically coupled in diffusion-limited settings, such as tumors. Here, we examined the pH sensitivity of hypoxic signaling in colorectal cancer cells that can survive acidosis. HIF-1α stabilization under acidotic hypoxia was transient, declining over 48 h. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (e.g., CA9, PDK1), but these did not reflect a proteome-wide downregulation. Enrichment analyses suggested a role for lysosomal degradation. Indeed, HIF-1α destabilization was blocked by inactivating lysosomes, but not proteasome inhibitors. Acidotic hypoxia stimulated lysosomal activity and autophagy via mammalian target of rapamycin complex I (mTORC1), resulting in HIF-1α degradation. This response protects cells from excessive acidification by unchecked fermentation. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling.
    DOI:  https://doi.org/10.1083/jcb.202409103
  32. Sci Adv. 2025 Jun 27. 11(26): eads6132
    External strain on the plasma membrane is relayed to the endoplasmic reticulum by membrane contact sites and alters cellular energetics.
    Ziming Chen, Peilin Chen, Jiayue Li, Euphemie Landao-Bassonga, John Papadimitriou, Junjie Gao, Delin Liu, Andrew Tai, Jinjin Ma, David Lloyd, Brendan F Kennedy, Ming Hao Zheng.
      Mechanotransduction is essential for living cells to adapt to their extracellular environment. However, it is unclear how the biophysical adaptation of intracellular organelles responds to mechanical stress or how these adaptive changes affect cellular homeostasis. Here, using the tendon cell as a mechanosensitive cell type within a bioreactor, we show that the tension of the plasma membrane (PM) and the endoplasmic reticulum (ER) adaptively increases in response to repetitive external stimuli. Depletion of stromal interaction molecule 1 (STIM1), the highest expressed PM-ER tether protein, interfered with mechanotransduction from the PM to the ER, and affected the ER tension. We found that an optimized mechanical strain increased ER tension in a homeostatic manner, but excessive strain resulted in ER expansion, as well as activating ER stress. Last, we showed that changes in ER tension were linked with ER-mitochondria interactions and associated with cellular energetics and function. Together, these findings identify a PM-ER mechanotransduction mechanism that dose-dependently regulates cellular metabolism.
    DOI:  https://doi.org/10.1126/sciadv.ads6132
  33. Sci Adv. 2025 Jun 27. 11(26): eadw6814
    Sequestration of ribosome biogenesis factors in HSV-1 nuclear aggregates revealed by spatially resolved thermal profiling.
    Peter J Metzger, Tavis J Reed, Krystal K Lum, Jordy F Botello, Lifei Jiang, Clifford P Brangwynne, Olga G Troyanskaya, Ileana M Cristea.
      Viruses exploit host cell reliance on compartmentalization to facilitate their replication. Herpes simplex virus type 1 (HSV-1) modulates the subcellular localization of host proteins to suppress immune activation, license viral gene expression, and achieve translational shutoff. To spatially resolve dynamic protein-protein interaction (PPI) networks during infection with an immunostimulatory HSV-1 strain, we integrated nuclear/cytoplasmic fractionation with thermal proximity coaggregation analysis (N/C-TPCA). The resulting expanded depth and spatial resolution of PPIs charted compartment-specific assemblies of protein complexes throughout infection. We find that a broader suite of host chaperones than previously anticipated exhibits nuclear recruitment to form condensates known as virus-induced chaperone-enriched (VICE) domains. Monitoring protein and RNA constituents and ribosome activity, we establish that VICE domains sequester ribosome biogenesis factors from ribosomal RNA, accompanying a cell-wide defect in ribosome supply. These findings highlight infection-driven VICE domains as nodes of translational remodeling and demonstrate the utility of N/C-TPCA to study dynamic biological contexts.
    DOI:  https://doi.org/10.1126/sciadv.adw6814
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