bims-ginsta Biomed News
on Genome instability
Issue of 2026–02–22
thirty-two papers selected by
Jinrong Hu, National University of Singapore
  1. Tissue mechanics and systemic signaling safeguard epithelial tissue against spindle misorientation.
  2. Global reorganization of genome architecture at the transition to gametogenesis.
  3. Insolubilome profiling defines molecular features that influence protein insolubility with aging.
  4. Acute NIPBL depletion reveals in vivo dynamics of loop extrusion and its role in transcription activation.
  5. TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1.
  6. Extrusion fountains are hallmarks of chromosome organization emerging upon zygotic genome activation.
  7. Single-cell and isoform-specific translational profiling of the mouse brain.
  8. Z-DNA formation regulates the totipotent-like state and primes Zscan4-dependent chromatin compartmentalization.
  9. Adaptor-mediated recruitment of three dyneins to dynactin enhances force generation.
  10. Aneuploidy of chromosome 8 promotes the mesenchymal lineage during cell fate transitions.
  11. BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
  12. Engineering intrinsically disordered regions for guiding genome navigation.
  13. A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis and cancer growth suppression.
  14. cPLA2α targeting to exosomes connects nuclear deformation to LTB4-signaling during neutrophil chemotaxis.
  15. Giant DNA viruses encode a hallmark translation initiation complex of eukaryotic life.
  16. Single-cell spatial proteomics maps human liver zonation patterns and their vulnerability to disruption in tissue architecture.
  17. Induction of senescence during postpartum mammary gland involution supports tissue remodeling and promotes postpartum tumorigenesis.
  18. Trimodal single-cell profiling of transcriptome, epigenome and 3D genome in complex tissues with scHiCAR.
  19. A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1.
  20. The integrated stress response promotes immune evasion through lipocalin 2.
  21. Ribosomal RNA expansion segments mediate the oligomerization of inactive animal ribosomes.
  22. Distinct impact of PI(4)P flux on PI(4,5)P2 steady states and oscillations.
  23. A single-cell time-series atlas of endothelial cell embryonic development.
  24. Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
  25. Subcellular localization as a driver of protein function.
  26. Conformational biosensors delineate endosomal G protein regulation by GPCRs.
  27. Prevention of transgene silencing during human pluripotent stem cell differentiation.
  28. Lamin B receptor upregulation in metastatic melanoma causes nuclear envelope fragility in confined migration during cancer invasion.
  29. Fluorescence Amplification Tags for Single-Molecule Imaging and Tracking of Proteins, RNA, and DNA in Live Cells.
  30. TRPML1 suppresses pulmonary fibrosis by limiting collagen and elastin deposition.
  31. Spatial relationships between vinculin tension and actin at cell adhesions define cell colony positioning and identity.
  32. Roles of microtubules and LIS1 in dynein transport machinery assembly.
  1. Dev Cell. 2026 Feb 16. pii: S1534-5807(26)00035-3. [Epub ahead of print]
    Tissue mechanics and systemic signaling safeguard epithelial tissue against spindle misorientation.
    Floris Bosveld, Baptiste Tesson, Eric van Leen, Sam Amirebrahimi, Raphael Thinat, Yohanns Bellaïche.
      Multicellular organisms possess conserved safeguard mechanisms maintaining tissue integrity. Exploring these mechanisms is instrumental in understanding how tissues robustly develop and prevent tumor initiation. Here, we investigate how epithelial tissues preserve their architecture and cell number upon spindle misorientation. Spindle misorientation can cause epithelial cells to be mispositioned within or outside the tissue, leading to significant cell loss. By inducing spindle misorientation in Drosophila epithelial tissue, we found that non-centrosomal microtubules and cell contractility prevent excessive cell loss by promoting the reintegration of mispositioned cells into the epithelium. Additionally, we demonstrated that tissue mechanics and cell-size sensing monitor and compensate for cell loss predominantly by reducing physiological apoptosis through Hippo/YAP signaling. Lastly, systemic tumor necrosis factor (TNF) signaling protects the organism by eliminating potentially harmful non-reintegrating cells. Overall, our results delineate the complementary roles of mechanics and systemic signaling in controlling cell number and position at both tissue and organismal levels.
    Keywords:  Drosophila; Hippo/YAP; TNF; apoptosis; cell division; cytoskeleton; epithelium; mechanics; mitotic spindle
    DOI:  https://doi.org/10.1016/j.devcel.2026.01.012
  2. Nat Struct Mol Biol. 2026 Feb 20.
    Global reorganization of genome architecture at the transition to gametogenesis.
    Tien-Chi Huang, Maria Rigau, Valeriya Malysheva, Chad Whilding, Stella Siciliani, Jingyu Li, Irina Balaguer Balsells, Pavel Artemov, Camille Dion, Mikhail Spivakov, Juan M Vaquerizas, Petra Hajkova.
      Global epigenetic resetting in the gonadal primordial germ cells (PGCs) enables transition from early PGCs to gametogenesis and eventual restoring of totipotency after fertilization. This reprogramming process involves global DNA demethylation, changes in nuclear morphology and remodeling of repressive histone modifications. Here, using combined cytological and Hi-C-based methods, we reveal that, following the epigenetic reprogramming and concomitant with their commitment to gametogenesis, premeiotic gonadal germ cells display a distinct chromosome and genome architecture. This involves separation of individual chromosomes, anchoring of centromeres at the nuclear periphery, reduction in interchromosome interactions and disentangling of chromosome ends. Furthermore, genome-wide contact mapping documents remodeling of the three-dimensional (3D) genome architecture across all observable levels, including disruption of topologically associating domains (TADs), loss of detectable loops and reduced active-active compartment interactions. We further show that the diminished TADs correlate with the reduced levels of CCCTC-binding factor, thus providing an in vivo physiological model to understand genome folding principles. Lastly, we show that PGC-like cells, derived from embryonic stem cells, do not exhibit the same chromatin organization as embryonic germ cells. Collectively, our findings uncover the existence of a distinct chromatin architecture in premeiotic male and female gonadal germ cells and show that, alongside global DNA demethylation, the germline epigenetic reprogramming involves erasure of memory at the genome architectural level through profound reorganization of the 3D genome.
    DOI:  https://doi.org/10.1038/s41594-026-01747-1
  3. Dev Cell. 2026 Feb 19. pii: S1534-5807(26)00038-9. [Epub ahead of print]
    Insolubilome profiling defines molecular features that influence protein insolubility with aging.
    Anna Stephan, Flavia A Graca, Vishwajeeth R Pagala, Liam C Hunt, Chia-Lung Chuang, John Grime, Daniel Alford, Xusheng Wang, Anthony A High, Junmin Peng, Fabio Demontis.
      Solubility regulates protein function, but how it is governed by aging remains elusive. Here, we utilized mass spectrometry to define the relative composition of the soluble and insoluble tissue/organ fractions during mouse aging. In the young, there is a wide (∼100-1,000×) range of insoluble/soluble protein ratios that differ tissue-specifically. With aging, some proteins become relatively more insoluble, while others are conversely regulated or unaffected. Age-related insoluble/soluble changes are not merely dictated by histological similarity, diverge in related tissues with distinct degeneration propensities, and correlate tissue-specifically with structural features. Proteins that become age-insoluble in multiple organs include aggregation-prone circulating factors and ectopically expressed proteins. For instance, although primarily expressed by the epidermis, hornerin insolubility increases with aging in skeletal muscle, and experimental hornerin upregulation causes muscle weakness. Thus, age-insoluble proteins are useful biomarkers but can also contribute to age-related functional decline, highlighting a multifaceted remodeling of the insolubilome with aging.
    Keywords:  aging; ectopic proteins; insolubilome; inter-organ signaling; protein solubility; proteostasis
    DOI:  https://doi.org/10.1016/j.devcel.2026.01.015
  4. Nat Genet. 2026 Feb 16.
    Acute NIPBL depletion reveals in vivo dynamics of loop extrusion and its role in transcription activation.
    Tessa M Popay, Ami Pant, Femke Munting, Melodi Tastemel, Morgan E Black, Nicholas Haghani, Jesse R Dixon.
      The organization of the genome in three-dimensional space is highly dynamic, yet how these dynamics are regulated and the role they play in genome function is poorly understood. Here we utilized acute depletion of NIPBL to characterize cohesin-mediated loop extrusion in vivo. We find that many chromatin loops are rapidly diminished upon loss of NIBPL, but some cohesin-dependent chromatin loops persist for multiple hours. These persistent loops required NIPBL for their establishment during mitotic exit, were associated with distinct chromatin states and were preferentially dependent on STAG1 for their persistence. Furthermore, by depleting NIPBL from multiple cell types, we find that NIPBL specifically regulates cell identity genes by supporting a unique local genome conformation defined by greater spatial proximity to nearby super-enhancers and weaker transcription start site insulation of genomic contacts. Overall, we show that NIPBL-mediated loop extrusion is critical to genome organization and transcription regulation in vivo.
    DOI:  https://doi.org/10.1038/s41588-026-02516-y
  5. Nat Commun. 2026 Feb 17.
    TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1.
    Liming Meng, Jing Lv, Ying Yi, Xianchun Lan, Chenchao Yan, Lihang Zhu, Jie Yang, Wei Jiang.
      Cell fate determination is closely linked to metabolic state, yet how metabolic remodeling influences human pluripotent stem cells differentiation into three germ layers remains incompletely understood. Here, we reveal that definitive endoderm differentiation from human pluripotent stem cells requires a TGFβ-driven metabolic switch characterized by reduced lactate production and enhanced TCA cycle activity and oxidative phosphorylation, mediated by PDHB. Disruption of glucose utilization or pyruvate entry into the TCA cycle markedly impairs endoderm differentiation, whereas inhibition of lactate production enhances differentiation efficiency. Mechanistically, blockade of glucose metabolism or the TCA cycle reduces intracellular ATP levels, compromising the activity of BAF complex, an ATP-dependent chromatin remodeling complex centered on BRG1. This complex promotes chromatin accessibility and activates endodermal gene programs during differentiation. Together, these findings highlight metabolic reprogramming as a key regulator of human endoderm fate through ATP-dependent control of chromatin remodeling.
    DOI:  https://doi.org/10.1038/s41467-026-69510-0
  6. Nat Commun. 2026 Feb 14.
    Extrusion fountains are hallmarks of chromosome organization emerging upon zygotic genome activation.
    Aleksandra Galitsyna, Sergey V Ulianov, Mariia Bazarevich, Nikolai S Bykov, Marina Veil, Meijiang Gao, Kristina Perevoschikova, Mikhail S Gelfand, Sergey V Razin, Leonid Mirny, Daria Onichtchouk.
      The initiation of gene expression during development, known as zygotic genome activation (ZGA), is accompanied by massive changes in chromosome organization. However, the earliest events of chromosome folding and their functional roles remain unclear. Using Hi-C on zebrafish embryos, we discovered that chromosome folding begins early in development with the formation of fountains, distinct elements of chromosome organization. Emerging preferentially at enhancers, fountains show an initial accumulation of cohesin, which later redistributes to CTCF sites at TAD borders. Knockouts of pioneer transcription factors driving ZGA enhancers cause a specific loss of fountains, establishing a causal link between enhancer activation and fountain formation. Polymer simulations demonstrate that fountains may arise as sites of facilitated cohesin loading, requiring two-sided but desynchronized loop extrusion, potentially caused by cohesin collisions with obstacles or internal switching. Moreover, we detected cohesin-dependent fountain patterns at enhancers in mouse cells and found them reemerging with cohesin loading after mitosis. Altogether, fountains represent enhancer-specific elements of chromosome organization and suggest that chromosome folding during development and after cell division starts with facilitated cohesin loading. Observations in multiple systems further support facilitated loading at enhancers as a widespread phenomenon.
    DOI:  https://doi.org/10.1038/s41467-026-69105-9
  7. Nature. 2026 Feb 18.
    Single-cell and isoform-specific translational profiling of the mouse brain.
    Samantha L Sison, Federico Zampa, Eric R Kofman, Su Yeun Choi, Pratibha Jagannatha, Grady G Nguyen, Jack T Naritomi, Asa Shin, Akanksha Khorgade, Wenhao Jin, Chun-Yuan Chen, David M Sievert, Sourish Mukhopadhyay, Orel Mizrahi, Steven M Blue, Ryan J Marina, Dong Yang, Cailynn C Wang, Zhengyuan Pang, Kristopher W Brannan, Li Ye, Aziz M Al'Khafaji, Gene W Yeo, Giordano Lippi.
      The brain displays the richest repertoire of post-transcriptional mechanisms regulating mRNA translation1-11. Among these, alternative splicing has been shown to drive cell-type specificity and, when disrupted, is strongly linked to neurological disorders12-17. However, genome-wide measurements of mRNA translation with isoform sensitivity at single-cell resolution have not been achieved. To address this, we deployed Surveying Ribosomal Targets by APOBEC-Mediated Profiling (Ribo-STAMP) coupled with short-read and long-read single-cell RNA sequencing in the brain18. We generated the first isoform-sensitive single-cell translatomes of the mouse hippocampus at postnatal day 25, discovering cell-type-specific translation of 3,857 alternative transcripts across 1,641 genes and identifying isoforms of the same genes undergoing differential translation within and across 8 different cell types. We defined high and low translational states in CA1 and CA3 neurons, with synaptic and metabolic genes enriched in high states. We found that CA3 exhibited higher basal translation compared with CA1, as confirmed by metabolic labelling of newly synthesized proteins and immunohistochemistry of translational machinery components. This accessible platform will expand our understanding of how cell-type-specific and isoform-specific translation drives brain physiology and disease.
    DOI:  https://doi.org/10.1038/s41586-026-10118-1
  8. Nat Struct Mol Biol. 2026 Feb 17.
    Z-DNA formation regulates the totipotent-like state and primes Zscan4-dependent chromatin compartmentalization.
    Shireen Shajahan, Yann Loe-Mie, Laure Asselin, Marion Salmon-Legagneur, Tatiana Traboulsi, Agnès Thierry, Anne Dejean, Jack-Christophe Cossec.
      The progression from the one-cell to the two-cell stage constitutes a remarkable transition, accompanied by the activation of a specific set of embryonic genes, epigenome reprogramming and nuclear architecture reorganization. Some of these characteristics are recapitulated in vitro with the spontaneous emergence of two-cell-like cells from mouse embryonic stem cells, which exhibit a transcriptomic signature resembling the two-cell stage, including the expression of genes such as Dux, Zscan4 and the repetitive element MERVL, as well as a more relaxed chromatin state. Here we show that interchromosomal and intrachromosomal interactions driven by Zscan4 chromatin factors form during this transition and segregate into a distinct genomic compartment, the Z compartment, independently of cohesin and CCCTC-binding factor. Mechanistically, the formation of Z-DNA, an alternative DNA conformation regulated by polyamine levels, appears to promote the emergence of totipotent-like cells and the establishment of the Z compartment. This compartment is characterized by a decrease in active histone marks and a reduced expression of genes associated with differentiation and late developmental processes. Overall, these findings suggest that Z-DNA formation may have a dual role, first in initiating zygotic genome activation (ZGA) and later in guiding genome compartmentalization to safeguard the totipotent-like state by restricting the expression of non-ZGA genes within a permissive chromatin environment.
    DOI:  https://doi.org/10.1038/s41594-026-01751-5
  9. Nat Cell Biol. 2026 Feb 16.
    Adaptor-mediated recruitment of three dyneins to dynactin enhances force generation.
    Lu Rao, Xinglei Liu, Mirjam Arnold, Kyoko Okada, Richard J McKenney, Kristy Stengel, Simone Sidoli, Florian Berger, Arne Gennerich.
      Cytoplasmic dynein is an essential microtubule motor protein that powers organelle transport and mitotic spindle assembly. Its activity depends on dynein-dynactin-cargo adaptor complexes, such as dynein-dynactin-BicD2, which typically function with two dynein motors. We show that mechanical tension recruits a third dynein motor via an auxiliary BicD2 adaptor binding the light intermediate chain of the third dynein, stabilizing multidynein assemblies and enhancing force generation. Lis1 prevents dynein from transitioning into a force-limiting phi-like conformation, allowing single-dynein dynein-dynactin-BicD2 to sustain forces up to approximately 4.5 pN, whereas force generation often ends at about 2.5 pN without Lis1. Complexes with two or three dyneins generate 7 pN and 9 pN, respectively, consistent with a staggered motor arrangement that enhances collective output. Under load, dynein-dynactin-BicD2 primarily takes 8-nm steps, challenging existing dynein coordination models. These findings reveal adaptive mechanisms that enable robust intracellular transport under varying mechanical demands.
    DOI:  https://doi.org/10.1038/s41556-026-01877-0
  10. Sci Adv. 2026 Feb 20. 12(8): eaea1660
    Aneuploidy of chromosome 8 promotes the mesenchymal lineage during cell fate transitions.
    Cai Liang, Guanchen Li, Qiuqin Zhang, Xinlei Wang, Yu Liu, Wenjuan Yin, Ting Tao, Jinhu Wang, Haishan Gao, Shutao Qi, Hongtao Yu.
      Aneuploidy is present in about 90% human solid tumors. Certain tumors remain addicted to aneuploidy. Paradoxically, artificially induced aneuploidy in normal cells elicits cellular stresses and decreases cell fitness. How aneuploidy initially emerges during tumorigenesis is thus unclear. Using human embryonic stem cells (ESCs) as a model, we show that aneuploid ESCs form immature teratomas with an enrichment of mesenchymal tissues. Specifically, chromosome 8 (chr8) gain, a prevalent form of aneuploidy in human cancers, promotes the expansion of mesenchymal stem cells (MSCs) in teratomas and MSC proliferation in vitro. We further show that human embryonal rhabdomyosarcomas, tumors of mesenchymal origin, lack dominant driver mutations but frequently harbor chr8 gain. Our study suggests a plausible mechanism for aneuploidy emergence during tumorigenesis, links specific aneuploidy to the mesenchymal lineage, and paves the way for identifying vulnerabilities of aneuploid MSCs, which may have important roles in tumorigenesis.
    DOI:  https://doi.org/10.1126/sciadv.aea1660
  11. Mol Cell. 2026 Feb 13. pii: S1097-2765(26)00032-8. [Epub ahead of print]
    BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
    Brandon Chen, Drew C Stark, Pankaj V Jadhav, Theophilus M Lynn-Nguyen, Benjamin S Halligan, Nicholas J Rossiter, Nicole Sindoni, Myungsun Shin, Joao A Paulo, Matthew Chang, Imhoi Koo, Sergei Koshkin, Sanjana Eyunni, Paolo Ronchi, Michelle T Paulsen, Harrison S Greenbaum, Mariana T Ruckert, Pietro Morlacchi, David A Hanna, Jason Lin, Rachel M Guerra, Tao Liu, David J Pagliarini, Ruma Banerjee, Abhijit Parolia, Mats E Ljungman, Andrew D Patterson, Joseph D Mancias, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.
      Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCSs revealed common mechanisms of induction and function, providing clarity to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCSs and cellular metabolism.
    Keywords:  bromodomain protein; endoplasmic reticulum-mitochondria contact sites; high-throughput screening; mitochondrial electron transport chain
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.012
  12. Mol Cell. 2026 Feb 16. pii: S1097-2765(26)00061-4. [Epub ahead of print]
    Engineering intrinsically disordered regions for guiding genome navigation.
    Jing Liu, Divya Krishna Kumar, Bohdana Hurieva, Felix Jonas, Naama Barkai.
      Intrinsically disordered regions (IDRs) navigate transcription factors (TFs) to their binding sites in genomes, raising the question of how IDR sequences can encode for specific genome recognition. To define the principles of IDR-directed binding, we designed de novo IDRs and tested their activity in directing selective binding across the budding yeast genome. Our de novo IDRs were designed by dispersing hydrophobic amino acids within hundreds of hydrophilic residues, as we found to be required in native TF-directing IDRs. Although showing no alignment-based similarity to native TFs, the de novo IDRs were active in directing genome binding toward a tunable range of targets, as revealed by systematically varying the hydrophobic spread or disorder scaffold. Overall, the 185 synthetic IDRs tested displayed a continuum of sequence-directed binding preferences across hundreds of promoters. Our results open new doors for understanding and engineering selective binding across genomes.
    Keywords:  ChEC-seq; gene regulation; intrinsically disordered regions; synthetic biology; transcription factors
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.019
  13. Cell. 2026 Feb 19. pii: S0092-8674(26)00056-5. [Epub ahead of print]
    A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis and cancer growth suppression.
    Zhangchuan Xia, Xin Yang, Sviatlana N Samovich, Yulia Y Tyurina, Vladimir A Tyurin, Ning Kon, Jiankang Zhang, Xuejun Jiang, Brent R Stockwell, Jian Jin, Hülya Bayir, Valerian E Kagan, Wei Gu.
      Ferroptosis is a tumor-suppressive mechanism with therapeutic potential. While canonical ferroptosis is usually triggered by inducers, such as erastin and RSL-3, or by glutathione peroxidase (GPX)4 loss, how ferroptosis occurs naturally in vivo without these triggers has been unclear. Building on evidence that p53 can mediate ferroptosis as a natural tumor-suppressive pathway, we describe a noncanonical, in vivo ferroptosis driven by reactive oxygen species (ROS)-induced phosphatidic acid (PA) peroxidation that proceeds without inducers. We identify GPX1 as a key regulator of this ROS-induced ferroptosis by modulating PA peroxidation. GPX1's effects depend on OSBPL8, an endoplasmic reticulum (ER)-membrane-associated oxysterol-binding protein. ROS-driven lipid peroxidation accumulates at the ER before plasma membrane rupture and cell death; GPX1 is recruited to the ER via OSBPL8 and directly reduces oxidized PA. OSBPL8 and GPX1 are overexpressed in cancers; knockdown of either promotes ROS-induced ferroptosis and suppresses tumor growth. Our data link the GPX1-OSBPL8 axis to in vivo ferroptosis and tumor suppression.
    Keywords:  GPX1; GPX4; OSBPL8; ROS; cancer; ferroptosis; lipid peroxidation; p53; phosphatidic acid; phosphatidylethanolamine; tumor suppression
    DOI:  https://doi.org/10.1016/j.cell.2026.01.009
  14. Sci Adv. 2026 Feb 20. 12(8): eaea2784
    cPLA2α targeting to exosomes connects nuclear deformation to LTB4-signaling during neutrophil chemotaxis.
    Subhash B Arya, Fatima Jordan-Javed, Kristen Loesel, Yehyun Choi, Samuel P Collie, Lauren E Hein, Brendon M Baker, Euisik Yoon, Carole A Parent.
      Efficient neutrophil chemotaxis requires the integration of mechanical forces and lipid-mediated signaling. While the signaling lipid leukotriene B4 (LTB4) reinforces cellular polarity, how mechanical cues regulate its production remains unclear. We now show that cytosolic phospholipase A2α (cPLA2α), which is essential for the synthesis of LTB4, functions as a nuclear curvosensor. cPLA2α responds to nuclear squeezing by localizing to ceramide-rich inner nuclear membrane microdomains and incorporating onto the exofacial surface of nuclear envelope-derived exosomes. This unique topology enables localized LTB4 synthesis, which synchronizes calcium spikes, promotes myosin light chain II phosphorylation, and sustains polarity and directional persistence after constriction. In neutrophils passing through tight spaces, cPLA2α activity drives the chemotactic response to nuclear squeezing by promoting exosomal LTB4 production and persistence after constriction. These findings uncover a cPLA2α-dependent mechanochemical axis linking nuclear architecture to chemotactic efficiency and offer alternative strategies to modulate inflammatory responses.
    DOI:  https://doi.org/10.1126/sciadv.aea2784
  15. Cell. 2026 Feb 17. pii: S0092-8674(26)00055-3. [Epub ahead of print]
    Giant DNA viruses encode a hallmark translation initiation complex of eukaryotic life.
    J Maximilian Fels, Aidan B Hill, Richard Han, Jasmine M Garcia, Hugo Bisio, Chantal Abergel, Philip J Kranzusch, Amy S Y Lee.
      In contrast to living organisms, viruses were long thought to lack protein synthesis machinery and instead depend on host factors to translate viral transcripts. Here, we discover that giant DNA viruses encode a distinct and functional IF4F translation-initiation complex to drive protein synthesis, thereby blurring the line between cellular and acellular biology. During infection, eukaryotic IF4F on host ribosomes is replaced by an essential viral IF4F that regulates viral translation, virion formation, and replication plasticity during altered host states. Structural dissection of viral IF4F reveals that the mRNA cap-binding subunit mediates exclusive interactions with viral mRNAs, constituting a molecular switch from translating host to viral proteins. Thus, our study establishes that viruses express a eukaryotic translation-initiation complex for protein synthesis, illuminating a series of evolutionary innovations in a core process of life.
    Keywords:  5′ m7G RNA cap; eIF4F; giant DNA viruses; mimivirus; translation; translation-initiation factors
    DOI:  https://doi.org/10.1016/j.cell.2026.01.008
  16. Nat Metab. 2026 Feb 20.
    Single-cell spatial proteomics maps human liver zonation patterns and their vulnerability to disruption in tissue architecture.
    Caroline A M Weiss, Lauryn A Brown, Lucas Miranda, Paolo Pellizzoni, Sophia Steigerwald, Kirsten Remmert, Jonathan M Hernandez, Karsten Borgwardt, David E Kleiner, Shani Ben-Moshe, Florian A Rosenberger, Natalie Porat-Shliom, Matthias Mann.
      Understanding protein distribution patterns across tissue architecture is crucial for deciphering organ function in health and disease. Here we show the application of single-cell Deep Visual Proteomics to perform spatially resolved proteome analysis of individual cells in native liver tissue. We built a robust framework comprising strategic cell selection and continuous protein gradient mapping, allowing the investigation of larger clinical cohorts. We generated a comprehensive spatial map of the human hepatic proteome by analysing hundreds of isolated hepatocytes from 18 individuals. Among the 2,500 proteins identified per cell, about half exhibited zonated expression patterns. Cross-species comparison with male mice revealed conserved metabolic functions and human-specific features of liver zonation. Analysis of samples with disrupted liver architecture demonstrated widespread loss of protein zonation, with pericentral proteins being particularly susceptible. Our study provides a comprehensive and open-access resource of human liver organization while establishing a broadly applicable framework for spatial proteomics analyses along tissue gradients.
    DOI:  https://doi.org/10.1038/s42255-026-01459-2
  17. Nat Aging. 2026 Feb 18.
    Induction of senescence during postpartum mammary gland involution supports tissue remodeling and promotes postpartum tumorigenesis.
    Aurelie Chiche, Lamia Djoual, Elsa Charifou, Shuoyang Wang, Laurianne Temime, Marielle Saclier, Shaoxiang Wang, Jeremy Chantrel, Han Li.
      Cellular senescence is an evolutionarily conserved stress response that contributes to tissue repair and tumor suppression, yet its accumulation is also linked to aging and disease. Whether physiological senescence can be exploited by oncogenic events to promote tumorigenesis is unknown. Postpartum mammary gland involution is a major adult tissue remodeling event, resembling wound healing, and is closely associated with postpartum breast cancer. Here, we show that during mammary gland involution in mice, a p16Ink4a-dependent senescence response is induced in alveolar luminal cells. Eliminating senescent cells disrupts tissue remodeling and delays involution, demonstrating their physiological importance. However, in a postpartum breast cancer model where oncogenic activation coincides with involution, removing involution-associated senescent cells extended tumor latency. Mechanistically, senescent cells enhance tumor cell plasticity via the senescence-associated secretory phenotype, fostering metastasis. Our findings reveal that senescence, while required for postpartum tissue remodeling, can be hijacked to facilitate tumorigenesis, defining senescence as a unifying mechanism linking tissue repair to tumorigenesis.
    DOI:  https://doi.org/10.1038/s43587-025-01058-y
  18. Nat Biotechnol. 2026 Feb 19.
    Trimodal single-cell profiling of transcriptome, epigenome and 3D genome in complex tissues with scHiCAR.
    Xiaolin Wei, Yueyuan Xu, Dongchan Yang, Kyukwang Kim, Lizhi Yi, Wenzhe Luo, Xin Lin, Yu Xiang, Ashley B Williams, Xiaotao Wang, Sweta Srivas, Christabel Tan, Kan Zhang, Wei Li, Yang Eric Li, Feng Yue, Z Josh Huang, Inkyung Jung, Yarui Diao.
      The three-dimensional (3D) organization of cis-regulatory elements (CREs) is critical in transcription control. However, capturing transcriptome, epigenome and 3D genome from the same single cells remains challenging. Here we present scHiCAR (single-cell Hi-C with assay for transposase-accessible chromatin and RNA sequencing), a plate-based combinatorial barcoding method that simultaneously profiles mRNA, open chromatin and chromosome conformation capture from the same cells. Compared to existing single-cell 3D genome methods, scHiCAR more efficiently enriches long-range cis-interactions anchored at candidate CREs (cCREs). Applied to 1.62 million mouse brain cells and complemented with a deep-learning-based loop caller, scHiCAR accurately defines cell-type-specific transcriptomes, accessible cCREs and 5-kb-resolution enhancer-promoter pairs across 22 brain cell types. scHiCAR also performs robustly in challenging tissues such as skeletal muscle, enabling trimodal single-cell-level analysis of gene regulation dynamics during muscle stem cell regeneration. By providing a scalable and cost-effective system for single-cell trimodal analysis of gene-regulatory landscapes in complex tissues, scHiCAR reveals gene-locus-specific regulatory roles of 3D genome reorganization in transcriptional control.
    DOI:  https://doi.org/10.1038/s41587-026-03013-7
  19. Nat Commun. 2026 Feb 20.
    A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1.
    Mingming Yang, Qi Wang, Ruolan Yan, Dongkun Kang, Weihan Luo, Liti Zhang, Rong Liu, Liyong Wu, Jianlan Gu, Xiaochuan Wang.
      Dysfunction of transactive response DNA-binding protein 43 (TDP-43) drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), in part through inducing aberrant RNA splicing. However, whether such mis-splicing yields stable, pathogenic proteins remains unclear. Here, we identify a TDP-43-repressed cryptic exon in Protein kinase N1 (PKN1), designated PKN1-5a1, which is activated in ALS patient brains and introduces a premature termination codon. This aberrant transcript escapes nonsense-mediated decay and is translated into a truncated peptide, PKN1-N207 (PKN207), detectable in AD brains with TDP-43 pathology. In mice, PKN207 impairs cognition, memory, and synaptic plasticity. Our findings demonstrate that TDP-43 loss-induced cryptic splicing can generate stable neurotoxic polypeptides, revealing a peptide-mediated mechanism in TDP-43 proteinopathies.
    DOI:  https://doi.org/10.1038/s41467-026-68916-0
  20. Nature. 2026 Feb 18.
    The integrated stress response promotes immune evasion through lipocalin 2.
    Jozef P Bossowski, Ray Pillai, John Kilian, Angela Wong Lau, Mari Nakamura, Ali Rashidfarrokhi, Yuan Hao, Ruxuan Li, Katherine Wu, Takamitsu Hattori, Eliezra Glasser, Akiko Koide, Lidong Wang, Andre L Moreira, Cristina Hajdu, Sahith Rajalingam, Sarah E LeBoeuf, Hortense Le, Seungeun Lee, Jin Woo Oh, Cheolyong Joe, Hyemin Kim, Chan-Young Ock, Se-Hoon Lee, Hao Wang, Angana A H Patel, Volkan I Sayin, Aristotelis Tsirigos, Kwok-Kin Wong, Sergei B Koralov, Mario Pende, Francisco J Sánchez-Rivera, Diane M Simeone, Ioannis K Zervantonakis, Shohei Koide, Thales Papagiannakopoulos.
      Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.
    DOI:  https://doi.org/10.1038/s41586-026-10143-0
  21. Science. 2026 Feb 19. 391(6787): eadr4287
    Ribosomal RNA expansion segments mediate the oligomerization of inactive animal ribosomes.
    Andre Schwarz, Mara Mueller, Helene Will, Lea Dietrich, Stefano L Giandomenico, Georgi Tushev, Ina Bartnik, Iskander Khusainov, Claudia M Fusco, Erin M Schuman.
      Cells down-regulate protein synthesis when stressed to conserve energy and shift resources toward repair. We found that in some mammalian cells, including neurons, stress also resulted in the formation of inactive ribosome-ribosome clusters (disomes). We used cryo-electron tomography (cryo-ET) to visualize ribosomes in situ and observed that this ribosome dimerization was mediated by a homotypic interaction of the ribosomal RNA (rRNA) expansion segment ES31Lb. ES31Lb interactions were both necessary and sufficient for disome formation and conferred a growth advantage and stress resistance to brain cells. ES31Lb is predicted to homodimerize in ~20% of chordates, including variants in both chicken and human. Cryo-ET analysis of chicken tetrasomes revealed an interaction between ES31Lb and ES9La. Thus, in animal cells, translation regulation can use a flexible component of the protein synthesis machinery-rRNA expansion segments.
    DOI:  https://doi.org/10.1126/science.adr4287
  22. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2518354123
    Distinct impact of PI(4)P flux on PI(4,5)P2 steady states and oscillations.
    X J Xǔ, C S Tong, M Wu.
      Plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] regulates indispensable processes such as exocytosis, endocytosis, and actin cytoskeleton remodeling in eukaryotic cells. Since phosphatidylinositol 4-phosphate [PI(4)P] has long been regarded as the primary precursor of PI(4,5)P2, perturbing PM PI(4)P is expected to impact the dynamics of PM PI(4,5)P2. Yet, recent evidence suggests that PM PI(4)P has a limited role in the synthesis and function of PI(4,5)P2. In this paper, we address this puzzling discrepancy by studying the collective dynamics of PM PI(4)P and PI(4,5)P2. Leveraging live-cell imaging, we observed periodic traveling waves of PI(4)P on the PM of mast cells, challenging the notion that this precursor lipid is spatially homogeneous at the PM. We then found that a reduction in PM PI(4)P synthesis rate attenuated PI(4,5)P2 oscillation amplitude while conserving the total PM density of PI(4,5)P2. We assessed the functional consequences of PI(4,5)P2 oscillation amplitude by examining its interplay with Rho GTPase Cdc42, which cooperatively regulates the filamentous actin (F-actin) cytoskeleton with PI(4,5)P2. We showed that both PM PI(4)P and PI(4,5)P2 oscillations are coupled to oscillations of membrane-bound active Cdc42. Finally, we demonstrated that lowering PM PI(4)P synthesis rate alone was sufficient to reversibly quench Cdc42 oscillations and to suppress F-actin oscillations. These results suggest that, beyond the steady-state regime, oscillations of PI(4,5)P2 and its effector proteins require a critical threshold of PI(4)P flux.
    Keywords:  Rho GTPase; oscillations; phosphoinositides
    DOI:  https://doi.org/10.1073/pnas.2518354123
  23. Cell. 2026 Feb 16. pii: S0092-8674(26)00049-8. [Epub ahead of print]
    A single-cell time-series atlas of endothelial cell embryonic development.
    Lihui Lin, Jing Zhong, Fuqing Jiang, Yu-Xiang Wang, Lan-Yue Ma, Jia-Xin Yang, Yu-Yan Li, Rong-Rong Gao, Huijian Feng, Baomei Cai, Ziyu Feng, Xin Zhou, Ya-Hai Shu, Pan Chen, Xue Wu, Chen-Leng Cai, Qiang Wang, Guangming Wu, Duanqing Pei, Shangtao Cao, Yang Liu, Guangdun Peng, Jiekai Chen, Qi Chen.
      Endothelial cells (ECs) are essential components of the vertebrate circulatory system; however, a comprehensive atlas characterizing how ECs acquire organ-specific transcriptomic heterogeneity has not been established. Here, we generated a time-series endothelial resource covering the entirety of mouse embryonic development, including 26 time points and 8 organs. Time-series multi-organ comparison revealed emergence timing and lineage trajectory of organotypic ECs together with organ-specific genes and pathways. Using these resources, we found that most ECs showed distinguishable organ specificity before late gestation. The organotypic EC-enriched genes were associated with vascular function in the organs. Human and mouse pulmonary ECs underwent an evolutionarily conserved transcriptional transition. Endothelial-specific knockout of Casz1, a pulmonary EC-enriched transcription factor, resulted in impaired vascular growth, disturbed pulmonary endothelial organotypic differentiation, and deficient epithelial-EC crosstalk. Our work provides a powerful endothelial resource that reveals fundamental principles of organ-specific EC differentiation and uncovers previously unknown molecular mechanisms governing lung-specific vascular development.
    Keywords:  Casz1; angiogenesis; embryonic development; endothelial cells; interorgan comparison; lung development; organ-specific differentiation; organotypic vessel; single-cell atlas; vascular development
    DOI:  https://doi.org/10.1016/j.cell.2026.01.002
  24. Nat Metab. 2026 Feb 17.
    Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
    Andrea Curtabbi, Sara Natalia Jaroszewicz, Rocío Sanz-Cortés, Rebeca Acín-Pérez, Dimitrios Prymidis, Maksym Cherevatenko, Raquel Martínez-de-Mena, María Jesús Esteban-Amo, Miguel A de la Fuente, Christian Frezza, José Antonio Enríquez.
      Dihydroorotate dehydrogenase is a rate-limiting enzyme of de novo pyrimidine synthesis. In most eukaryotes, this enzyme is bound to the inner mitochondrial membrane, where it couples orotate synthesis to ubiquinone reduction. As ubiquinone must be regenerated by respiratory complex III, pyrimidine biosynthesis and cellular respiration are tightly coupled. Consequently, inhibition of respiration suppresses DNA synthesis and cell proliferation. Here we show that expression of the Saccharomyces cerevisiae URA1 gene (ScURA) in mammalian cells uncouples pyrimidine biosynthesis from mitochondrial electron transport. ScURA forms a homodimer in the cytosol that uses fumarate as an electron acceptor instead of ubiquinone, enabling respiration-independent pyrimidine biosynthesis. Cells expressing ScURA are resistant to drugs that inhibit complex III and the mitochondrial ribosome. Additionally, ScURA enables growth of mitochondrial-DNA-lacking ρ0 cells in uridine-deficient medium and ameliorates the phenotype of cellular models of mitochondrial diseases. Overall, this genetic tool uncovers the contribution of pyrimidine biosynthesis to the phenotypes arising from electron transport chain defects.
    DOI:  https://doi.org/10.1038/s42255-026-01454-7
  25. Nat Rev Mol Cell Biol. 2026 Feb 18.
    Subcellular localization as a driver of protein function.
    Alina Sigaeva, Charlotte Hutchings, Anthony Cesnik, Kathryn S Lilley, Emma Lundberg.
      Biological functions depend on the spatiotemporal distribution of proteins within cells. Key cellular activities such as signal transduction, metabolism, cell cycle and cell death are driven by the interactions of proteins that are localized in multiple cellular compartments. Such multilocalization can even allow protein with identical sequences to display multifunctionality, a phenomenon known as moonlighting. Despite its biological importance, the relationship between protein localization and function remains underexplored. In this Review, we discuss the known mechanisms of protein localization (including RNA transport, role of proteoforms and molecular interactions) and how subcellular localization controls protein function. Proper regulation of protein localization is crucial for specialized cell and tissue functions, including cell differentiation, polarization and the epithelial-mesenchymal transition. Protein mislocalization can also have important roles in pathological processes, such as in cancer, neurodegeneration and autoimmunity. We end with a discussion of current technological and conceptual challenges in the field of subcellular proteomics and spatial biology. Addressing these challenges will allow us to link the dynamic nature of protein localization and function across biological scales and contexts, with great impact on fundamental cell biology and clinical applications.
    DOI:  https://doi.org/10.1038/s41580-026-00947-3
  26. Nat Commun. 2026 Feb 18.
    Conformational biosensors delineate endosomal G protein regulation by GPCRs.
    Brian Wysolmerski, Nicole M Fisher, Andrew N Dates, Asuka Inoue, Emily E Blythe, Mark von Zastrow.
      Many GPCRs trigger a second phase of G protein-coupled signaling from endosomes after signaling from the plasma membrane, necessitating GPCRs to increase the concentration of active-state G proteins on the endosome membrane. How this is achieved remains unclear. Here, we show that three Gs-coupled GPCRs-the β2-adrenergic receptor, VIP-1 receptor, and adenosine 2B receptor-each trigger a net redistribution of Gαs from the plasma membrane to endosomes at native expression levels and without requiring receptor internalization. We then show that active-state Gαs production on endosomes, in contrast, is GPCR internalization-dependent. We further identify location bias in the selectivity of GPCR coupling between Gs and Gq on endosomes relative to the plasma membrane. We propose that endosomal Gs regulation involves discrete GPCR-G protein coupling reactions, one at the plasma membrane controlling Gs concentration and another at endosomes controlling Gs activity, and that GPCR endocytosis can switch signaling selectivity between G protein classes.
    DOI:  https://doi.org/10.1038/s41467-026-69329-9
  27. Cell Stem Cell. 2026 Feb 13. pii: S1934-5909(26)00030-5. [Epub ahead of print]
    Prevention of transgene silencing during human pluripotent stem cell differentiation.
    Takeshi Uenaka, Alan Napole, Aninda Dibya Saha, Duo Sun, Angelina Singavarapu, Elizabeth Calzada, Jiahui Chen, Lena Erlebach, Amanda McQuade, Daniel M Ramos, Alessandra Rigamonti, Lisa Salazar, Avi J Samelson, Kamilla Sedov, Natalie J Welsh, Katleen Wild, Qianxin Wu, Ernest Arenas, Andrew R Bassett, Martin Kampmann, Deborah Kronenberg-Versteeg, Florian T Merkle, Birgitt Schüle, Leslie M Thompson, William C Skarnes, Michael E Ward, Marius Wernig.
      Transgenes are often silenced upon differentiation of pluripotent stem cells using conventional expression systems. Here, we developed the TK4 PiggyBac vector to conduct a comparative analysis to evaluate the impact of various promoters, transcriptional regulatory elements, insulators, and genomic integration sites on transgene silencing during neuronal differentiation. Our findings reveal that specific combinations of CAG and Ubc promoters with the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) can prevent transgene silencing during differentiation, whereas chromatin insulators have less impact on sustained expression. Three novel safe harbor loci, distant from known genes, as well as the citrate lyase beta-like (CLYBL) locus, similarly support the prevention of transgene silencing. Remarkably, the TK4 vector showed complete resistance to silencing across various neuronal and microglial differentiation protocols, as independently confirmed by seven laboratories. This construct will be highly useful for assays requiring stable transgene expression during differentiation and holds potential for broad applications in various research fields.
    Keywords:  PiggyBac vector; UCOE; WPRE; chromatin insulator; human pluripotent stem cells; microglia; neuron; promoter activity; safe harbor locus; transgene silencing; ubiquitous chromatin opening element; woodchuck hepatitis posttranscriptional regulatory element
    DOI:  https://doi.org/10.1016/j.stem.2026.01.007
  28. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2513031123
    Lamin B receptor upregulation in metastatic melanoma causes nuclear envelope fragility in confined migration during cancer invasion.
    Michelle A Baird, Cayla E Jewett, Daniela A Malide, Lisa Kratz, Alexander X Cartagena-Rivera, Robert S Fischer, Clare M Waterman.
      Cancer cells migrate through regions of tissue confinement during metastasis, causing nuclear envelope (NE) rupture, which generates heritable DNA damage and disease aggression. We sought to determine if NE rupture was intrinsic to malignant transformation and seek a mechanistic cause. We found that metastatic cells from multiple cancer subtypes have increased NE fragility in confinement compared to their benign counterparts. Meta-analysis of transcriptomic data from clinical samples of melanoma progression together with an siRNA-based live-cell confinement screen revealed that lamin B receptor (LBR) transcriptional upregulation correlates with melanoma progression and NE fragility. LBR is an inner nuclear membrane protein (INM) that scaffolds lamins and chromatin and has sterol reductase activity in the cholesterol biosynthesis pathway. Applying superresolution and atomic force microscopies to characterize the cellular and biophysical events leading to NE rupture revealed that upregulated LBR increased nuclear deformability and can generate local ruptures of the INM, promoting blebs in the nuclear membrane that burst to release nuclear contents into the cytoplasm. Structure-function analysis showed that LBR's sterol reductase activity is required for its promotion of NE fragility in cells confined in vitro. Use of tumor organoids and an in vivo melanoma model revealed that upregulation of LBR was associated with increased NE fragility, metastatic invasion, and decreased patient survival. Thus, upregulation of LBR in melanoma promotes nuclear deformability, while LBR's sterol reductase activity causes fragility and instability of the nuclear membrane, and these changes in the nucleus provide a possible mechanism for increased genetic heterogeneity in melanomas.
    Keywords:  melanoma; metastasis; nuclear envelope; nuclear rupture; nucleus
    DOI:  https://doi.org/10.1073/pnas.2513031123
  29. Angew Chem Int Ed Engl. 2026 Feb 17. e20273
    Fluorescence Amplification Tags for Single-Molecule Imaging and Tracking of Proteins, RNA, and DNA in Live Cells.
    Yifan Bao, Tianle Xiong, Arnaud Gautier, Murat Sunbul, Lu Wang.
      Single-molecule imaging and tracking of DNA, RNA, and proteins have revolutionized molecular and cellular biology by shifting the focus from population-level analyses to the direct observation of individual molecular events. However, conventional fluorescent labeling strategies, which tag biomolecules with a single fluorophore, are often hindered by low brightness, suboptimal signal-to-noise ratio (SNR), and rapid photobleaching, limiting localization precision and tracking duration. To overcome these challenges in single-molecule imaging, fluorescence amplification tags (FATs) have been developed to enable the multiplexed labeling of individual macromolecules with multiple fluorescent reporters, enhancing signal intensity and photostability. This review presents a comprehensive overview of FAT design principles, working mechanisms, and their applications in labeling DNA, RNA, and proteins. We highlight their impact on elucidating dynamic genetic processes, including chromatin remodeling, gene expression regulation, mRNA translation, and protein interactions. Finally, we discuss existing challenges and propose future directions to further optimize FATs for single-molecule imaging and tracking.
    Keywords:  DNA; RNA; fluorescence amplification tag; protein; single‐molecule imaging
    DOI:  https://doi.org/10.1002/anie.202520273
  30. EMBO J. 2026 Feb 19.
    TRPML1 suppresses pulmonary fibrosis by limiting collagen and elastin deposition.
    Eva-Maria Weiden, Zala Serianz, Yvonne Klingl, Simone Jörs, Dawid Jaślan, Marco Keller, Sandra Prat Castro, Mane Mkhitaryan, Aicha Jeridi, Daria Briukhovetska, Barbara Spix, Anna Scotto Rosato, Ahmed Agami, Herbert B Schiller, Suhasini Rajan, Johann Schredelseker, Giorgio Fois, Manfred Frick, Sebastian Kobold, Margarethe Klein, Fabian Geisler, Jorge Garcia-Fortanet, Leon O Murphy, Franz Bracher, Christian Wahl-Schott, Thomas Gudermann, Alexander Dietrich, Martin Biel, Ali Önder Yildirim, Christian Grimm.
      In pulmonary fibrosis lung tissue is thickened and scarred, and the lungs become progressively stiffer and smaller, leading to low levels of blood oxygen and shortness of breath. Lung fibrosis is not curable and life expectancy is reduced. Fibrosis is characterized by an increased accumulation of extracellular matrix (ECM) proteins such as collagen and elastin. ECM proteins are degraded predominantly by matrix metalloproteinases (MMPs). Here, we show that the lysosomal cation channel TRPML1, which causes the lysosomal storage disorder mucolipidosis type IV (MLIV) when mutated or lost, regulates the levels of MMPs in the ECM of mouse airways, modulating exocytosis of MMP2, 8, 9, 12, and 19, which mediate collagen/elastin degradation. While TRPML1 loss reduces MMP levels in lung macrophage and fibroblast supernatants, small molecule activation of TRPML1 results in increased levels. MLIV mice display a fibrosis-like lung phenotype similar to the phenotype evoked by bleomycin. We thus identify TRPML1 as a regulator of MMP release in the lung with loss of TRPML1 resulting in lung fibrosis due to excessive extracellular collagen and elastin accumulation.
    Keywords:  Mcoln1; Pulmonary Fibrosis; TRPML; TRPML1; TRPML3
    DOI:  https://doi.org/10.1038/s44318-026-00712-4
  31. Biophys J. 2026 Feb 13. pii: S0006-3495(26)00112-8. [Epub ahead of print]
    Spatial relationships between vinculin tension and actin at cell adhesions define cell colony positioning and identity.
    Abigail Nagle, Cherry Leung, Elaheh Karbassi, Jessica Young, Michael Regnier, Jennifer Davis.
      The protein vinculin mediates actin-myosin-dependent adhesion strength to regulate force transmission at cellular adhesions. The precise distribution of forces sensed by vinculin that regulates downstream cellular processes remains unclear. To determine vinculin tension in multiple cell types, a FRET-based tension-sensitive module was knocked into the vinculin locus of human induced pluripotent stem cells. Measurements of vinculin tension and adhesion spatial distributions were used to create mechanical profiles that identify cellular origin and differentially correlate to cell shape characteristics. In stem cell colonies, edge cell morphology depended on high vinculin tension in basal adhesions connected to actin. These mechanical signatures were able to determine progression toward cardiomyocyte versus neural lineage commitment. Our findings suggest that spatial mapping of vinculin tension can define mechanical profiles that differentially correlate to cell morphologies that affect cell function and lineage fate.
    DOI:  https://doi.org/10.1016/j.bpj.2026.02.010
  32. Nature. 2026 Feb 18.
    Roles of microtubules and LIS1 in dynein transport machinery assembly.
    Qinhui Rao, Jun Yang, Pengxin Chai, Steven Markus, Kai Zhang.
      Cytoplasmic dynein-1, a microtubule (MT)-based motor protein, requires dynactin and a coiled-coil adaptor to form the processive dynein-dynactin-adaptor (DDA) complex1,2. The roles of MTs and dynein regulator lissencephaly-1 (LIS1) in DDA assembly have remained elusive. Here we use cryo-electron microscopy to determine the structural basis of MT- and LIS1-mediated DDA assembly. We show that an adaptor-independent dynein-dynactin complex spontaneously forms on MTs with an intrinsic 2:1 stoichiometry in a highly efficient manner, driven by parallel alignment of dynein tails upon MT binding. Adaptors can wedge into and exchange within the assembled MT-bound dynein-dynactin complex; these processes are enabled by relative rotations between dynein and dynactin and facilitated by the dynein light-intermediate chains that assist the adaptor 'search' mechanism. Although LIS1 is dispensable for efficient DD(A)-MT assembly, its presence expands the conformational landscape of DD(A) assemblies on MTs. Cryo-electron microscopy reveals that LIS1 bridges dynactin p150glued and dynein in both the closed Phi-like and open prepowerstroke states, stabilizing low-MT-affinity intermediates that tether dynein molecules in proximity to MTs and prime them for subsequent DD(A) assembly through alternative pathways. These findings demonstrate the dynamic adaptability of the dynein transport machinery and the coordinated roles of MTs and LIS1 in DDA assembly.
    DOI:  https://doi.org/10.1038/s41586-026-10153-y
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