Paquola A, Benson CE, Desale SE
… +7 more, Ozbalci C, Storck EM, Terry SJ, Rao BD, Nwite KN, Ferrentino F, Eggert US
Nat Cell Biol
· 2026 May · PMID 41975099
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Cells actively maintain complex lipidomes that encompass thousands of lipids; however, many of the roles of these lipids remain unexplored. Specific interactions between lipids and membrane proteins are a likely reason f...Cells actively maintain complex lipidomes that encompass thousands of lipids; however, many of the roles of these lipids remain unexplored. Specific interactions between lipids and membrane proteins are a likely reason for lipidome complexity. Here we report the development of a technique, named lipid-trap mass spectrometry (LTMS), to systematically study lipid-protein interactions directly captured from mammalian cells. LTMS uses immunoprecipitation of GFP-tagged proteins expressed in HeLa cells, followed by lipidomic analysis of lipids bound to the GFP-tagged protein. We applied LTMS to cell division to illustrate the technique. We chose this process because membranes regulate their lipid composition as they undergo major changes during cytokinesis, and many cytokinetic proteins, including RACGAP1 and ESCRT-III components CHMP4B and CHMP2A, are membrane-associated. Using LTMS, we found that RACGAP1 and CHMP4B associate with specific lipid species in dividing compared with non-dividing cells. We expand our understanding of lipid diversity during cell division and present a general approach to explore lipid-protein interactions to further our knowledge of the roles of lipids in mammalian cells.
Human stem-cell-based embryo models (hSCBEMs) offer unprecedented opportunities for basic and translational research. However, the rapid pace of scientific developments in the field challenges the slower, traditional mod...Human stem-cell-based embryo models (hSCBEMs) offer unprecedented opportunities for basic and translational research. However, the rapid pace of scientific developments in the field challenges the slower, traditional modes of ethics evaluation. To facilitate responsible research and governance, and ensure public trust, we propose using 'embedded ethics' as a purpose-anchored, dynamic, iterative and integrative approach where ethicists and scientists engage in continuous dialogue to ethically assess ongoing research. We outline a nested benchmarking strategy to periodically evaluate the scientific and ethical status of hSCBEMs within a project, using the human embryo as a reference and weighting criteria along a hierarchy of features that chart embryo-likeness, completeness and the developmental stage modelled. Embedded ethics guides the definition of decision points and ethical boundaries through an iterative assessment of project purpose and ethical and regulatory frameworks, and enables early identification of emerging issues and the co-construction of responsible paths forward.
Moris N, Martinez Arias A, Pera M
… +3 more, Rivron N, Sermon K, de Graeff N
Nat Cell Biol
· 2026 Apr · PMID 41951754
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Stem cell-based embryo models provide innovative ways to explore the principles of human development but also pose new challenges for regulation. Recent guidelines have argued for case-by-case evaluation of stem cell-bas...Stem cell-based embryo models provide innovative ways to explore the principles of human development but also pose new challenges for regulation. Recent guidelines have argued for case-by-case evaluation of stem cell-based embryo model research but it is still unclear what exactly such oversight should consider. Here we argue that effective review requires the identification of a set of attributes by which to evaluate research proposals. To define these, the underlying ethical values and morally relevant biological features present in embryo models must be identified to enable the practical implementation of oversight. We propose that developmental stage, tissue/organ integrity, fetal potential and the capacity to form neural circuits should be used together for evaluation purposes. We also highlight the importance of the wider context, including the proposed uses of embryo models, public perception and individual researcher responsibilities, and thus provide a general framework for regulatory consideration of human embryo model research.
Xiang J, Wang T, Tian S
… +23 more, Li J, Luo M, Wang Y, Du A, Chen X, Tian F, Wang L, Zhang Y, Han M, Hou W, Wang X, Hou T, Liu Q, Chen D, Wen L, Qin Z, Li X, Jiang C, Zhang Q, Liu P, Bian X, Wei W, Wang B
Acute activation of mTORC1 by amino acids (AAs) is pivotal for growth regulation, yet it remains unclear how the intracellular nutrient-sensing machinery might be rewired by environmental cues to execute distinct functio...Acute activation of mTORC1 by amino acids (AAs) is pivotal for growth regulation, yet it remains unclear how the intracellular nutrient-sensing machinery might be rewired by environmental cues to execute distinct functions. Here we report that, despite nutrient insufficiency, cancer-intrinsic AA-sensing mTORC1 signalling is hijacked by inflammatory cytokines in the tumour microenvironment (TME). ZBTB5 translates inflammatory signals to restore mTORC1 pathway via disrupting the GATOR1 complex. Mechanistically, inflammatory cues promote phosphorylation of ZBTB5-S127, thereby recruiting the Cullin3 E3 ubiquitin ligase to degrade NPRL2 within GATOR1 and reactivate mTORC1 signalling. Consequently, tumoural AA uptake is boosted to exacerbate nutrient restriction and death of CD8 T cells, leading to immunoevasion, tumour progression and inferior response to immune-checkpoint inhibitors. As such, blocking ZBTB5-pS127 ameliorates primary and acquired resistance to checkpoint blockade. Thus, targeting aberrant nutrient-sensing via the ZBTB5-pS127-mTORC1 axis represents a proof-of-concept strategy to sensitize cancer immunotherapy by alleviating AA restriction in the TME.
Trogocytosis, the transfer of plasma membrane fragments during cell-cell contact, offers potential for macromolecular delivery but is limited by the uncertain fate of trogocytosed molecules, restriction to membrane cargo...Trogocytosis, the transfer of plasma membrane fragments during cell-cell contact, offers potential for macromolecular delivery but is limited by the uncertain fate of trogocytosed molecules, restriction to membrane cargo and unclear generalizability. Here we demonstrate that donor cells engineered with designed receptors specific to surface ligands can transfer proteins to recipient cells through direct contact. We identified key engineering principles for enhancing transfer and ensuring cargo functionalization, including receptor design, pH-responsive membrane fusion, inducible cargo localization and release, and subcellular translocation. The method is broadly applicable across diverse cell types and operates through a dynamin- and endosome acidification-dependent pathway. Exploiting these findings, we developed TRANSFER, a versatile delivery system with programmable cell type specificity and tunability. TRANSFER can sense multiple ligand inputs, deliver large therapeutic protein cargos and mediate genome editing. The study establishes trogocytosis as a programmable, versatile framework for cell-based macromolecular delivery.
Frenster JD, Babin S, Casani-Galdon P
… +8 more, Josende-Garcia JB, Pascual-Mas P, Robertson G, Edri S, Wehmeyer AE, Arnold SJ, Garcia Ojalvo J, Martinez Arias A
Nat Cell Biol
· 2026 May · PMID 41922518
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Selective elimination of suboptimal cells is critical for the developmental integrity of early mammalian embryogenesis. Cell competition is a non-autonomous quality control in which 'winner' cells outcompete viable but s...Selective elimination of suboptimal cells is critical for the developmental integrity of early mammalian embryogenesis. Cell competition is a non-autonomous quality control in which 'winner' cells outcompete viable but suboptimal 'loser' cells based on fitness differences. Here we investigate cell competition dynamics using mosaic mouse gastruloids, a 3D embryonic stem cell-based model of gastrulation. Introducing just two Trp53-deficient supercompetitor cells suffices to impair growth in neighbouring wild-type cells through mitochondrial apoptosis. Competition is tightly restricted to a developmental transition stage between primed pluripotency and early gastrulation and involves gene regulatory networks of pluripotency exit. Heterochronic gastruloids from developmental stage-shifted cells, EpiGastruloids, and dynamic p53-degrons reveal that both winners and losers must reside within this permissive stage, during which acute relative p53 protein levels determine competitive outcomes. These findings advance our understanding of cell fitness evaluation and establish gastruloids as a powerful 3D model for investigating developmental stage-specific cell competition in mammalian embryogenesis.
You W, Hu C, Zhang Y
… +17 more, Huang Y, Yuan J, Wu CY, Kong D, Zhao M, Han Y, Li S, Shan R, Lu J, Cheng M, Li Q, Yao B, Yu XF, Xia Q, Chong W, Kuang DM, Chen Y
Nat Cell Biol
· 2026 May · PMID 41912896
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Patients with impaired tumour-specific major histocompatibility complex class I (tsMHC-I) often fail to respond to immune checkpoint blockade (ICB), presenting a major clinical challenge. However, through our multicentre...Patients with impaired tumour-specific major histocompatibility complex class I (tsMHC-I) often fail to respond to immune checkpoint blockade (ICB), presenting a major clinical challenge. However, through our multicentre investigation, we observed that a subset of patients with tsMHC-I remains responsive to ICB, a phenomenon that has not been fully explained. Here we identify a COTL1 natural killer (NK) subset that mediates ICB responsiveness in these patients. Mechanistically, PD-L1 macrophages coexpress GITRL and engage GITR on COTL1 NK cells, whereas PD-L1 blockade relieves the PD-1-mediated inhibition of GITR signalling and promotes NK cell activation. Activated COTL1 NK cells enhance immunological synapse stability and IFN-γ production via a metabolic-H3K27ac-RBPJ axis, thereby upregulating tsMHC-I expression and reinforcing adaptive anti-tumour immunity. Notably, GITR activation significantly enhances the sensitivity to anti-PD-L1 therapy in tsMHC-I models. Our findings identify COTL1 NK cells as key determinants of ICB responsiveness and highlight the GITRL-GITR axis as a promising therapeutic target for tsMHC-I tumours.
Yu X, Song X, Schäfer RA
… +9 more, Meng Q, Tiek D, Wu R, He Q, Walker M, Cao Q, Yang R, Hu B, Cheng SY
Nat Cell Biol
· 2026 May · PMID 41896311
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EGFR amplification frequently occurs within extrachromosomal DNAs (ecDNAs) and is the most prevalent mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments has been unsuccessful. Here we show a long n...EGFR amplification frequently occurs within extrachromosomal DNAs (ecDNAs) and is the most prevalent mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments has been unsuccessful. Here we show a long non-coding RNA (lncRNA) that is co-amplified with EGFR, which we name hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-selective lncRNA that promotes tumorigenicity independent of EGFR signalling. HELDR exhibits widespread chromatin association and recruits the transcription co-activator p300 to the KAT7 promoter. p300-induced H3K27ac at the KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac and H4K12ac that activate KAT7-driven gene programmes that are critical for GBM malignancy. Targeting KAT7 or HELDR markedly enhances therapeutic effects of anti-EGFR treatments for GBM. These results not only reveal the role of HELDR in EGFR-amplified GBM but also provide a strong rationale to characterize the role of lncRNAs co-amplified with driver oncogenes in human cancers.
Markiewicz-Potoczny M, Lee SY, Chatterjee S
… +6 more, Mabin JW, Zinsser A, Sandhu R, Tricola G, Hogg JR, Lazzerini Denchi E
Nat Cell Biol
· 2026 Apr · PMID 41876871
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Telomeres are protective DNA caps at chromosome ends that prevent cells from mistakenly recognizing them as broken DNA. These structures are safeguarded by a protein complex called Shelterin, particularly through the TRF...Telomeres are protective DNA caps at chromosome ends that prevent cells from mistakenly recognizing them as broken DNA. These structures are safeguarded by a protein complex called Shelterin, particularly through the TRF2 protein encoded by Trf2. Surprisingly, in mouse embryonic stem cells, TRF2 is not essential for telomere protection, suggesting that other mechanisms compensate for its loss. Here we show that a cellular quality control system called nonsense-mediated mRNA decay (NMD), which normally eliminates defective RNA molecules, plays an unexpected role in maintaining telomere integrity in pluripotent cells. Through a genome-wide genetic screen, we discovered that NMD is essential for cell survival when TRF2 is absent. NMD accomplishes this by degrading an aberrant form of the messenger RNA encoded by Trf1, which produces the TRF1 protein, another Shelterin component. Without NMD, this aberrant RNA produces a truncated, harmful version of TRF1 that interferes with normal telomere protection. Our findings reveal that embryonic stem cells use a unique strategy for chromosome end protection, linking RNA quality control to genome stability in a previously unrecognized way.
Lennartz HM, Khan S, Leng W
… +8 more, Böhlig K, Fabig G, Kieswald Y, Elsner F, Scher N, Wilsch-Bräuninger M, Avinoam O, Nadler A
Nat Cell Biol
· 2026 Apr · PMID 41862633
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Lipids and proteins compartmentalize biological membranes into nanoscale domains, which are crucial for signalling, intracellular trafficking and many other cellular processes. Studying nanodomain function requires the a...Lipids and proteins compartmentalize biological membranes into nanoscale domains, which are crucial for signalling, intracellular trafficking and many other cellular processes. Studying nanodomain function requires the ability to measure protein and lipid localization at the nanoscale. Current methods for visualizing lipid localization do not meet this requirement. Here we introduce a correlative light and electron microscopy workflow to image lipids (Lipid-CLEM), combining near-native lipid probes and on-section labelling by click chemistry. This approach enables the quantification of relative lipid densities in membrane nanodomains. We find differential partitioning of sphingomyelin into intraluminal vesicles, recycling tubules and the boundary membrane of the early endosome, representing a degree of nanoscale organization previously observed only for proteins. We anticipate that our Lipid-CLEM workflow will greatly facilitate the mechanistic analysis of lipid functions in cell biology, allowing for the simultaneous investigation of proteins and lipids during membrane nanodomain assembly and function.
Hodgson RE, Huang WP, Lang R
… +23 more, Kumar V, An H, Stender EGP, Chalakova ZP, Driver MD, Sanchez Avila A, Ellis BCS, Day E, Rayment JA, Baeg K, Strange A, Moll T, Wright GSA, van Vugt JJFA, Project MinE ALS Sequencing Consortium, Allen SP, Locker N, Pitout I, Fletcher S, Onck PR, Duss O, Cooper-Knock J, Shelkovnikova TA
Nat Cell Biol
· 2026 Apr · PMID 41851271
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The paraspeckle is a disease-relevant biomolecular condensate assembled from long non-coding RNA (lncRNA) NEAT1_2 ribonucleoprotein particles. Paraspeckle biogenesis is suppressed in normal tissues, yet it can be rapidly...The paraspeckle is a disease-relevant biomolecular condensate assembled from long non-coding RNA (lncRNA) NEAT1_2 ribonucleoprotein particles. Paraspeckle biogenesis is suppressed in normal tissues, yet it can be rapidly upregulated under stress. Here we demonstrate that a neurodegeneration-linked RNA-binding protein TDP-43 inhibits NEAT1_2 ribonucleoprotein particle condensation into the paraspeckle, in a concentration-dependent manner, which requires its intact polymerization and RNA binding. This effect is counterbalanced by core paraspeckle proteins such as FUS. Below disruptive concentrations, TDP-43 can be recruited into paraspeckles, forming non-liquid clusters. Under stress, TDP-43 sequestration into de novo nuclear condensates alleviates paraspeckle suppression and increases their dynamism. NEAT1_2 middle-part and 3'-end UG repeats mediate paraspeckle regulation by TDP-43 cotranscriptionally and post assembly, respectively. The deletion of the 3'-end UG repeat increases paraspeckle stability and cytoprotection in stressed human neurons. Consistently, longer 3'-end UG repeats are linked to shorter survival in the neurodegenerative disease amyotrophic lateral sclerosis. Thus, TDP-43 is a critical regulator of paraspeckle condensates linked to cytoprotection.
He S, Lemma LM, Martinez-Calvo A
… +12 more, He G, Hennacy JH, Wang L, Ergun SL, Rai AK, Wang C, Bunday L, Kayser-Browne A, Wang Q, Brangwynne CP, Wingreen NS, Jonikas MC
Nat Cell Biol
· 2026 Apr · PMID 41845050
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Biomolecular condensates spatially organize cellular functions, but the regulation of their size, number, dissolution and re-condensation is poorly understood. The pyrenoid, an algal biomolecular condensate that mediates...Biomolecular condensates spatially organize cellular functions, but the regulation of their size, number, dissolution and re-condensation is poorly understood. The pyrenoid, an algal biomolecular condensate that mediates one-third of global CO fixation, typically exists as one large condensate per chloroplast, but during cell division it transiently dissolves and reconfigures into multiple smaller condensates. Here, we identify a kinase, KEY1, in the model alga Chlamydomonas reinhardtii that regulates pyrenoid condensate size and number dynamics throughout the cell cycle and is necessary for normal pyrenoid function and growth. Unlike the wild type, key1 mutant cells have multiple smaller condensates throughout the cell cycle that fail to dissolve during cell division. We show that KEY1 localizes to the condensates and promotes their dissolution by disrupting interactions between their core constituents, the CO-fixing enzyme Rubisco and its linker protein EPYC1, through EPYC1 phosphorylation. We develop a biophysical model that recapitulates KEY1-mediated condensate size and number regulation and suggests a mechanism for controlling condensate position. These data provide a foundation for the mechanistic understanding of the regulation of size, number, position and dissolution in pyrenoids and other biomolecular condensates.
Hoffmann L, Duchmann M, Lazarow K
… +11 more, Huang YH, Lukas F, Lo WT, Feil R, Schmied C, Lehmann M, Lunn JE, Piazza I, von Kries JP, Haucke V, Maritzen T
Nat Cell Biol
· 2026 Apr · PMID 41840126
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Cellular adhesion to the extracellular matrix is essential for morphogenesis, tissue integrity and survival signalling. The best understood adhesion structures are focal adhesions (FAs). In spite of their importance, our...Cellular adhesion to the extracellular matrix is essential for morphogenesis, tissue integrity and survival signalling. The best understood adhesion structures are focal adhesions (FAs). In spite of their importance, our knowledge of upstream factors that integrate FA dynamics with other cellular processes, such as metabolism, remains fragmentary. Using a genome-wide screen, we identify aldolase A, a key glycolytic enzyme that converts fructose-1,6-bisphosphate (FBP), as a regulatory switch that links metabolic flux to FA assembly and cell morphogenesis. We show that cellular FBP serves as a signalling metabolite, which transmits information about the metabolic cell state to the actin-based machinery for cell adhesion and protrusion. This mechanism involves FBP binding to the Rac1 inhibitor RCC2 and a concomitant elevation of Rac1 activity resulting in actin reorganization, increased FA assembly and elevated protrusive activity. Here we predict this mechanism to be crucial for processes ranging from development to cancer.
Chica N, Andersen AN, Orellana-Muñoz S
… +11 more, Garcia I, P AN, Nakken S, Ayuda-Durán P, Håkensbakken L, Schultz SW, Rødningen E, Putnam CD, Zucknick M, Rusten TE, Enserink JM
Nat Cell Biol
· 2026 Mar · PMID 41826700
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Recycling of cellular components through autophagy maintains homeostasis in changing nutrient environments. Although its core mechanisms are extensively studied, understanding of its systems-wide dynamic regulation remai...Recycling of cellular components through autophagy maintains homeostasis in changing nutrient environments. Although its core mechanisms are extensively studied, understanding of its systems-wide dynamic regulation remains limited, particularly regarding how autophagy is inactivated once nutrients are restored. Here we mapped the genetic network that controls activation and inactivation of autophagy during nitrogen changes by combining time-resolved high-content imaging, deep learning and latent feature analysis. This dataset, termed AutoDRY, categorizes 5,919 mutants based on nutrient response kinetics and their contributions to autophagosome formation and clearance. Integrating these profiles with functional and genetic network data uncovered hierarchical and multilayered control of autophagy and revealed multiple new regulatory pathways. Notably, we identified the retrograde pathway as a pivotal time-varying modulator that tunes the expression of core autophagy genes and plays a central role in autophagy inactivation. Together, this study establishes a systems-level resource to guide future investigations of autophagy.
Skafar V, de Souza I, Ghosh B
… +30 more, Ferreira Dos Santos A, Porto Freitas F, Chen Z, Sun S, Donate Castillo M, Nepachalovich P, Seufert L, Bothe S, Tschuck J, Mathur A, Nunes-Alves A, Buhr J, Aponte-Santamaría C, Schmitz W, Mack M, Eilers M, Bargou R, Chaufan M, Kaur M, Palma M, Ubellacker JM, Elling U, Augustin HG, Hadian K, Meierjohann S, Proneth B, Conrad M, Fedorova M, Alborzinia H, Friedmann Angeli JP
Nat Cell Biol
· 2026 Apr · PMID 41826699
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Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. More recently, ferroptosis sup...Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor, acting via the regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterized, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here we report a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B) as a modulator of ferroptosis sensitivity. We demonstrate that riboflavin supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitizes cancer cells to ferroptosis. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients, as well as their contributions to a cell's antioxidant capacity.