Pub Date : 2025-12-19DOI: 10.1038/s41556-025-01834-3
Jarrett Smith, David P. Bartel
When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs. Smith and Bartel show that mRNA recruitment to stress granules imparts resistance to the integrated stress response translational shutdown.
{"title":"The G3BP stress-granule proteins reinforce the integrated stress response translation programme","authors":"Jarrett Smith, David P. Bartel","doi":"10.1038/s41556-025-01834-3","DOIUrl":"10.1038/s41556-025-01834-3","url":null,"abstract":"When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs. Smith and Bartel show that mRNA recruitment to stress granules imparts resistance to the integrated stress response translational shutdown.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"135-148"},"PeriodicalIF":19.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01834-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1038/s41556-025-01835-2
Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H. Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B. Compeer, Felix C. Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L. Dustin, Linda V. Sinclair, Pekka Katajisto, Anna Katharina Simon
T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function. Borsa et al. show that asymmetric T cell division after activation requires autophagy to promote mitochondrial turnover, with T cells inheriting older mitochondria showing decreased degradation, reduced memory potential and altered metabolism.
{"title":"Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment","authors":"Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H. Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B. Compeer, Felix C. Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L. Dustin, Linda V. Sinclair, Pekka Katajisto, Anna Katharina Simon","doi":"10.1038/s41556-025-01835-2","DOIUrl":"10.1038/s41556-025-01835-2","url":null,"abstract":"T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function. Borsa et al. show that asymmetric T cell division after activation requires autophagy to promote mitochondrial turnover, with T cells inheriting older mitochondria showing decreased degradation, reduced memory potential and altered metabolism.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"66-81"},"PeriodicalIF":19.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01835-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1038/s41556-025-01832-5
Byung Ho Lee, Kana Fuji, Heike Petzold, Phil Seymour, Siham Yennek, Coline Schewin, Allison Lewis, Daniel Riveline, Tetsuya Hiraiwa, Masaki Sano, Anne Grapin-Botton
Lumen formation in organ epithelia involves processes such as polarization, secretion, exocytosis and contractility, but what controls lumen shape remains unclear. Here we study how lumina develop spherical or complex structures using pancreatic organoids. Combining computational phase-field modelling and experiments, we found that lumen morphology depends on the balance between cell cycle duration and lumen pressure, low pressure and high proliferation produce complex shapes. Manipulating proliferation and lumen pressure can alter or reverse lumen development both in silico and in vitro. Increasing epithelial permeability reduces lumen pressure, converting from spherical to complex lumina. During pancreas development, the epithelium is initially permeable and becomes sealed, experimentally increasing permeability at late stages impairs ductal morphogenesis. Overall, our work underscores how proliferation, pressure and permeability orchestrate lumen shape, offering insights for tissue engineering and cystic disease treatment. Using pancreatic organoids, Lee et al. show that the balance between epithelial tissue permeability-driven lumenal pressure and cell proliferation affects ductal morphogenesis.
{"title":"Permeability-driven pressure and cell proliferation control lumen morphogenesis in pancreatic organoids","authors":"Byung Ho Lee, Kana Fuji, Heike Petzold, Phil Seymour, Siham Yennek, Coline Schewin, Allison Lewis, Daniel Riveline, Tetsuya Hiraiwa, Masaki Sano, Anne Grapin-Botton","doi":"10.1038/s41556-025-01832-5","DOIUrl":"10.1038/s41556-025-01832-5","url":null,"abstract":"Lumen formation in organ epithelia involves processes such as polarization, secretion, exocytosis and contractility, but what controls lumen shape remains unclear. Here we study how lumina develop spherical or complex structures using pancreatic organoids. Combining computational phase-field modelling and experiments, we found that lumen morphology depends on the balance between cell cycle duration and lumen pressure, low pressure and high proliferation produce complex shapes. Manipulating proliferation and lumen pressure can alter or reverse lumen development both in silico and in vitro. Increasing epithelial permeability reduces lumen pressure, converting from spherical to complex lumina. During pancreas development, the epithelium is initially permeable and becomes sealed, experimentally increasing permeability at late stages impairs ductal morphogenesis. Overall, our work underscores how proliferation, pressure and permeability orchestrate lumen shape, offering insights for tissue engineering and cystic disease treatment. Using pancreatic organoids, Lee et al. show that the balance between epithelial tissue permeability-driven lumenal pressure and cell proliferation affects ductal morphogenesis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"113-124"},"PeriodicalIF":19.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01832-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1038/s41556-025-01813-8
Komal Makwana, Louise Tilley, Probir Chakravarty, Jamie Thompson, Peter Baillie-Benson, Ignacio Rodriguez-Polo, Naomi Moris
Human stem cell-based embryo models provide experimentally amenable in vitro systems for developmental research. A key feature of embryo models is their multi-lineage differentiation, which allows for the study of tissue co-development. Here we develop human trunk-like structures that have morphologically organized somites and a neural tube that form through self-organized, endogenous signalling. Transcriptomic comparison with human embryo datasets suggests that human trunk-like structure cells approximate Carnegie stage 13–14 (28–35 days after fertilization). The absence of a notochord leads to a dorsal identity, but exogenous Sonic Hedgehog signalling activation ventralizes both the somites and the neural tube in a dose-dependent manner. We further identify reciprocal signalling: neural tube-derived cues induce medial ALDH1A2 in somites, which in turn generate retinoic acid signals that drive spontaneous neural-tube patterning. Together, our data highlight the value of modularity in embryo models, which we leverage to explore human trunk co-development. Makwana, Tilley et al. generate human stem cell-based trunk-like structures approximating Carnegie stage 13–14 of development. They use them to model and study the development of the thoracic and lumbar trunk.
{"title":"Modelling co-development between the somites and neural tube in human trunk-like structures","authors":"Komal Makwana, Louise Tilley, Probir Chakravarty, Jamie Thompson, Peter Baillie-Benson, Ignacio Rodriguez-Polo, Naomi Moris","doi":"10.1038/s41556-025-01813-8","DOIUrl":"10.1038/s41556-025-01813-8","url":null,"abstract":"Human stem cell-based embryo models provide experimentally amenable in vitro systems for developmental research. A key feature of embryo models is their multi-lineage differentiation, which allows for the study of tissue co-development. Here we develop human trunk-like structures that have morphologically organized somites and a neural tube that form through self-organized, endogenous signalling. Transcriptomic comparison with human embryo datasets suggests that human trunk-like structure cells approximate Carnegie stage 13–14 (28–35 days after fertilization). The absence of a notochord leads to a dorsal identity, but exogenous Sonic Hedgehog signalling activation ventralizes both the somites and the neural tube in a dose-dependent manner. We further identify reciprocal signalling: neural tube-derived cues induce medial ALDH1A2 in somites, which in turn generate retinoic acid signals that drive spontaneous neural-tube patterning. Together, our data highlight the value of modularity in embryo models, which we leverage to explore human trunk co-development. Makwana, Tilley et al. generate human stem cell-based trunk-like structures approximating Carnegie stage 13–14 of development. They use them to model and study the development of the thoracic and lumbar trunk.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2049-2062"},"PeriodicalIF":19.1,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01813-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1038/s41556-025-01823-6
Antonia Hauth, Jasper Panten, Emma Kneuss, Christel Picard, Nicolas Servant, Isabell Rall, Yuvia A. Pérez-Rico, Lena Clerquin, Nila Servaas, Laura Villacorta, Ferris Jung, Christy Luong, Howard Y. Chang, Judith B. Zaugg, Oliver Stegle, Duncan T. Odom, Edith Heard, Agnese Loda
In placental XX females, one X chromosome is silenced during a narrow developmental time window by X-chromosome inactivation, which is mediated by Xist noncoding RNA. Although most X-linked genes are silenced during X-chromosome inactivation, some genes can escape. Here, by increasing its endogenous level, we show that Xist RNA can silence escapees well beyond early embryogenesis both in vitro, in differentiated cells, as well as in vivo, in mouse pre- and post-implantation embryos. We further demonstrate that Xist RNA plays a role in eliminating topologically associating domain-like structures spanning clusters of escapees, and this is dependent on SPEN. The function of Xist in silencing escapees and eliminating topological domains is initially fully reversible, but sustained Xist upregulation leads to irreversible silencing and CpG island DNA methylation of escapees. Thus, gene activity and three-dimensional topology of the inactive X chromosome are directly controlled by Xist, well beyond an early developmental time window. The authors show that increased Xist RNA levels can induce de novo silencing of genes that normally escape X inactivation. SPEN depletion prevents the silencing of escape genes upon Xist RNA overexpression in neural progenitors.
{"title":"Escape from X inactivation is directly modulated by Xist noncoding RNA","authors":"Antonia Hauth, Jasper Panten, Emma Kneuss, Christel Picard, Nicolas Servant, Isabell Rall, Yuvia A. Pérez-Rico, Lena Clerquin, Nila Servaas, Laura Villacorta, Ferris Jung, Christy Luong, Howard Y. Chang, Judith B. Zaugg, Oliver Stegle, Duncan T. Odom, Edith Heard, Agnese Loda","doi":"10.1038/s41556-025-01823-6","DOIUrl":"10.1038/s41556-025-01823-6","url":null,"abstract":"In placental XX females, one X chromosome is silenced during a narrow developmental time window by X-chromosome inactivation, which is mediated by Xist noncoding RNA. Although most X-linked genes are silenced during X-chromosome inactivation, some genes can escape. Here, by increasing its endogenous level, we show that Xist RNA can silence escapees well beyond early embryogenesis both in vitro, in differentiated cells, as well as in vivo, in mouse pre- and post-implantation embryos. We further demonstrate that Xist RNA plays a role in eliminating topologically associating domain-like structures spanning clusters of escapees, and this is dependent on SPEN. The function of Xist in silencing escapees and eliminating topological domains is initially fully reversible, but sustained Xist upregulation leads to irreversible silencing and CpG island DNA methylation of escapees. Thus, gene activity and three-dimensional topology of the inactive X chromosome are directly controlled by Xist, well beyond an early developmental time window. The authors show that increased Xist RNA levels can induce de novo silencing of genes that normally escape X inactivation. SPEN depletion prevents the silencing of escape genes upon Xist RNA overexpression in neural progenitors.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"166-181"},"PeriodicalIF":19.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01823-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1038/s41556-025-01829-0
Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He
Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1–DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization. Zhang et al. characterize the mitochondrial inner membrane subdomain organizer (MISO) protein, which responds to inner mitochondrial membrane stress by inducing membrane subdomains promoting homeostatic fission and mtDNA degradation.
{"title":"MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains","authors":"Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He","doi":"10.1038/s41556-025-01829-0","DOIUrl":"10.1038/s41556-025-01829-0","url":null,"abstract":"Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1–DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization. Zhang et al. characterize the mitochondrial inner membrane subdomain organizer (MISO) protein, which responds to inner mitochondrial membrane stress by inducing membrane subdomains promoting homeostatic fission and mtDNA degradation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"255-267"},"PeriodicalIF":19.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Melanin pigments block genotoxic agents by positioning on the sun-exposed side of the nucleus in human skin keratinocytes. How this positioning is regulated and its role in genome photoprotection remain unknown. Here, by developing a model of human keratinocytes internalizing extracellular melanin into pigment organelles, we show that keratin 5 and keratin 14 intermediate filaments and microtubules control the three-dimensional perinuclear position of pigments, shielding DNA from photodamage. Imaging and microrheology in a human-disease-related model identify structural keratin cages surrounding pigment organelles to stiffen their microenvironment and maintain their three-dimensional position. Optimum supranuclear spatialization of pigment organelles is required for DNA photoprotection and relies on intermediate filaments and microtubules bridged by plectin cytolinkers. Thus, the mechanically driven proximity of pigment organelles to the nucleus is a key photoprotective parameter. Uncovering how human skin counteracts solar radiation by positioning the melanin microparasol next to the genome anticipates that dynamic spatialization of organelles is a physiological response to ultraviolet stress. Benito-Martínez, Salavessa and colleagues show that keratin intermediate filaments and microtubules control the three-dimensional perinuclear position of melanin-containing organelles, shielding the DNA from photodamage.
{"title":"Keratin intermediate filaments mechanically position melanin pigments for genome photoprotection","authors":"Silvia Benito-Martínez, Laura Salavessa, Anne-Sophie Macé, Myckaëla Rouabah, Nathan Lardier, Vincent Fraisier, Julia Sirés-Campos, Riddhi Atul Jani, Maryse Romao, Vanessa Roca, Charlène Gayrard, Marion Plessis, Ilse Hurbain, Cécile Nait-Meddour, Sandrine Etienne-Manneville, Etienne Morel, Michele Boniotto, Jean-Baptiste Manneville, Françoise Bernerd, Christine Duval, Graça Raposo, Cédric Delevoye","doi":"10.1038/s41556-025-01817-4","DOIUrl":"10.1038/s41556-025-01817-4","url":null,"abstract":"Melanin pigments block genotoxic agents by positioning on the sun-exposed side of the nucleus in human skin keratinocytes. How this positioning is regulated and its role in genome photoprotection remain unknown. Here, by developing a model of human keratinocytes internalizing extracellular melanin into pigment organelles, we show that keratin 5 and keratin 14 intermediate filaments and microtubules control the three-dimensional perinuclear position of pigments, shielding DNA from photodamage. Imaging and microrheology in a human-disease-related model identify structural keratin cages surrounding pigment organelles to stiffen their microenvironment and maintain their three-dimensional position. Optimum supranuclear spatialization of pigment organelles is required for DNA photoprotection and relies on intermediate filaments and microtubules bridged by plectin cytolinkers. Thus, the mechanically driven proximity of pigment organelles to the nucleus is a key photoprotective parameter. Uncovering how human skin counteracts solar radiation by positioning the melanin microparasol next to the genome anticipates that dynamic spatialization of organelles is a physiological response to ultraviolet stress. Benito-Martínez, Salavessa and colleagues show that keratin intermediate filaments and microtubules control the three-dimensional perinuclear position of melanin-containing organelles, shielding the DNA from photodamage.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"98-112"},"PeriodicalIF":19.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1038/s41556-025-01849-w
Cynthia A. Harris, James A. Olzmann
FSP1 is a key suppressor of lipid peroxidation and ferroptosis, yet it is largely dispensable in standard cell culture models. Two new studies now show that FSP1 becomes essential for tumour growth in vivo, establishing it as a context-specific cancer vulnerability and highlighting the therapeutic potential of FSP1 inhibition.
{"title":"In vivo models bring FSP1 inhibitors to life","authors":"Cynthia A. Harris, James A. Olzmann","doi":"10.1038/s41556-025-01849-w","DOIUrl":"10.1038/s41556-025-01849-w","url":null,"abstract":"FSP1 is a key suppressor of lipid peroxidation and ferroptosis, yet it is largely dispensable in standard cell culture models. Two new studies now show that FSP1 becomes essential for tumour growth in vivo, establishing it as a context-specific cancer vulnerability and highlighting the therapeutic potential of FSP1 inhibition.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"6-7"},"PeriodicalIF":19.1,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1038/s41556-025-01807-6
Caitlin E. Cornell, Aymeric Chorlay, Deepak Krishnamurthy, Nicholas R. Martin, Lucia Baldauf, Daniel A. Fletcher
Macrophages are known to engulf small membrane fragments, or trogocytose, target cells and pathogens, rather than fully phagocytose them. However, little is known about what causes macrophages to choose trogocytosis versus phagocytosis. Here we report that cortical tension of target cells is a key regulator of macrophage trogocytosis. At low tension, macrophages will preferentially trogocytose antibody-opsonized cells, while at high tension, they tend towards phagocytosis. Using model vesicles, we demonstrate that macrophages will rapidly switch from trogocytosis to phagocytosis when membrane tension is increased. Stiffening the cortex of target cells also biases macrophages to phagocytose them, a trend that can be countered by increasing antibody surface density and is captured in a mechanical model of trogocytosis. This work suggests that the target cell, rather than the macrophage, determines whether phagocytosis or trogocytosis occurs, and that macrophages do not require a distinct molecular pathway for trogocytosis. Cornell et al. show that target cells with low cortical tension induce macrophages to preferentially trogocytose, or engulf in small fragments, whereas target cells with high cortical tension tend towards phagocytosis.
{"title":"Target cell cortical tension regulates macrophage trogocytosis","authors":"Caitlin E. Cornell, Aymeric Chorlay, Deepak Krishnamurthy, Nicholas R. Martin, Lucia Baldauf, Daniel A. Fletcher","doi":"10.1038/s41556-025-01807-6","DOIUrl":"10.1038/s41556-025-01807-6","url":null,"abstract":"Macrophages are known to engulf small membrane fragments, or trogocytose, target cells and pathogens, rather than fully phagocytose them. However, little is known about what causes macrophages to choose trogocytosis versus phagocytosis. Here we report that cortical tension of target cells is a key regulator of macrophage trogocytosis. At low tension, macrophages will preferentially trogocytose antibody-opsonized cells, while at high tension, they tend towards phagocytosis. Using model vesicles, we demonstrate that macrophages will rapidly switch from trogocytosis to phagocytosis when membrane tension is increased. Stiffening the cortex of target cells also biases macrophages to phagocytose them, a trend that can be countered by increasing antibody surface density and is captured in a mechanical model of trogocytosis. This work suggests that the target cell, rather than the macrophage, determines whether phagocytosis or trogocytosis occurs, and that macrophages do not require a distinct molecular pathway for trogocytosis. Cornell et al. show that target cells with low cortical tension induce macrophages to preferentially trogocytose, or engulf in small fragments, whereas target cells with high cortical tension tend towards phagocytosis.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2078-2088"},"PeriodicalIF":19.1,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01807-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-12DOI: 10.1038/s41556-025-01818-3
Chaoyang Wu, Zheng Liu
Macrophages can either engulf targets whole (phagocytosis) or nibble them in small fragments (trogocytosis). Work now shows that this decision is controlled by cortical tension in the targets: low tension favours trogocytosis, whereas higher tension favours phagocytosis. These findings offer a new mechanical lens on immune recognition.
{"title":"Mechanical switch from nibbling to engulfment","authors":"Chaoyang Wu, Zheng Liu","doi":"10.1038/s41556-025-01818-3","DOIUrl":"10.1038/s41556-025-01818-3","url":null,"abstract":"Macrophages can either engulf targets whole (phagocytosis) or nibble them in small fragments (trogocytosis). Work now shows that this decision is controlled by cortical tension in the targets: low tension favours trogocytosis, whereas higher tension favours phagocytosis. These findings offer a new mechanical lens on immune recognition.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2043-2045"},"PeriodicalIF":19.1,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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