Pub Date : 2025-09-09DOI: 10.1038/s41580-025-00881-w
Stefan Petrovic, George W. Mobbs, André Hoelz
The defining property of eukaryotic cells is the storage of heritable genetic material in a nuclear compartment. For eukaryotic cells to carry out the myriad biochemical processes necessary for their function, macromolecules must be efficiently exchanged between the nucleus and cytoplasm. The nuclear pore complex (NPC) — which is a massive assembly of ~35 different proteins present in multiple copies totalling ~1,000 protein subunits and architecturally conserved across eukaryotes — establishes a size-selective channel for regulated bidirectional transport of folded macromolecules and macromolecular assemblies across the nuclear envelope. In this Review, we provide an overview of insights gained from recent near-atomic composite structures of the NPC and their importance in advancing our understanding of NPC function. We discuss advances in our understanding of the permeability barrier, modes of nucleocytoplasmic transport, and the mobile transport factors involved. Finally, we present future research directions aimed at elucidating the nuclear basket architecture, mechanisms of mRNA export, NPC biogenesis and mechanosensation. Recent near-atomic structures of the nuclear pore complex provide insights into its assembly and function — how it acts as a selective permeability barrier, regulates nucleocytoplasmic transport such as mRNA export, and integrates mechanical forces experienced by the cell and nucleus.
{"title":"Structure, function and assembly of nuclear pore complexes","authors":"Stefan Petrovic, George W. Mobbs, André Hoelz","doi":"10.1038/s41580-025-00881-w","DOIUrl":"10.1038/s41580-025-00881-w","url":null,"abstract":"The defining property of eukaryotic cells is the storage of heritable genetic material in a nuclear compartment. For eukaryotic cells to carry out the myriad biochemical processes necessary for their function, macromolecules must be efficiently exchanged between the nucleus and cytoplasm. The nuclear pore complex (NPC) — which is a massive assembly of ~35 different proteins present in multiple copies totalling ~1,000 protein subunits and architecturally conserved across eukaryotes — establishes a size-selective channel for regulated bidirectional transport of folded macromolecules and macromolecular assemblies across the nuclear envelope. In this Review, we provide an overview of insights gained from recent near-atomic composite structures of the NPC and their importance in advancing our understanding of NPC function. We discuss advances in our understanding of the permeability barrier, modes of nucleocytoplasmic transport, and the mobile transport factors involved. Finally, we present future research directions aimed at elucidating the nuclear basket architecture, mechanisms of mRNA export, NPC biogenesis and mechanosensation. Recent near-atomic structures of the nuclear pore complex provide insights into its assembly and function — how it acts as a selective permeability barrier, regulates nucleocytoplasmic transport such as mRNA export, and integrates mechanical forces experienced by the cell and nucleus.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 1","pages":"35-54"},"PeriodicalIF":90.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145017929","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 : 2025-09-05DOI: 10.1038/s41580-025-00901-9
Eytan Zlotorynski
Independently of its nuclear DNA-binding activity, the transcription factor PXR has a cytoplasmic function: it binds to mRNAs and promotes their stability.
转录因子PXR独立于其核dna结合活性，具有细胞质功能：与mrna结合并促进其稳定性。
{"title":"The double life of a transcription factor in the cytoplasm","authors":"Eytan Zlotorynski","doi":"10.1038/s41580-025-00901-9","DOIUrl":"10.1038/s41580-025-00901-9","url":null,"abstract":"Independently of its nuclear DNA-binding activity, the transcription factor PXR has a cytoplasmic function: it binds to mRNAs and promotes their stability.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 10","pages":"732-732"},"PeriodicalIF":90.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41580-025-00901-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002905","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 : 2025-08-26DOI: 10.1038/s41580-025-00889-2
Kevin Struhl
Although enhancers activate transcription from long distances, they stimulate transcription only through short-range interactions with the RNA polymerase II machinery. I posit that action at a distance is mediated by loops between distal and proximal enhancers that thereby bring proteins associated with distal enhancers near promoters. This Comment posits that enhancers stimulate the transcription machinery only through short-range interactions and, therefore, that enhancer activity at a distance is mediated by chromatin loops between distal and proximal enhancers, not between enhancers and promoters.
{"title":"Distal enhancers loop to proximal enhancers, not to promoters","authors":"Kevin Struhl","doi":"10.1038/s41580-025-00889-2","DOIUrl":"10.1038/s41580-025-00889-2","url":null,"abstract":"Although enhancers activate transcription from long distances, they stimulate transcription only through short-range interactions with the RNA polymerase II machinery. I posit that action at a distance is mediated by loops between distal and proximal enhancers that thereby bring proteins associated with distal enhancers near promoters. This Comment posits that enhancers stimulate the transcription machinery only through short-range interactions and, therefore, that enhancer activity at a distance is mediated by chromatin loops between distal and proximal enhancers, not between enhancers and promoters.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 10","pages":"730-731"},"PeriodicalIF":90.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900396","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 : 2025-08-22DOI: 10.1038/s41580-025-00888-3
Boyi Gan
Disulfidptosis is an emerging form of redox-driven cell death with implications in cancer and immunity. This Comment explores gaps in our mechanistic understanding, unanswered questions, and the therapeutic potential of targeting disulfidptosis, highlighting key challenges and future directions in decoding this unique cell death pathway. In this Comment, Boyi Gan discusses disulfidptosis, a newly identified, redox-driven cell death pathway triggered by disulfide stress, and highlights its therapeutic potential while underscoring gaps in mechanistic understanding and key challenges for future research.
{"title":"Redox-driven cell death by disulfidptosis and its therapeutic potential","authors":"Boyi Gan","doi":"10.1038/s41580-025-00888-3","DOIUrl":"10.1038/s41580-025-00888-3","url":null,"abstract":"Disulfidptosis is an emerging form of redox-driven cell death with implications in cancer and immunity. This Comment explores gaps in our mechanistic understanding, unanswered questions, and the therapeutic potential of targeting disulfidptosis, highlighting key challenges and future directions in decoding this unique cell death pathway. In this Comment, Boyi Gan discusses disulfidptosis, a newly identified, redox-driven cell death pathway triggered by disulfide stress, and highlights its therapeutic potential while underscoring gaps in mechanistic understanding and key challenges for future research.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 10","pages":"727-729"},"PeriodicalIF":90.2,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900413","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 : 2025-08-21DOI: 10.1038/s41580-025-00891-8
Lisa Heinke
Paul et al. demonstrate that entry into the cell cycle from quiescence involves a transient, partial inactivation of the APC/C ubiquitin ligase, which halts the degradation of glycolysis enzymes and ensures sufficient ATP production for cell division.
{"title":"Snoozing APC/C for a sweet cell cycle entry","authors":"Lisa Heinke","doi":"10.1038/s41580-025-00891-8","DOIUrl":"10.1038/s41580-025-00891-8","url":null,"abstract":"Paul et al. demonstrate that entry into the cell cycle from quiescence involves a transient, partial inactivation of the APC/C ubiquitin ligase, which halts the degradation of glycolysis enzymes and ensures sufficient ATP production for cell division.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 10","pages":"733-733"},"PeriodicalIF":90.2,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900563","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 : 2025-08-19DOI: 10.1038/s41580-025-00876-7
Xinlei Sheng, Hening Lin, Philip A. Cole, Yingming Zhao
Histone l-lactylation is a newly identified, metabolism-linked short-chain Lys acylation. Mounting evidence indicates that Lys l-lactylation has key roles in transcription regulation and many other cellular processes and is associated with diverse pathophysiological changes. In this Review, we discuss the unique features of histone l-lactylation, emphasizing the differences between l-lactylation and its isomers, such as d-lactylation. We discuss the regulation of l-lactylation by writers and erasers, its readers and its cofactor l-lactyl-CoA. We highlight the dynamic regulation of nuclear l-lactyl-CoA and l-lactyl-CoA synthetases, which are crucial determinants of the specificity of histone Lys l-lactylation. We also discuss an emerging l-lactyl-CoA-independent l-lactylation pathway. By integrating these findings, we aim to deepen our understanding of the biochemistry and regulation of histone l-lactylation and its broad biological significance. Lys l-lactylation of histones is a newly identified short-chain acylation that regulates transcription and other cellular processes, with diverse pathophysiological outcomes, notably in cancer. This Review discusses the unique biochemical features of Lys l-lactylation and its dynamic regulation by various metabolism-related mechanisms.
组蛋白l -酰化是一种新发现的与代谢相关的短链赖氨酸酰化。越来越多的证据表明，Lys l -乳酸化在转录调控和许多其他细胞过程中起关键作用，并与多种病理生理变化有关。在这篇综述中，我们讨论了组蛋白l -乳酸化的独特特征，强调了l -乳酸化与其异构体（如d -乳酸化）之间的区别。我们讨论了l-乳酸化的调控通过书写和擦除，它的阅读器和它的辅助因子l-乳酸辅酶a。我们强调了核l-乳酸辅酶a和l-乳酸辅酶a合成酶的动态调控，这是组蛋白Lys l-乳酸化特异性的关键决定因素。我们还讨论了一种新兴的不依赖于辅酶a的l-乳酸化途径。通过整合这些发现，我们旨在加深我们对组蛋白l -乳酸化的生物化学和调控及其广泛的生物学意义的理解。
{"title":"Biochemistry and regulation of histone lysine l-lactylation","authors":"Xinlei Sheng, Hening Lin, Philip A. Cole, Yingming Zhao","doi":"10.1038/s41580-025-00876-7","DOIUrl":"10.1038/s41580-025-00876-7","url":null,"abstract":"Histone l-lactylation is a newly identified, metabolism-linked short-chain Lys acylation. Mounting evidence indicates that Lys l-lactylation has key roles in transcription regulation and many other cellular processes and is associated with diverse pathophysiological changes. In this Review, we discuss the unique features of histone l-lactylation, emphasizing the differences between l-lactylation and its isomers, such as d-lactylation. We discuss the regulation of l-lactylation by writers and erasers, its readers and its cofactor l-lactyl-CoA. We highlight the dynamic regulation of nuclear l-lactyl-CoA and l-lactyl-CoA synthetases, which are crucial determinants of the specificity of histone Lys l-lactylation. We also discuss an emerging l-lactyl-CoA-independent l-lactylation pathway. By integrating these findings, we aim to deepen our understanding of the biochemistry and regulation of histone l-lactylation and its broad biological significance. Lys l-lactylation of histones is a newly identified short-chain acylation that regulates transcription and other cellular processes, with diverse pathophysiological outcomes, notably in cancer. This Review discusses the unique biochemical features of Lys l-lactylation and its dynamic regulation by various metabolism-related mechanisms.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 2","pages":"95-109"},"PeriodicalIF":90.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883260","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 : 2025-08-07DOI: 10.1038/s41580-025-00887-4
Kim Baumann
This study reports the successful reprogramming of human blood cells to pluripotent stem cells using small molecules.
本研究报告了利用小分子成功地将人血细胞重编程为多能干细胞。
{"title":"Chemical reprogramming of human blood cells","authors":"Kim Baumann","doi":"10.1038/s41580-025-00887-4","DOIUrl":"10.1038/s41580-025-00887-4","url":null,"abstract":"This study reports the successful reprogramming of human blood cells to pluripotent stem cells using small molecules.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 9","pages":"647-647"},"PeriodicalIF":90.2,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792332","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 : 2025-08-06DOI: 10.1038/s41580-025-00884-7
Eytan Zlotorynski
H3.14, a histone variant of unknown role, has a dual transcriptional function in the abiotic stress response in plants: activation of stress response genes and inhibition of growth genes.
{"title":"A histone variant that manages abiotic stress in plants","authors":"Eytan Zlotorynski","doi":"10.1038/s41580-025-00884-7","DOIUrl":"10.1038/s41580-025-00884-7","url":null,"abstract":"H3.14, a histone variant of unknown role, has a dual transcriptional function in the abiotic stress response in plants: activation of stress response genes and inhibition of growth genes.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 9","pages":"646-646"},"PeriodicalIF":90.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786650","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 : 2025-08-04DOI: 10.1038/s41580-025-00873-w
Maja Radulovic, Chonglin Yang, Harald Stenmark
Lysosomes are membranous organelles that are crucial for cell function and organ physiology. Serving as the terminal stations of the endocytic pathway, lysosomes have fundamental roles in the degradation of endogenous and exogenous macromolecules and particles as well as damaged or superfluous organelles. Moreover, the lysosomal membrane is a docking and activation platform for several signalling components, including mTOR complex 1 (mTORC1), which orchestrates metabolic signalling in the cell. The integrity of their membrane is crucial for lysosomes to function as hubs for the regulation of cell metabolism. Various agents, including pathogens, nanoparticles and drugs, can compromise lysosomal membrane integrity. Membrane permeabilization causes leakage of proteases and cations into the cytosol, which can induce cell death pathways and innate immunity signalling. Multiple pathways repair damaged lysosomes, and severely damaged lysosomes are degraded by an autophagic process, lysophagy. Moreover, lysosome damage activates transcriptional programmes that orchestrate lysosome biogenesis to replenish the cellular lysosome pool. In this Review, we discuss recent insights into the mechanisms that ensure the maintenance of lysosomal membrane homeostasis, including novel mechanisms of lysosomal membrane repair and the interplay between lysosome damage, repair, lysophagy and lysosome biogenesis. We highlight the importance of lysosomal membrane homeostasis in cell function, physiology, disease and ageing, and discuss the potential for therapeutic exploitation of lysosomal membrane permeabilization. Lysosomes degrade cellular components, and their membrane is an important signalling hub. Recent insights into the mechanisms that maintain lysosomal membrane homeostasis — including the interplay between membrane damage, repair, lysophagy and lysosome biogenesis — highlight their importance in physiology, in disease and during ageing.
{"title":"Lysosomal membrane homeostasis and its importance in physiology and disease","authors":"Maja Radulovic, Chonglin Yang, Harald Stenmark","doi":"10.1038/s41580-025-00873-w","DOIUrl":"10.1038/s41580-025-00873-w","url":null,"abstract":"Lysosomes are membranous organelles that are crucial for cell function and organ physiology. Serving as the terminal stations of the endocytic pathway, lysosomes have fundamental roles in the degradation of endogenous and exogenous macromolecules and particles as well as damaged or superfluous organelles. Moreover, the lysosomal membrane is a docking and activation platform for several signalling components, including mTOR complex 1 (mTORC1), which orchestrates metabolic signalling in the cell. The integrity of their membrane is crucial for lysosomes to function as hubs for the regulation of cell metabolism. Various agents, including pathogens, nanoparticles and drugs, can compromise lysosomal membrane integrity. Membrane permeabilization causes leakage of proteases and cations into the cytosol, which can induce cell death pathways and innate immunity signalling. Multiple pathways repair damaged lysosomes, and severely damaged lysosomes are degraded by an autophagic process, lysophagy. Moreover, lysosome damage activates transcriptional programmes that orchestrate lysosome biogenesis to replenish the cellular lysosome pool. In this Review, we discuss recent insights into the mechanisms that ensure the maintenance of lysosomal membrane homeostasis, including novel mechanisms of lysosomal membrane repair and the interplay between lysosome damage, repair, lysophagy and lysosome biogenesis. We highlight the importance of lysosomal membrane homeostasis in cell function, physiology, disease and ageing, and discuss the potential for therapeutic exploitation of lysosomal membrane permeabilization. Lysosomes degrade cellular components, and their membrane is an important signalling hub. Recent insights into the mechanisms that maintain lysosomal membrane homeostasis — including the interplay between membrane damage, repair, lysophagy and lysosome biogenesis — highlight their importance in physiology, in disease and during ageing.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 1","pages":"71-87"},"PeriodicalIF":90.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777819","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}
{"title":"Author Correction: Modelling human brain development and disease with organoids","authors":"Marcella Birtele, Madeline Lancaster, Giorgia Quadrato","doi":"10.1038/s41580-025-00886-5","DOIUrl":"10.1038/s41580-025-00886-5","url":null,"abstract":"","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 9","pages":"725-725"},"PeriodicalIF":90.2,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41580-025-00886-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777818","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}
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