Pub Date : 2025-09-29DOI: 10.1038/s41580-025-00899-0
Hesso Farhan, Ishier Raote, Felix Campelo, Liang Ge, Koret Hirschberg, Alison Forrester, Giulia Zanetti, Jennifer Lippincott-Schwartz, José Carlos Pastor-Pareja, Franck Perez, Kota Saito, Vivek Malhotra
Endoplasmic reticulum exit sites (ERES) are specialized, ribosome-free ER subdomains that serve as dynamic portals for COPII-mediated export of proteins from the ER. Beyond their role in the secretory pathway, ERES are implicated in diverse processes, including autophagy and the maturation of lipid droplets, highlighting their functional plasticity. ERES integrate cargo load, membrane tension and spatial cues to remodel their architecture and function in real time. This Roadmap synthesizes our current knowledge on the biogenesis, structural diversity and regulatory logic of ERES. We highlight key unanswered questions in the field, particularly concerning how ERES integrate signals to coordinate protein trafficking under varying cellular states. Finally, we propose a multidisciplinary framework — leveraging advances in high-resolution imaging, synthetic reconstitution and computational modelling — to delineate the principles governing the function and plasticity of ERES. Understanding these mechanisms holds significant potential for developing targeted therapeutic strategies in diseases linked to trafficking dysfunction. Endoplasmic reticulum exit sites (ERES) are specialized ER subdomains that regulate the export of secreted cargo. This Roadmap explores how ERES integrate biochemical and mechanical signals to coordinate trafficking and proposes a multidisciplinary strategy to investigate their function, including in disease.
{"title":"Towards a unified framework for the function of endoplasmic reticulum exit sites","authors":"Hesso Farhan, Ishier Raote, Felix Campelo, Liang Ge, Koret Hirschberg, Alison Forrester, Giulia Zanetti, Jennifer Lippincott-Schwartz, José Carlos Pastor-Pareja, Franck Perez, Kota Saito, Vivek Malhotra","doi":"10.1038/s41580-025-00899-0","DOIUrl":"10.1038/s41580-025-00899-0","url":null,"abstract":"Endoplasmic reticulum exit sites (ERES) are specialized, ribosome-free ER subdomains that serve as dynamic portals for COPII-mediated export of proteins from the ER. Beyond their role in the secretory pathway, ERES are implicated in diverse processes, including autophagy and the maturation of lipid droplets, highlighting their functional plasticity. ERES integrate cargo load, membrane tension and spatial cues to remodel their architecture and function in real time. This Roadmap synthesizes our current knowledge on the biogenesis, structural diversity and regulatory logic of ERES. We highlight key unanswered questions in the field, particularly concerning how ERES integrate signals to coordinate protein trafficking under varying cellular states. Finally, we propose a multidisciplinary framework — leveraging advances in high-resolution imaging, synthetic reconstitution and computational modelling — to delineate the principles governing the function and plasticity of ERES. Understanding these mechanisms holds significant potential for developing targeted therapeutic strategies in diseases linked to trafficking dysfunction. Endoplasmic reticulum exit sites (ERES) are specialized ER subdomains that regulate the export of secreted cargo. This Roadmap explores how ERES integrate biochemical and mechanical signals to coordinate trafficking and proposes a multidisciplinary strategy to investigate their function, including in disease.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 12","pages":"957-969"},"PeriodicalIF":90.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189269","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 : 2025-09-26DOI: 10.1038/s41580-025-00903-7
Jonathan N. Pruneda, Roko Žaja, Michael S. Cohen, Karla L. H. Feijs-Žaja
Evidence is mounting that crosstalk between ubiquitylation and ADP-ribosylation is crucial for maintaining proteostasis. Recent studies have revealed that mono(ADP-ribose) can recruit and activate specific ubiquitin E3 ligases. In this Comment, we discuss MARUbylation — the (literal) linking of mono(ADP-ribose) and ubiquitin into a distinct new hybrid modification. A newly discovered hybrid protein modification of mono(ADP-ribose) and ubiquitin is recognized by dedicated effectors that promote processing of the modified proteins.
{"title":"The emergence of MARUbe — a hybrid ADP-ribose–ubiquitin modification","authors":"Jonathan N. Pruneda, Roko Žaja, Michael S. Cohen, Karla L. H. Feijs-Žaja","doi":"10.1038/s41580-025-00903-7","DOIUrl":"10.1038/s41580-025-00903-7","url":null,"abstract":"Evidence is mounting that crosstalk between ubiquitylation and ADP-ribosylation is crucial for maintaining proteostasis. Recent studies have revealed that mono(ADP-ribose) can recruit and activate specific ubiquitin E3 ligases. In this Comment, we discuss MARUbylation — the (literal) linking of mono(ADP-ribose) and ubiquitin into a distinct new hybrid modification. A newly discovered hybrid protein modification of mono(ADP-ribose) and ubiquitin is recognized by dedicated effectors that promote processing of the modified proteins.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 11","pages":"820-821"},"PeriodicalIF":90.2,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153416","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 : 2025-09-24DOI: 10.1038/s41580-025-00878-5
Sasha Mendjan, Alison Deyett, Deborah Yelon
Heart development has been extensively explored on the anatomical, cellular and molecular levels. Yet, the intricate interplay of tissue organization, cellular lineages and molecular factors that orchestrate heart development, culminating in forming a seamlessly synchronized functional heart, remains challenging to investigate. Mechanistic studies conducted both in vivo using animal models and in vitro stem-cell-derived systems aim to unravel this complexity. In this Review, we discuss how the recent surge in technological advancements in imaging and genomics, coupled with the evolution of next-generation cardiac organoid models, has provided profound insights into these processes, holding significant implications for the development of novel therapies for congenital or acquired heart diseases. We discuss the development of the heart as the first functional organ — from the morphogenesis of the mesoderm, heart tube and cardiac chambers to the establishment of the initial heartbeat and pacemaker and further how morphogenesis and function collaboratively drive heart maturation. The development of a functional heart depends on the specification of multiple cell types, including pacemaker cells, and complex tissue re-organization. This Review discusses recent insights into these processes from in vivo studies and cardiac organoid models.
{"title":"Coordination of cardiogenesis in vivo and in vitro","authors":"Sasha Mendjan, Alison Deyett, Deborah Yelon","doi":"10.1038/s41580-025-00878-5","DOIUrl":"10.1038/s41580-025-00878-5","url":null,"abstract":"Heart development has been extensively explored on the anatomical, cellular and molecular levels. Yet, the intricate interplay of tissue organization, cellular lineages and molecular factors that orchestrate heart development, culminating in forming a seamlessly synchronized functional heart, remains challenging to investigate. Mechanistic studies conducted both in vivo using animal models and in vitro stem-cell-derived systems aim to unravel this complexity. In this Review, we discuss how the recent surge in technological advancements in imaging and genomics, coupled with the evolution of next-generation cardiac organoid models, has provided profound insights into these processes, holding significant implications for the development of novel therapies for congenital or acquired heart diseases. We discuss the development of the heart as the first functional organ — from the morphogenesis of the mesoderm, heart tube and cardiac chambers to the establishment of the initial heartbeat and pacemaker and further how morphogenesis and function collaboratively drive heart maturation. The development of a functional heart depends on the specification of multiple cell types, including pacemaker cells, and complex tissue re-organization. This Review discusses recent insights into these processes from in vivo studies and cardiac organoid models.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 1","pages":"19-34"},"PeriodicalIF":90.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133933","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 : 2025-09-22DOI: 10.1038/s41580-025-00892-7
Monther Abu-Remaileh, Chii Jou Chan, Leilei Chen, Gozde S. Demirer, Ana Fiszbein, Florian Jug, Ana Victoria Lechuga-Vieco, Raphaëlle Luisier, Julia Pagan, Benjamin R. Sabari, Sichen Shao, Liming Sun, Jan J. Żylicz
To celebrate the journal’s 25th anniversary, we asked 13 researchers to offer a glimpse of what their research field might look like in 2050. They consider how technological breakthroughs — for example, artificial intelligence-powered virtual cells — could transform our understanding of how molecules, organelles and cells behave in different contexts, revolutionize therapies and enable the design of resilient crops.
{"title":"Visions of the future of molecular cell biology","authors":"Monther Abu-Remaileh, Chii Jou Chan, Leilei Chen, Gozde S. Demirer, Ana Fiszbein, Florian Jug, Ana Victoria Lechuga-Vieco, Raphaëlle Luisier, Julia Pagan, Benjamin R. Sabari, Sichen Shao, Liming Sun, Jan J. Żylicz","doi":"10.1038/s41580-025-00892-7","DOIUrl":"10.1038/s41580-025-00892-7","url":null,"abstract":"To celebrate the journal’s 25th anniversary, we asked 13 researchers to offer a glimpse of what their research field might look like in 2050. They consider how technological breakthroughs — for example, artificial intelligence-powered virtual cells — could transform our understanding of how molecules, organelles and cells behave in different contexts, revolutionize therapies and enable the design of resilient crops.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 10","pages":"735-740"},"PeriodicalIF":90.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111432","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 : 2025-09-22DOI: 10.1038/s41580-025-00904-6
Kim Baumann
Acute kidney injury induces somatic mitochondrial DNA mutations that impair energy metabolism and the resilience of kidney tissue to following injuries.
急性肾损伤诱导体细胞线粒体DNA突变，损害肾组织的能量代谢和对后续损伤的恢复能力。
{"title":"Tissue injury leads to the accumulation of somatic mtDNA mutations","authors":"Kim Baumann","doi":"10.1038/s41580-025-00904-6","DOIUrl":"10.1038/s41580-025-00904-6","url":null,"abstract":"Acute kidney injury induces somatic mitochondrial DNA mutations that impair energy metabolism and the resilience of kidney tissue to following injuries.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 11","pages":"822-822"},"PeriodicalIF":90.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117044","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 : 2025-09-22DOI: 10.1038/s41580-025-00902-8
Nataliya Petryk
A 2017 cryo-electron microscopy structure that resolved the orientation of the replicative helicase CMG at the DNA replication fork caused a major shift in our understanding of DNA replication.
{"title":"Turning the replisome around","authors":"Nataliya Petryk","doi":"10.1038/s41580-025-00902-8","DOIUrl":"10.1038/s41580-025-00902-8","url":null,"abstract":"A 2017 cryo-electron microscopy structure that resolved the orientation of the replicative helicase CMG at the DNA replication fork caused a major shift in our understanding of DNA replication.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 12","pages":"908-908"},"PeriodicalIF":90.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145125262","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 : 2025-09-17DOI: 10.1038/s41580-025-00900-w
Helder I. Nakaya
Artificial intelligence (AI) will enable scientists to interact with computational tools in plain language, increasing their accessibility — students will ask profound questions instead of wrestling with installation. But when models state false information, ease of use can mask dangerous failure, so preserving critical thinking will be crucial when embracing this progress. Artificial intelligence will transform the way researchers engage with computational tools, making the interfaces user friendly and the tools more accessible.
{"title":"AI will create the next generation of user-friendly interfaces","authors":"Helder I. Nakaya","doi":"10.1038/s41580-025-00900-w","DOIUrl":"10.1038/s41580-025-00900-w","url":null,"abstract":"Artificial intelligence (AI) will enable scientists to interact with computational tools in plain language, increasing their accessibility — students will ask profound questions instead of wrestling with installation. But when models state false information, ease of use can mask dangerous failure, so preserving critical thinking will be crucial when embracing this progress. Artificial intelligence will transform the way researchers engage with computational tools, making the interfaces user friendly and the tools more accessible.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 11","pages":"819-819"},"PeriodicalIF":90.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078216","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 : 2025-09-16DOI: 10.1038/s41580-025-00893-6
Mitinori Saitou, Masahiro Nagano, Ken Mizuta
Human germ cells are the foundation of human reproduction and development, ensuring heredity and contributing to genetic diversity. Accordingly, their anomalies lead to critical diseases, including infertility. Recent advances in genomics and stem cell-based in vitro gametogenesis research have expanded our knowledge of how human germ cells are specified and differentiate during embryonic and fetal development, elucidating evolutionarily distinctive as well as conserved properties of human germ cell development. Here, based on the evidence from both in vivo and in vitro studies, we provide an integrated review of the progress in our understanding of human embryonic and fetal germ cell development, encompassing germ cell specification, epigenetic reprogramming and sex-specific germ cell development. Knowledge of the mechanisms of human germ cell development will enable its in vitro reconstitution, which in turn will serve as a foundation for innovative medical strategies to prevent germ cell-related diseases, including infertility. Human germ cells are specified during early development and eventually differentiate into sperm and oocytes. Recent studies have revealed key signalling pathways and epigenetic mechanisms of their development, enabling in vitro reconstitution and potential treatments for germ cell-related diseases.
{"title":"Mechanisms of human germ cell development","authors":"Mitinori Saitou, Masahiro Nagano, Ken Mizuta","doi":"10.1038/s41580-025-00893-6","DOIUrl":"10.1038/s41580-025-00893-6","url":null,"abstract":"Human germ cells are the foundation of human reproduction and development, ensuring heredity and contributing to genetic diversity. Accordingly, their anomalies lead to critical diseases, including infertility. Recent advances in genomics and stem cell-based in vitro gametogenesis research have expanded our knowledge of how human germ cells are specified and differentiate during embryonic and fetal development, elucidating evolutionarily distinctive as well as conserved properties of human germ cell development. Here, based on the evidence from both in vivo and in vitro studies, we provide an integrated review of the progress in our understanding of human embryonic and fetal germ cell development, encompassing germ cell specification, epigenetic reprogramming and sex-specific germ cell development. Knowledge of the mechanisms of human germ cell development will enable its in vitro reconstitution, which in turn will serve as a foundation for innovative medical strategies to prevent germ cell-related diseases, including infertility. Human germ cells are specified during early development and eventually differentiate into sperm and oocytes. Recent studies have revealed key signalling pathways and epigenetic mechanisms of their development, enabling in vitro reconstitution and potential treatments for germ cell-related diseases.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 2","pages":"153-171"},"PeriodicalIF":90.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067884","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":"The hunter becomes the hunted in target-directed microRNA degradation","authors":"Katherine McJunkin","doi":"10.1038/s41580-025-00894-5","DOIUrl":"10.1038/s41580-025-00894-5","url":null,"abstract":"Two 2010 papers showed that microRNA interactions with certain RNAs result not in target destruction but in the decay of the microRNA.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 11","pages":"825-825"},"PeriodicalIF":90.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059294","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}
Ageing is characterized by progressive functional decline and increase in disease risk and imposes substantial burdens on human health. Identifying aging biomarkers in primates is crucial for advancing our understanding of human ageing and for informing interventions to mitigate age-related pathologies. However, a comprehensive grasp of these biomarkers is still lacking, hindering the translation of fundamental research into clinical practice. In this Review, we present the current knowledge on biomarkers of ageing at the cellular, tissue and organism levels in humans and non-human primates. Through systematic analysis of representative biomarkers across diverse biological contexts and scales, we discuss both the variability and the conservation of ageing-associated physiological changes, underscoring their importance in assessing and intervening in the ageing process. Finally, we critically assess challenges in ageing research and outline strategic avenues for future investigation. The use of biomarkers of ageing is crucial for investigating age-related processes. This Review discusses biomarkers of ageing and of ageing-associated physiological changes, at the cellular, tissue and organism levels in humans and non-human primates.
{"title":"Biomarkers of ageing of humans and non-human primates","authors":"Zeming Wu, Jing Qu, Weiqi Zhang, Aging Biomarker Consortium, Guang-Hui Liu","doi":"10.1038/s41580-025-00883-8","DOIUrl":"10.1038/s41580-025-00883-8","url":null,"abstract":"Ageing is characterized by progressive functional decline and increase in disease risk and imposes substantial burdens on human health. Identifying aging biomarkers in primates is crucial for advancing our understanding of human ageing and for informing interventions to mitigate age-related pathologies. However, a comprehensive grasp of these biomarkers is still lacking, hindering the translation of fundamental research into clinical practice. In this Review, we present the current knowledge on biomarkers of ageing at the cellular, tissue and organism levels in humans and non-human primates. Through systematic analysis of representative biomarkers across diverse biological contexts and scales, we discuss both the variability and the conservation of ageing-associated physiological changes, underscoring their importance in assessing and intervening in the ageing process. Finally, we critically assess challenges in ageing research and outline strategic avenues for future investigation. The use of biomarkers of ageing is crucial for investigating age-related processes. This Review discusses biomarkers of ageing and of ageing-associated physiological changes, at the cellular, tissue and organism levels in humans and non-human primates.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 11","pages":"826-847"},"PeriodicalIF":90.2,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031952","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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