Pub Date : 2025-11-03DOI: 10.1038/s41580-025-00925-1
Christian Kofoed
In this Tools of the Trade article, Kofoed (Muir lab) describes the development of the dual-component platform splicing-modulated actuation upon recognition of targets (SMART), which combines detection of cells with specific surface markers with a customizable output.
{"title":"Transforming cell-surface signatures into customizable protein functions","authors":"Christian Kofoed","doi":"10.1038/s41580-025-00925-1","DOIUrl":"10.1038/s41580-025-00925-1","url":null,"abstract":"In this Tools of the Trade article, Kofoed (Muir lab) describes the development of the dual-component platform splicing-modulated actuation upon recognition of targets (SMART), which combines detection of cells with specific surface markers with a customizable output.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 2","pages":"91-91"},"PeriodicalIF":90.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427580","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 : 2025-11-03DOI: 10.1038/s41580-025-00924-2
Siyuan Wang
Siyuan (Steven) Wang discusses a 1984 study that reported that transcriptional regulation (in this case, in bacteria) depends on the formation of DNA loops.
{"title":"DNA looping regulates transcription","authors":"Siyuan Wang","doi":"10.1038/s41580-025-00924-2","DOIUrl":"10.1038/s41580-025-00924-2","url":null,"abstract":"Siyuan (Steven) Wang discusses a 1984 study that reported that transcriptional regulation (in this case, in bacteria) depends on the formation of DNA loops.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 2","pages":"94-94"},"PeriodicalIF":90.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427583","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 : 2025-10-31DOI: 10.1038/s41580-025-00919-z
Leo Kiss
In this Tools of the Trade article, Kiss (Schulman lab) discusses the development of UbiREAD, a method that delivers in vitro-ubiquitinated protein reporters into cells to systematically assess how different ubiquitin chain configurations affect protein stability and degradation.
{"title":"Decoding ubiquitin signals inside cells","authors":"Leo Kiss","doi":"10.1038/s41580-025-00919-z","DOIUrl":"10.1038/s41580-025-00919-z","url":null,"abstract":"In this Tools of the Trade article, Kiss (Schulman lab) discusses the development of UbiREAD, a method that delivers in vitro-ubiquitinated protein reporters into cells to systematically assess how different ubiquitin chain configurations affect protein stability and degradation.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 12","pages":"905-905"},"PeriodicalIF":90.2,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145411768","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 : 2025-10-27DOI: 10.1038/s41580-025-00890-9
Anne Wentink, Rina Rosenzweig, Harm Kampinga, Bernd Bukau
The 70-kDa heat shock protein (Hsp70) chaperone is essential to maintain cellular protein homeostasis, facilitating the folding, assembly, membrane translocation and quality control of proteins. Hsp70s achieve their functions through ‘selective promiscuity’, interacting with a wide range of substrate proteins while minimizing undesired interactions. J-domain proteins (JDPs) and nucleotide exchange factors (NEFs) are key to substrate recognition, remodelling and release from chaperone complexes. JDPs either target Hsp70s to specific subcellular sites where substrates reside (recruiters) or bind substrates directly by using highly specific (specialists) or multiple, versatile (generalists) binding sites. Through diverse substrate-binding modes and regulatory mechanisms, the 50 human JDPs confer remarkable client specificity to Hsp70s, a function that is comparable to that achieved by close to 600 E3 ubiquitin ligases in targeting proteins for degradation. Moreover, JDPs, together with NEFs, dictate the fate of Hsp70 clients by directing them to distinct protein quality control pathways, resulting in their folding or degradation. These recent mechanistic insights into Hsp70 regulation not only highlight the versatility and complexity of the Hsp70 network but also offer new avenues for more specific interventions in ageing-related and other protein folding diseases. Hsp70 chaperones facilitate protein folding, complex assembly and translocation through membranes. This Review discusses recent insights into how Hsp70 and its co-chaperones — J-domain proteins and nucleotide exchange factors — exert such functions, achieve substrate specificity and determine protein fate (folding or degradation).
{"title":"Mechanisms and regulation of the Hsp70 chaperone network","authors":"Anne Wentink, Rina Rosenzweig, Harm Kampinga, Bernd Bukau","doi":"10.1038/s41580-025-00890-9","DOIUrl":"10.1038/s41580-025-00890-9","url":null,"abstract":"The 70-kDa heat shock protein (Hsp70) chaperone is essential to maintain cellular protein homeostasis, facilitating the folding, assembly, membrane translocation and quality control of proteins. Hsp70s achieve their functions through ‘selective promiscuity’, interacting with a wide range of substrate proteins while minimizing undesired interactions. J-domain proteins (JDPs) and nucleotide exchange factors (NEFs) are key to substrate recognition, remodelling and release from chaperone complexes. JDPs either target Hsp70s to specific subcellular sites where substrates reside (recruiters) or bind substrates directly by using highly specific (specialists) or multiple, versatile (generalists) binding sites. Through diverse substrate-binding modes and regulatory mechanisms, the 50 human JDPs confer remarkable client specificity to Hsp70s, a function that is comparable to that achieved by close to 600 E3 ubiquitin ligases in targeting proteins for degradation. Moreover, JDPs, together with NEFs, dictate the fate of Hsp70 clients by directing them to distinct protein quality control pathways, resulting in their folding or degradation. These recent mechanistic insights into Hsp70 regulation not only highlight the versatility and complexity of the Hsp70 network but also offer new avenues for more specific interventions in ageing-related and other protein folding diseases. Hsp70 chaperones facilitate protein folding, complex assembly and translocation through membranes. This Review discusses recent insights into how Hsp70 and its co-chaperones — J-domain proteins and nucleotide exchange factors — exert such functions, achieve substrate specificity and determine protein fate (folding or degradation).","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 2","pages":"110-128"},"PeriodicalIF":90.2,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145373842","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 : 2025-10-17DOI: 10.1038/s41580-025-00908-2
Ellen Kazumi Okuda, Laurell Fridolin Kessler
In this Tools of the Trade article, Okuda and Kessler (Müller-McNicoll and Heilemann labs) discuss how the combination of two novel methods enabled them to study the architecture and interaction of nuclear membraneless organelles.
{"title":"A new rapid-degradation system combined with super-resolution microscopy","authors":"Ellen Kazumi Okuda, Laurell Fridolin Kessler","doi":"10.1038/s41580-025-00908-2","DOIUrl":"10.1038/s41580-025-00908-2","url":null,"abstract":"In this Tools of the Trade article, Okuda and Kessler (Müller-McNicoll and Heilemann labs) discuss how the combination of two novel methods enabled them to study the architecture and interaction of nuclear membraneless organelles.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 12","pages":"904-904"},"PeriodicalIF":90.2,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311249","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 : 2025-10-16DOI: 10.1038/s41580-025-00912-6
Charles Barlowe
Two seminal studies from the 1980s catalysed major advances in the trafficking field, when converging research in yeast and mammalian cells revealed the molecular machinery of the secretory pathway.
{"title":"The secretory pathway gets a molecular framework","authors":"Charles Barlowe","doi":"10.1038/s41580-025-00912-6","DOIUrl":"10.1038/s41580-025-00912-6","url":null,"abstract":"Two seminal studies from the 1980s catalysed major advances in the trafficking field, when converging research in yeast and mammalian cells revealed the molecular machinery of the secretory pathway.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 12","pages":"907-907"},"PeriodicalIF":90.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305695","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 : 2025-10-13DOI: 10.1038/s41580-025-00896-3
Sonia Cruciani, Eva Maria Novoa
Nanopore direct RNA sequencing has enabled the detection of RNA modifications in native RNA molecules, initially through the analysis of signal alterations and base-calling errors. More recently, modification prediction has been integrated into the base-calling step using pretrained, modification-aware base-calling models. So far, such models have been made available for N6-methyladenosine (m6A), inosine (I), pseudouridine (Ψ) and N5-methylcytosine (m5C), enabling RNA modification mapping in single-molecule resolution. However, their performance remains largely unclear. In this Progress, we discuss key limitations and uncertainties associated with base-calling models, including their potential cross-reactivities with other modifications, variability in false positive rates across models, unclear threshold choices for modification calling, insufficient orthogonal validation of model accuracy and lack of standardized analysis pipelines. To illustrate some of these issues, we compared the performance of three base-calling models on identical RNA samples, observing over 20-fold differences in the number of predicted m6A-modified sites. As these models are increasingly adopted, it is crucial to understand their limitations to ensure best practices and avoid misinterpretation of epitranscriptomics data. Nanopore RNA sequencing is a potent technology for the detection of RNA modifications. Nanopore modification-aware base-calling models have been recently developed, and this Progress article discusses their limitations, including modification cross-reactivities, variability in false positive rates and modification-calling threshold choices.
{"title":"The new era of single-molecule RNA modification detection through nanopore base-calling models","authors":"Sonia Cruciani, Eva Maria Novoa","doi":"10.1038/s41580-025-00896-3","DOIUrl":"10.1038/s41580-025-00896-3","url":null,"abstract":"Nanopore direct RNA sequencing has enabled the detection of RNA modifications in native RNA molecules, initially through the analysis of signal alterations and base-calling errors. More recently, modification prediction has been integrated into the base-calling step using pretrained, modification-aware base-calling models. So far, such models have been made available for N6-methyladenosine (m6A), inosine (I), pseudouridine (Ψ) and N5-methylcytosine (m5C), enabling RNA modification mapping in single-molecule resolution. However, their performance remains largely unclear. In this Progress, we discuss key limitations and uncertainties associated with base-calling models, including their potential cross-reactivities with other modifications, variability in false positive rates across models, unclear threshold choices for modification calling, insufficient orthogonal validation of model accuracy and lack of standardized analysis pipelines. To illustrate some of these issues, we compared the performance of three base-calling models on identical RNA samples, observing over 20-fold differences in the number of predicted m6A-modified sites. As these models are increasingly adopted, it is crucial to understand their limitations to ensure best practices and avoid misinterpretation of epitranscriptomics data. Nanopore RNA sequencing is a potent technology for the detection of RNA modifications. Nanopore modification-aware base-calling models have been recently developed, and this Progress article discusses their limitations, including modification cross-reactivities, variability in false positive rates and modification-calling threshold choices.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 1","pages":"10-18"},"PeriodicalIF":90.2,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283457","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 : 2025-10-10DOI: 10.1038/s41580-025-00916-2
Min Zhang
The discovery of a cis-regulatory element required for xenobiotic gene activation highlighted the crucial role of enhancers in drug metabolism.
外源基因激活所需的顺式调控元件的发现突出了增强剂在药物代谢中的关键作用。
{"title":"Cis-regulatory elements that tune transcriptional responses in liver drug metabolism and outcomes","authors":"Min Zhang","doi":"10.1038/s41580-025-00916-2","DOIUrl":"10.1038/s41580-025-00916-2","url":null,"abstract":"The discovery of a cis-regulatory element required for xenobiotic gene activation highlighted the crucial role of enhancers in drug metabolism.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 12","pages":"909-909"},"PeriodicalIF":90.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261531","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 : 2025-10-09DOI: 10.1038/s41580-025-00913-5
Vinicius Maracaja-Coutinho, Helder I. Nakaya
Single-cell genomics and artificial intelligence (AI) hold great promise for precision medicine, yet biased datasets risk deepening health inequities. Latin American and Caribbean initiatives such as LatinCells are generating inclusive, AI-ready data and changing the region’s researchers from being sample providers to leaders that shape a more equitable genomics medicine. Latin American–Caribbean single-cell genomics initiatives are generating inclusive AI-ready data for precision medicine, and empowering the region’s scientists to become researcher leaders.
{"title":"Single-cell research in Latin America and the Caribbean builds genomics datasets for equitable AI-powered precision medicine","authors":"Vinicius Maracaja-Coutinho, Helder I. Nakaya","doi":"10.1038/s41580-025-00913-5","DOIUrl":"10.1038/s41580-025-00913-5","url":null,"abstract":"Single-cell genomics and artificial intelligence (AI) hold great promise for precision medicine, yet biased datasets risk deepening health inequities. Latin American and Caribbean initiatives such as LatinCells are generating inclusive, AI-ready data and changing the region’s researchers from being sample providers to leaders that shape a more equitable genomics medicine. Latin American–Caribbean single-cell genomics initiatives are generating inclusive AI-ready data for precision medicine, and empowering the region’s scientists to become researcher leaders.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"27 1","pages":"1-3"},"PeriodicalIF":90.2,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254753","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 : 2025-10-06DOI: 10.1038/s41580-025-00895-4
Carlos Alfonso-Gonzalez,Valérie Hilgers
The maturation of mRNAs is crucial for gene regulation and proteome diversification. Transcripts are processed co-transcriptionally through a complex interplay of mechanisms that involve numerous protein machineries. In eukaryotes, most genes undergo alternative RNA processing through the context-dependent use of transcription start sites (TSSs), splice sites and polyadenylation sites. The accurate measurement of alternative TSS usage, alternative splicing and alternative polyadenylation has been enabled by short-read RNA-sequencing technologies. However, elucidating the timing, coordination and functional outcomes of alternative RNA processing is challenging, especially in vivo. The development of long-read sequencing (LRS) methodologies enables the characterization of various aspects of co-transcriptional RNA processing, each methodology providing unique perspectives and limitations. In this Review, we discuss recent advances in short-read sequencing and LRS technologies that measure transcripts in their nascent and mature state and at single-cell resolution and with whole-molecule read length in the case of LRS. We integrate new findings that functionally link alternative TSS, alternative splicing and alternative polyadenylation, with new implications for diseases such as cancer and neurodevelopmental and neurodegenerative disorders. Finally, we discuss insights gained using CRISPR tools into the coordination of RNA processing events.
{"title":"Elucidating the coordination of RNA processing using short-read and long-read RNA-sequencing methods.","authors":"Carlos Alfonso-Gonzalez,Valérie Hilgers","doi":"10.1038/s41580-025-00895-4","DOIUrl":"https://doi.org/10.1038/s41580-025-00895-4","url":null,"abstract":"The maturation of mRNAs is crucial for gene regulation and proteome diversification. Transcripts are processed co-transcriptionally through a complex interplay of mechanisms that involve numerous protein machineries. In eukaryotes, most genes undergo alternative RNA processing through the context-dependent use of transcription start sites (TSSs), splice sites and polyadenylation sites. The accurate measurement of alternative TSS usage, alternative splicing and alternative polyadenylation has been enabled by short-read RNA-sequencing technologies. However, elucidating the timing, coordination and functional outcomes of alternative RNA processing is challenging, especially in vivo. The development of long-read sequencing (LRS) methodologies enables the characterization of various aspects of co-transcriptional RNA processing, each methodology providing unique perspectives and limitations. In this Review, we discuss recent advances in short-read sequencing and LRS technologies that measure transcripts in their nascent and mature state and at single-cell resolution and with whole-molecule read length in the case of LRS. We integrate new findings that functionally link alternative TSS, alternative splicing and alternative polyadenylation, with new implications for diseases such as cancer and neurodevelopmental and neurodegenerative disorders. Finally, we discuss insights gained using CRISPR tools into the coordination of RNA processing events.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"52 1","pages":""},"PeriodicalIF":112.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235540","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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