Pub Date : 2024-10-23DOI: 10.1038/s41580-024-00795-z
James L. Kirkland
James Kirkland discusses how work by Norman Sharpless and colleagues, published in 2004, paved the way for the development of senolytics, which are now in early phase clinical trials for the treatment of multiple disorders.
{"title":"The prompt to discover senolytics","authors":"James L. Kirkland","doi":"10.1038/s41580-024-00795-z","DOIUrl":"10.1038/s41580-024-00795-z","url":null,"abstract":"James Kirkland discusses how work by Norman Sharpless and colleagues, published in 2004, paved the way for the development of senolytics, which are now in early phase clinical trials for the treatment of multiple disorders.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 12","pages":"953-953"},"PeriodicalIF":81.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487328","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 : 2024-10-21DOI: 10.1038/s41580-024-00784-2
Shalini Oberdoerffer, Wendy V. Gilbert
RNA modifications are essential for human health — too much or too little of them leads to serious illnesses ranging from neurodevelopmental disorders to cancer. Technical advances in RNA modification sequencing are beginning to uncover the RNA targets of diverse RNA-modifying enzymes that are dysregulated in disease. However, the emerging transcriptome-wide maps of modified nucleosides installed by these enzymes should be considered as first drafts. In particular, a range of technical artefacts lead to false negatives — modified sites that are overlooked owing to technique-dependent, and often sequence-context-specific, ‘blind spots’. In this Review, we discuss potential sources of false negatives in sequencing-based RNA modification maps, propose mitigation strategies and suggest guidelines for transparent reporting of sensitivity to detect modified sites in profiling studies. Important considerations for recognition and avoidance of false negatives include assessment and reporting of position-specific sequencing depth, identification of protocol-dependent RNA capture biases and applying controls for false negatives as well as for false positives. Despite their limitations, emerging maps of RNA modifications reveal exciting and largely uncharted potential for post-transcriptional control of all aspects of RNA function. Specialized RNA modification sequencing techniques are helping to uncover how dysregulation of RNA modification leads to disease. This Review discusses how technical artefacts can cause false negatives (overlooked modified sites) in RNA modification maps, proposes mitigation strategies and suggests guidelines for detection-sensitivity reporting.
{"title":"All the sites we cannot see: Sources and mitigation of false negatives in RNA modification studies","authors":"Shalini Oberdoerffer, Wendy V. Gilbert","doi":"10.1038/s41580-024-00784-2","DOIUrl":"10.1038/s41580-024-00784-2","url":null,"abstract":"RNA modifications are essential for human health — too much or too little of them leads to serious illnesses ranging from neurodevelopmental disorders to cancer. Technical advances in RNA modification sequencing are beginning to uncover the RNA targets of diverse RNA-modifying enzymes that are dysregulated in disease. However, the emerging transcriptome-wide maps of modified nucleosides installed by these enzymes should be considered as first drafts. In particular, a range of technical artefacts lead to false negatives — modified sites that are overlooked owing to technique-dependent, and often sequence-context-specific, ‘blind spots’. In this Review, we discuss potential sources of false negatives in sequencing-based RNA modification maps, propose mitigation strategies and suggest guidelines for transparent reporting of sensitivity to detect modified sites in profiling studies. Important considerations for recognition and avoidance of false negatives include assessment and reporting of position-specific sequencing depth, identification of protocol-dependent RNA capture biases and applying controls for false negatives as well as for false positives. Despite their limitations, emerging maps of RNA modifications reveal exciting and largely uncharted potential for post-transcriptional control of all aspects of RNA function. Specialized RNA modification sequencing techniques are helping to uncover how dysregulation of RNA modification leads to disease. This Review discusses how technical artefacts can cause false negatives (overlooked modified sites) in RNA modification maps, proposes mitigation strategies and suggests guidelines for detection-sensitivity reporting.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 3","pages":"237-248"},"PeriodicalIF":81.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451812","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 : 2024-10-17DOI: 10.1038/s41580-024-00785-1
Luis-Carlos Tábara, Mayuko Segawa, Julien Prudent
Mitochondria not only synthesize energy required for cellular functions but are also involved in numerous cellular pathways including apoptosis, calcium homoeostasis, inflammation and immunity. Mitochondria are dynamic organelles that undergo cycles of fission and fusion, and these transitions between fragmented and hyperfused networks ensure mitochondrial function, enabling adaptations to metabolic changes or cellular stress. Defects in mitochondrial morphology have been associated with numerous diseases, highlighting the importance of elucidating the molecular mechanisms regulating mitochondrial morphology. Here, we discuss recent structural insights into the assembly and mechanism of action of the core mitochondrial dynamics proteins, such as the dynamin-related protein 1 (DRP1) that controls division, and the mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) driving membrane fusion. Furthermore, we provide an updated view of the complex interplay between different proteins, lipids and organelles during the processes of mitochondrial membrane fusion and fission. Overall, we aim to present a valuable framework reflecting current perspectives on how mitochondrial membrane remodelling is regulated. Mitochondrial fusion and fission events are tightly regulated by core mitochondrial dynamics proteins. Recent structural and functional findings have characterized how these proteins interact with each other, with the mitochondrial membrane and with other organelles to guide membrane remodelling.
{"title":"Molecular mechanisms of mitochondrial dynamics","authors":"Luis-Carlos Tábara, Mayuko Segawa, Julien Prudent","doi":"10.1038/s41580-024-00785-1","DOIUrl":"10.1038/s41580-024-00785-1","url":null,"abstract":"Mitochondria not only synthesize energy required for cellular functions but are also involved in numerous cellular pathways including apoptosis, calcium homoeostasis, inflammation and immunity. Mitochondria are dynamic organelles that undergo cycles of fission and fusion, and these transitions between fragmented and hyperfused networks ensure mitochondrial function, enabling adaptations to metabolic changes or cellular stress. Defects in mitochondrial morphology have been associated with numerous diseases, highlighting the importance of elucidating the molecular mechanisms regulating mitochondrial morphology. Here, we discuss recent structural insights into the assembly and mechanism of action of the core mitochondrial dynamics proteins, such as the dynamin-related protein 1 (DRP1) that controls division, and the mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) driving membrane fusion. Furthermore, we provide an updated view of the complex interplay between different proteins, lipids and organelles during the processes of mitochondrial membrane fusion and fission. Overall, we aim to present a valuable framework reflecting current perspectives on how mitochondrial membrane remodelling is regulated. Mitochondrial fusion and fission events are tightly regulated by core mitochondrial dynamics proteins. Recent structural and functional findings have characterized how these proteins interact with each other, with the mitochondrial membrane and with other organelles to guide membrane remodelling.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 2","pages":"123-146"},"PeriodicalIF":81.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448321","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 : 2024-10-16DOI: 10.1038/s41580-024-00792-2
Raffaella Di Micco
Raffaella Di Micco discusses the importance of a 2020 study in which CAR-T cells were engineered to eliminate senescent cells.
拉法埃拉-迪米科（Raffaella Di Micco）讨论了 2020 年一项研究的重要性，在这项研究中，CAR-T 细胞被设计成能消除衰老细胞。
{"title":"Goodbye, senescent cells: CAR-T cells unleashed to fight ageing","authors":"Raffaella Di Micco","doi":"10.1038/s41580-024-00792-2","DOIUrl":"10.1038/s41580-024-00792-2","url":null,"abstract":"Raffaella Di Micco discusses the importance of a 2020 study in which CAR-T cells were engineered to eliminate senescent cells.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 12","pages":"955-955"},"PeriodicalIF":81.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439669","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 : 2024-10-16DOI: 10.1038/s41580-024-00793-1
Ana O’Loghlen
Ana O’Loghlen highlights a recent study that indicates that inhibiting the pro-inflammatory cytokine IL-11 has anti-ageing effects, and how such findings could have implications for the treatment of ageing-associated diseases.
Ana O'Loghlen重点介绍了最近的一项研究，该研究表明抑制促炎细胞因子IL-11具有抗衰老作用，以及这些发现如何对治疗衰老相关疾病产生影响。
{"title":"IL-11 as a master regulator of ageing","authors":"Ana O’Loghlen","doi":"10.1038/s41580-024-00793-1","DOIUrl":"10.1038/s41580-024-00793-1","url":null,"abstract":"Ana O’Loghlen highlights a recent study that indicates that inhibiting the pro-inflammatory cytokine IL-11 has anti-ageing effects, and how such findings could have implications for the treatment of ageing-associated diseases.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 12","pages":"956-956"},"PeriodicalIF":81.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439670","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 : 2024-10-14DOI: 10.1038/s41580-024-00790-4
Allison B. Herman, Myriam Gorospe
Enrichment of senescent cells from organs holds great promise for studying cell senescence and ageing, and for identifying therapeutic vulnerabilities.
从器官中富集衰老细胞为研究细胞衰老和老化以及确定治疗漏洞带来了巨大希望。
{"title":"Molecular tools for analysing in vivo senescence","authors":"Allison B. Herman, Myriam Gorospe","doi":"10.1038/s41580-024-00790-4","DOIUrl":"10.1038/s41580-024-00790-4","url":null,"abstract":"Enrichment of senescent cells from organs holds great promise for studying cell senescence and ageing, and for identifying therapeutic vulnerabilities.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 12","pages":"954-954"},"PeriodicalIF":81.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431521","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 : 2024-10-11DOI: 10.1038/s41580-024-00780-6
Ahmet Yildiz
Kinesins are a diverse superfamily of microtubule-based motors that perform fundamental roles in intracellular transport, cytoskeletal dynamics and cell division. These motors share a characteristic motor domain that powers unidirectional motility and force generation along microtubules, and they possess unique tail domains that recruit accessory proteins and facilitate oligomerization, regulation and cargo recognition. The location, direction and timing of kinesin-driven processes are tightly regulated by various cofactors, adaptors, microtubule tracks and microtubule-associated proteins. This Review focuses on recent structural and functional studies that reveal how members of the kinesin superfamily use the energy of ATP hydrolysis to transport cargoes, depolymerize microtubules and regulate microtubule dynamics. I also survey how accessory proteins and post-translational modifications regulate the autoinhibition, cargo binding and motility of some of the best-studied kinesins. Despite much progress, the mechanism and regulation of kinesins are still emerging, and unresolved questions can now be tackled using newly developed approaches in biophysics and structural biology. Kinesin-mediated transport of intracellular cargo depends on finely tuned interactions between kinesin motor domains, microtubules and cofactors. Recent structural and functional insights are uncovering the mechanochemical cycle that drives kinesin motility, as well as the regulatory processes that modulate kinesin activity.
驱动蛋白是基于微管的马达的一个多样化超家族，在细胞内运输、细胞骨架动力学和细胞分裂中发挥着重要作用。这些驱动蛋白都有一个特征性的马达结构域，能沿微管进行单向运动并产生力，它们还拥有独特的尾部结构域，能招募附属蛋白并促进寡聚化、调控和货物识别。驱动蛋白驱动过程的位置、方向和时间受到各种辅助因子、适配器、微管轨道和微管相关蛋白的严格调控。本综述将重点介绍最近的结构和功能研究，这些研究揭示了驱动蛋白超家族成员如何利用 ATP 水解的能量来运输货物、解聚微管以及调节微管动力学。我还考察了附属蛋白和翻译后修饰是如何调控一些研究得最好的驱动蛋白的自抑制、货物结合和运动性的。尽管取得了很大进展，但驱动蛋白的机制和调控仍在不断涌现，现在可以利用生物物理学和结构生物学的新方法来解决悬而未决的问题。
{"title":"Mechanism and regulation of kinesin motors","authors":"Ahmet Yildiz","doi":"10.1038/s41580-024-00780-6","DOIUrl":"10.1038/s41580-024-00780-6","url":null,"abstract":"Kinesins are a diverse superfamily of microtubule-based motors that perform fundamental roles in intracellular transport, cytoskeletal dynamics and cell division. These motors share a characteristic motor domain that powers unidirectional motility and force generation along microtubules, and they possess unique tail domains that recruit accessory proteins and facilitate oligomerization, regulation and cargo recognition. The location, direction and timing of kinesin-driven processes are tightly regulated by various cofactors, adaptors, microtubule tracks and microtubule-associated proteins. This Review focuses on recent structural and functional studies that reveal how members of the kinesin superfamily use the energy of ATP hydrolysis to transport cargoes, depolymerize microtubules and regulate microtubule dynamics. I also survey how accessory proteins and post-translational modifications regulate the autoinhibition, cargo binding and motility of some of the best-studied kinesins. Despite much progress, the mechanism and regulation of kinesins are still emerging, and unresolved questions can now be tackled using newly developed approaches in biophysics and structural biology. Kinesin-mediated transport of intracellular cargo depends on finely tuned interactions between kinesin motor domains, microtubules and cofactors. Recent structural and functional insights are uncovering the mechanochemical cycle that drives kinesin motility, as well as the regulatory processes that modulate kinesin activity.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"26 2","pages":"86-103"},"PeriodicalIF":81.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405490","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 : 2024-10-09DOI: 10.1038/s41580-024-00791-3
Akiko Takahashi
Akiko Takahashi discusses the seminal 1997 paper by Serrano et al. who found that oncogene activation results in a similar phenotype to replicative senescence, establishing the connection between senescence and cancer.
{"title":"The discovery of oncogene-induced senescence","authors":"Akiko Takahashi","doi":"10.1038/s41580-024-00791-3","DOIUrl":"10.1038/s41580-024-00791-3","url":null,"abstract":"Akiko Takahashi discusses the seminal 1997 paper by Serrano et al. who found that oncogene activation results in a similar phenotype to replicative senescence, establishing the connection between senescence and cancer.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 12","pages":"951-951"},"PeriodicalIF":81.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385083","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 : 2024-10-04DOI: 10.1038/s41580-024-00781-5
Elias H. Barriga
Elias Barriga discusses a seminal 2006 paper from Zhao et al., which was the first study to integrate electrotaxis signals into the established molecular framework enabling directed cell migration.
Elias Barriga 讨论了 Zhao 等人在 2006 年发表的一篇开创性论文，该论文是将电传共振信号整合到促成定向细胞迁移的既定分子框架中的第一项研究。
{"title":"Following the electric current","authors":"Elias H. Barriga","doi":"10.1038/s41580-024-00781-5","DOIUrl":"10.1038/s41580-024-00781-5","url":null,"abstract":"Elias Barriga discusses a seminal 2006 paper from Zhao et al., which was the first study to integrate electrotaxis signals into the established molecular framework enabling directed cell migration.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 11","pages":"844-844"},"PeriodicalIF":81.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374108","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 : 2024-10-04DOI: 10.1038/s41580-024-00783-3
Pauline Kasper, Lisa Heinke
De Caestecker and Macara find that the sorting of membrane proteins in the Golgi relies on a size filter that enables correct localization of proteins with a short cytosolic domain to the apical membrane.
De Caestecker 和 Macara 发现，膜蛋白在高尔基体中的分拣依赖于一个尺寸过滤器，它能将具有短细胞膜结构域的蛋白质正确定位到顶端膜上。
{"title":"Sorting membrane proteins by size in the Golgi","authors":"Pauline Kasper, Lisa Heinke","doi":"10.1038/s41580-024-00783-3","DOIUrl":"10.1038/s41580-024-00783-3","url":null,"abstract":"De Caestecker and Macara find that the sorting of membrane proteins in the Golgi relies on a size filter that enables correct localization of proteins with a short cytosolic domain to the apical membrane.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":"25 11","pages":"842-842"},"PeriodicalIF":81.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374107","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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