Pub Date : 2024-09-02DOI: 10.1038/s41556-024-01494-9
Matthew Eroglu, Tanner Zocher, Jacob McAuley, Rachel Webster, Maggie Z. X. Xiao, Bin Yu, Calvin Mok, W. Brent Derry
All known heritable phenotypic information in animals is transmitted by direct inheritance of nucleic acids, their covalent modifications or histone modifications that modulate expression of associated genomic regions. Nonetheless, numerous familial traits and disorders cannot be attributed to known heritable molecular factors. Here we identify amyloid-like protein structures that are stably inherited in wild-type animals and influence traits. Their perturbation by genetic, environmental or pharmacological treatments leads to developmental phenotypes that can be epigenetically passed onto progeny. Injection of amyloids isolated from different phenotypic backgrounds into naive animals recapitulates the associated phenotype in offspring. Genetic and proteomic analyses reveal that the 26S proteasome and its conserved regulators maintain heritable amyloids across generations, which enables proper germ cell sex differentiation. We propose that inheritance of a proteinaceous epigenetic memory coordinates developmental timing and patterning with the environment to confer adaptive fitness. Eroglu et al. describe protein amyloid structures that are stably inherited across generations and transmit epigenetic memory in Caenorhabditis elegans. MSTR protein loss results in a transgenerational feminization phenotype through ectopic GLD-1 expression.
{"title":"Noncanonical inheritance of phenotypic information by protein amyloids","authors":"Matthew Eroglu, Tanner Zocher, Jacob McAuley, Rachel Webster, Maggie Z. X. Xiao, Bin Yu, Calvin Mok, W. Brent Derry","doi":"10.1038/s41556-024-01494-9","DOIUrl":"10.1038/s41556-024-01494-9","url":null,"abstract":"All known heritable phenotypic information in animals is transmitted by direct inheritance of nucleic acids, their covalent modifications or histone modifications that modulate expression of associated genomic regions. Nonetheless, numerous familial traits and disorders cannot be attributed to known heritable molecular factors. Here we identify amyloid-like protein structures that are stably inherited in wild-type animals and influence traits. Their perturbation by genetic, environmental or pharmacological treatments leads to developmental phenotypes that can be epigenetically passed onto progeny. Injection of amyloids isolated from different phenotypic backgrounds into naive animals recapitulates the associated phenotype in offspring. Genetic and proteomic analyses reveal that the 26S proteasome and its conserved regulators maintain heritable amyloids across generations, which enables proper germ cell sex differentiation. We propose that inheritance of a proteinaceous epigenetic memory coordinates developmental timing and patterning with the environment to confer adaptive fitness. Eroglu et al. describe protein amyloid structures that are stably inherited across generations and transmit epigenetic memory in Caenorhabditis elegans. MSTR protein loss results in a transgenerational feminization phenotype through ectopic GLD-1 expression.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1712-1724"},"PeriodicalIF":17.3,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118148","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 : 2024-08-29DOI: 10.1038/s41556-024-01495-8
Xiaofu Cao, Shiying Huang, Mateusz M. Wagner, Yuan-Ting Cho, Din-Chi Chiu, Krista M. Wartchow, Artur Lazarian, Laura Beth McIntire, Marcus B. Smolka, Jeremy M. Baskin
Tools for acute manipulation of protein localization enable elucidation of spatiotemporally defined functions, but their reliance on exogenous triggers can interfere with cell physiology. This limitation is particularly apparent for studying mitosis, whose highly choreographed events are sensitive to perturbations. Here we exploit the serendipitous discovery of a phosphorylation-controlled, cell cycle-dependent localization change of the adaptor protein PLEKHA5 to develop a system for mitosis-specific protein recruitment to the plasma membrane that requires no exogenous stimulus. Mitosis-enabled anchor-away/recruiter system comprises an engineered, 15 kDa module derived from PLEKHA5 capable of recruiting functional protein cargoes to the plasma membrane during mitosis, either through direct fusion or via GFP–GFP nanobody interaction. Applications of the mitosis-enabled anchor-away/recruiter system include both knock sideways to rapidly extract proteins from their native localizations during mitosis and conditional recruitment of lipid-metabolizing enzymes for mitosis-selective editing of plasma membrane lipid content, without the need for exogenous triggers or perturbative synchronization methods. Cao et al. describe the development and application of an engineered protein system (MARS) derived from PLEKHA5 that allows mitosis-specific recruitment of proteins to the plasma membrane to study protein function in cell division.
{"title":"A phosphorylation-controlled switch confers cell cycle-dependent protein relocalization","authors":"Xiaofu Cao, Shiying Huang, Mateusz M. Wagner, Yuan-Ting Cho, Din-Chi Chiu, Krista M. Wartchow, Artur Lazarian, Laura Beth McIntire, Marcus B. Smolka, Jeremy M. Baskin","doi":"10.1038/s41556-024-01495-8","DOIUrl":"10.1038/s41556-024-01495-8","url":null,"abstract":"Tools for acute manipulation of protein localization enable elucidation of spatiotemporally defined functions, but their reliance on exogenous triggers can interfere with cell physiology. This limitation is particularly apparent for studying mitosis, whose highly choreographed events are sensitive to perturbations. Here we exploit the serendipitous discovery of a phosphorylation-controlled, cell cycle-dependent localization change of the adaptor protein PLEKHA5 to develop a system for mitosis-specific protein recruitment to the plasma membrane that requires no exogenous stimulus. Mitosis-enabled anchor-away/recruiter system comprises an engineered, 15 kDa module derived from PLEKHA5 capable of recruiting functional protein cargoes to the plasma membrane during mitosis, either through direct fusion or via GFP–GFP nanobody interaction. Applications of the mitosis-enabled anchor-away/recruiter system include both knock sideways to rapidly extract proteins from their native localizations during mitosis and conditional recruitment of lipid-metabolizing enzymes for mitosis-selective editing of plasma membrane lipid content, without the need for exogenous triggers or perturbative synchronization methods. Cao et al. describe the development and application of an engineered protein system (MARS) derived from PLEKHA5 that allows mitosis-specific recruitment of proteins to the plasma membrane to study protein function in cell division.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1804-1816"},"PeriodicalIF":17.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090018","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 : 2024-08-29DOI: 10.1038/s41556-024-01488-7
So Jung Park, Sung Min Son, Antonio Daniel Barbosa, Lidia Wrobel, Eleanna Stamatakou, Ferdinando Squitieri, Gabriel Balmus, David C. Rubinsztein
Autophagy is a conserved pathway where cytoplasmic contents are engulfed by autophagosomes, which then fuse with lysosomes enabling their degradation. Mutations in core autophagy genes cause neurological conditions, and autophagy defects are seen in neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. Thus, we have sought to understand the cellular pathway perturbations that autophagy-perturbed cells are vulnerable to by seeking negative genetic interactions such as synthetic lethality in autophagy-null human cells using available data from yeast screens. These revealed that loss of proteasome and nuclear pore complex components cause synergistic viability changes akin to synthetic fitness loss in autophagy-null cells. This can be attributed to the cytoplasm-to-nuclear transport of proteins during autophagy deficiency and subsequent degradation of these erstwhile cytoplasmic proteins by nuclear proteasomes. As both autophagy and cytoplasm-to-nuclear transport are defective in Huntington’s disease, such cells are more vulnerable to perturbations of proteostasis due to these synthetic interactions. Park et al. show that cells with impaired autophagy shuttle cytoplasmic proteins to the nucleus for degradation by nuclear proteasomes, revealing synergistic vulnerabilities in diseases where autophagy and nucleocytoplasmic transport are compromised.
{"title":"Nuclear proteasomes buffer cytoplasmic proteins during autophagy compromise","authors":"So Jung Park, Sung Min Son, Antonio Daniel Barbosa, Lidia Wrobel, Eleanna Stamatakou, Ferdinando Squitieri, Gabriel Balmus, David C. Rubinsztein","doi":"10.1038/s41556-024-01488-7","DOIUrl":"10.1038/s41556-024-01488-7","url":null,"abstract":"Autophagy is a conserved pathway where cytoplasmic contents are engulfed by autophagosomes, which then fuse with lysosomes enabling their degradation. Mutations in core autophagy genes cause neurological conditions, and autophagy defects are seen in neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. Thus, we have sought to understand the cellular pathway perturbations that autophagy-perturbed cells are vulnerable to by seeking negative genetic interactions such as synthetic lethality in autophagy-null human cells using available data from yeast screens. These revealed that loss of proteasome and nuclear pore complex components cause synergistic viability changes akin to synthetic fitness loss in autophagy-null cells. This can be attributed to the cytoplasm-to-nuclear transport of proteins during autophagy deficiency and subsequent degradation of these erstwhile cytoplasmic proteins by nuclear proteasomes. As both autophagy and cytoplasm-to-nuclear transport are defective in Huntington’s disease, such cells are more vulnerable to perturbations of proteostasis due to these synthetic interactions. Park et al. show that cells with impaired autophagy shuttle cytoplasmic proteins to the nucleus for degradation by nuclear proteasomes, revealing synergistic vulnerabilities in diseases where autophagy and nucleocytoplasmic transport are compromised.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1691-1699"},"PeriodicalIF":17.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01488-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090104","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 : 2024-08-28DOI: 10.1038/s41556-024-01479-8
Using single-cell RNA sequencing analysis of bone-colonizing tumour cells and in vivo screening, lymphotoxin-β (LTβ) was identified as a key factor promoting bone colonization and outgrowth of breast cancer metastases. Blocking LTβ signalling significantly suppressed bone metastasis, highlighting its potential as a therapeutic target for breast cancer with bone metastatic disease.
{"title":"The dual roles of lymphotoxin-β in promoting breast cancer bone metastasis","authors":"","doi":"10.1038/s41556-024-01479-8","DOIUrl":"10.1038/s41556-024-01479-8","url":null,"abstract":"Using single-cell RNA sequencing analysis of bone-colonizing tumour cells and in vivo screening, lymphotoxin-β (LTβ) was identified as a key factor promoting bone colonization and outgrowth of breast cancer metastases. Blocking LTβ signalling significantly suppressed bone metastasis, highlighting its potential as a therapeutic target for breast cancer with bone metastatic disease.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1384-1385"},"PeriodicalIF":17.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142084966","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 : 2024-08-28DOI: 10.1038/s41556-024-01486-9
Daniel Ramsköld, Gert-Jan Hendriks, Anton J. M. Larsson, Juliane V. Mayr, Christoph Ziegenhain, Michael Hagemann-Jensen, Leonard Hartmanis, Rickard Sandberg
Analyses of transcriptional bursting from single-cell RNA-sequencing data have revealed patterns of variation and regulation in the kinetic parameters that could be inferred. Here we profiled newly transcribed (4-thiouridine-labelled) RNA across 10,000 individual primary mouse fibroblasts to more broadly infer bursting kinetics and coordination. We demonstrate that inference from new RNA profiles could separate the kinetic parameters that together specify the burst size, and that the synthesis rate (and not the transcriptional off rate) controls the burst size. Importantly, transcriptome-wide inference of transcriptional on and off rates provided conclusive evidence that RNA polymerase II transcribes genes in bursts. Recent reports identified examples of transcriptional co-bursting, yet no global analyses have been performed. The deep new RNA profiles we generated with allelic resolution demonstrated that co-bursting rarely appears more frequently than expected by chance, except for certain gene pairs, notably paralogues located in close genomic proximity. Altogether, new RNA single-cell profiling critically improves the inference of transcriptional bursting and provides strong evidence for independent transcriptional bursting of mammalian genes. Ramskold, Hendriks, Larsson et al. use deep single-cell profiling of newly transcribed RNA to uncover the kinetics and dynamics of transcriptional bursting at allelic resolution in primary mouse cells.
{"title":"Single-cell new RNA sequencing reveals principles of transcription at the resolution of individual bursts","authors":"Daniel Ramsköld, Gert-Jan Hendriks, Anton J. M. Larsson, Juliane V. Mayr, Christoph Ziegenhain, Michael Hagemann-Jensen, Leonard Hartmanis, Rickard Sandberg","doi":"10.1038/s41556-024-01486-9","DOIUrl":"10.1038/s41556-024-01486-9","url":null,"abstract":"Analyses of transcriptional bursting from single-cell RNA-sequencing data have revealed patterns of variation and regulation in the kinetic parameters that could be inferred. Here we profiled newly transcribed (4-thiouridine-labelled) RNA across 10,000 individual primary mouse fibroblasts to more broadly infer bursting kinetics and coordination. We demonstrate that inference from new RNA profiles could separate the kinetic parameters that together specify the burst size, and that the synthesis rate (and not the transcriptional off rate) controls the burst size. Importantly, transcriptome-wide inference of transcriptional on and off rates provided conclusive evidence that RNA polymerase II transcribes genes in bursts. Recent reports identified examples of transcriptional co-bursting, yet no global analyses have been performed. The deep new RNA profiles we generated with allelic resolution demonstrated that co-bursting rarely appears more frequently than expected by chance, except for certain gene pairs, notably paralogues located in close genomic proximity. Altogether, new RNA single-cell profiling critically improves the inference of transcriptional bursting and provides strong evidence for independent transcriptional bursting of mammalian genes. Ramskold, Hendriks, Larsson et al. use deep single-cell profiling of newly transcribed RNA to uncover the kinetics and dynamics of transcriptional bursting at allelic resolution in primary mouse cells.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1725-1733"},"PeriodicalIF":17.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01486-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142084967","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 : 2024-08-26DOI: 10.1038/s41556-024-01474-z
Kaiwen W. Chen, Petr Broz
The gasdermins are a family of pore-forming proteins that have recently emerged as executors of pyroptosis, a lytic form of cell death that is induced by the innate immune system to eradicate infected or malignant cells. Mammalian gasdermins comprise a cytotoxic N-terminal domain, a flexible linker and a C-terminal repressor domain. Proteolytic cleavage in the linker releases the cytotoxic domain, thereby allowing it to form β-barrel membrane pores. Formation of gasdermin pores in the plasma membrane eventually leads to a loss of the electrochemical gradient, cell death and membrane rupture. Here we review recent work that has expanded our understanding of gasdermin biology and function in mammals by revealing their activation mechanism, their regulation and their roles in autoimmunity, host defence and cancer. We further highlight fungal and bacterial gasdermin pore formation pointing to a conserved mechanism of cell death induction. Gasdermins are a family of proteins that form membrane pores and elicit pyroptosis. This Review discusses recent work highlighting their regulation and emerging biological roles, including in non-lethal pore formation and host defence.
气孔形成蛋白（gasdermins）是一个气孔形成蛋白家族，最近新出现的气孔形成蛋白（gasdermins）是热核变性（pyroptosis）的执行者，热核变性是一种溶解性细胞死亡形式，由先天性免疫系统诱导，以消灭受感染的细胞或恶性细胞。哺乳动物的气蛋白由一个细胞毒性 N 端结构域、一个柔性连接体和一个 C 端抑制结构域组成。连接体上的蛋白水解裂解释放出细胞毒性结构域，从而使其能够形成β-桶状膜孔。质膜上气孔的形成最终会导致电化学梯度的丧失、细胞死亡和膜破裂。在此，我们回顾了最近的研究工作，这些工作通过揭示气孔蛋白的激活机制、调控及其在自身免疫、宿主防御和癌症中的作用，拓展了我们对哺乳动物气孔蛋白生物学和功能的认识。我们进一步强调了真菌和细菌气孔的形成，指出了诱导细胞死亡的保守机制。
{"title":"Gasdermins as evolutionarily conserved executors of inflammation and cell death","authors":"Kaiwen W. Chen, Petr Broz","doi":"10.1038/s41556-024-01474-z","DOIUrl":"10.1038/s41556-024-01474-z","url":null,"abstract":"The gasdermins are a family of pore-forming proteins that have recently emerged as executors of pyroptosis, a lytic form of cell death that is induced by the innate immune system to eradicate infected or malignant cells. Mammalian gasdermins comprise a cytotoxic N-terminal domain, a flexible linker and a C-terminal repressor domain. Proteolytic cleavage in the linker releases the cytotoxic domain, thereby allowing it to form β-barrel membrane pores. Formation of gasdermin pores in the plasma membrane eventually leads to a loss of the electrochemical gradient, cell death and membrane rupture. Here we review recent work that has expanded our understanding of gasdermin biology and function in mammals by revealing their activation mechanism, their regulation and their roles in autoimmunity, host defence and cancer. We further highlight fungal and bacterial gasdermin pore formation pointing to a conserved mechanism of cell death induction. Gasdermins are a family of proteins that form membrane pores and elicit pyroptosis. This Review discusses recent work highlighting their regulation and emerging biological roles, including in non-lethal pore formation and host defence.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1394-1406"},"PeriodicalIF":17.3,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073302","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 : 2024-08-23DOI: 10.1038/s41556-024-01477-w
In cells migrating through complex three-dimensional microenvironments, microtubules are adaptively reinforced at areas of high compressive stress. This reinforcement controls the release of microtubule-bound contractility effectors to locally modify force generation in space and time, enabling motility and cell survival in mechanically strenuous settings.
{"title":"Adaptive microtubule reinforcement enables cell migration through 3D environments","authors":"","doi":"10.1038/s41556-024-01477-w","DOIUrl":"10.1038/s41556-024-01477-w","url":null,"abstract":"In cells migrating through complex three-dimensional microenvironments, microtubules are adaptively reinforced at areas of high compressive stress. This reinforcement controls the release of microtubule-bound contractility effectors to locally modify force generation in space and time, enabling motility and cell survival in mechanically strenuous settings.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1382-1383"},"PeriodicalIF":17.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045555","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 : 2024-08-22DOI: 10.1038/s41556-024-01482-z
Yan Zhen, Harald Stenmark
Autophagy decreases with age, and this is in part attributed to increasing levels of the autophagy-suppressing protein Rubicon. Cell biologists now find another ageing-associated function for Rubicon — the release of exosomes containing microRNAs that control senescence and longevity.
{"title":"Exosome regulation by Rubicon in ageing","authors":"Yan Zhen, Harald Stenmark","doi":"10.1038/s41556-024-01482-z","DOIUrl":"10.1038/s41556-024-01482-z","url":null,"abstract":"Autophagy decreases with age, and this is in part attributed to increasing levels of the autophagy-suppressing protein Rubicon. Cell biologists now find another ageing-associated function for Rubicon — the release of exosomes containing microRNAs that control senescence and longevity.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1380-1381"},"PeriodicalIF":17.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021887","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}
Cells release intraluminal vesicles in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNA interference screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for intraluminal vesicle formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon–WIPI axis functions as a key regulator of exosome biogenesis and is responsible for age-dependent changes in exosome quantity and quality. Yanagawa et al. show that the autophagy-related protein Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Rubicon promotes both an increase in exosome release during ageing and the pro-senescent effects of these exosomes.
{"title":"The Rubicon–WIPI axis regulates exosome biogenesis during ageing","authors":"Kyosuke Yanagawa, Akiko Kuma, Maho Hamasaki, Shunbun Kita, Tadashi Yamamuro, Kohei Nishino, Shuhei Nakamura, Hiroko Omori, Tatsuya Kaminishi, Satoshi Oikawa, Yoshio Kato, Ryuya Edahiro, Ryosuke Kawagoe, Takako Taniguchi, Yoko Tanaka, Takayuki Shima, Keisuke Tabata, Miki Iwatani, Nao Bekku, Rikinari Hanayama, Yukinori Okada, Takayuki Akimoto, Hidetaka Kosako, Akiko Takahashi, Iichiro Shimomura, Yasushi Sakata, Tamotsu Yoshimori","doi":"10.1038/s41556-024-01481-0","DOIUrl":"10.1038/s41556-024-01481-0","url":null,"abstract":"Cells release intraluminal vesicles in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNA interference screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for intraluminal vesicle formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon–WIPI axis functions as a key regulator of exosome biogenesis and is responsible for age-dependent changes in exosome quantity and quality. Yanagawa et al. show that the autophagy-related protein Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Rubicon promotes both an increase in exosome release during ageing and the pro-senescent effects of these exosomes.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1558-1570"},"PeriodicalIF":17.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021888","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 : 2024-08-21DOI: 10.1038/s41556-024-01489-6
Srikanth Kodali, Ludovica Proietti, Gemma Valcarcel, Anna V. López-Rubio, Patrizia Pessina, Thomas Eder, Junchao Shi, Annie Jen, Núria Lupión-Garcia, Anne C. Starner, Mason D. Bartels, Yingzhi Cui, Caroline M. Sands, Ainoa Planas-Riverola, Alba Martínez, Talia Velasco-Hernandez, Laureano Tomás-Daza, Bernhard Alber, Gabriele Manhart, Isabella Maria Mayer, Karoline Kollmann, Alessandro Fatica, Pablo Menendez, Evgenia Shishkova, Rachel E. Rau, Biola M. Javierre, Joshua Coon, Qi Chen, Eric L. Van Nostrand, Jose L. Sardina, Florian Grebien, Bruno Di Stefano
Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and future therapeutic interventions. Kodali, Proietti et al. report that increased numbers of P-bodies in leukaemia cells account for sequestration and prevention of tumour-suppressive mRNAs from being translated, which could be targeted as a potential intervention in myeloid leukaemia.
转录后机制是祖细胞特性的基本保障，在癌症中往往会出现失调。在这里，我们通过在正常和恶性造血祖细胞中进行全基因组 CRISPR 筛选，确定了 P-抗体的调控因子是急性髓性白血病（AML）的关键漏洞。我们发现白血病细胞中的 P 型体数量异常增多，并表明 P 型体的组装对急性髓性白血病的发生和维持至关重要。值得注意的是，P-抗体的缺失对同源造血几乎没有影响，但会影响再生造血。从人类急性髓细胞性白血病细胞中纯化的 P-体的分子特征揭示了它们在从翻译机制中封存编码强效肿瘤抑制因子的信使 RNA 方面的关键作用。P 型体的溶解促进了这些 mRNA 的翻译，进而重新连接了白血病细胞中的基因表达和染色质结构。总之，我们的研究结果凸显了在组织稳态和肿瘤发生过程中，RNA在P体中的螯合作用具有鲜明的对比性和独特性。这些见解为了解骨髓性白血病和未来的治疗干预开辟了潜在的途径。
{"title":"RNA sequestration in P-bodies sustains myeloid leukaemia","authors":"Srikanth Kodali, Ludovica Proietti, Gemma Valcarcel, Anna V. López-Rubio, Patrizia Pessina, Thomas Eder, Junchao Shi, Annie Jen, Núria Lupión-Garcia, Anne C. Starner, Mason D. Bartels, Yingzhi Cui, Caroline M. Sands, Ainoa Planas-Riverola, Alba Martínez, Talia Velasco-Hernandez, Laureano Tomás-Daza, Bernhard Alber, Gabriele Manhart, Isabella Maria Mayer, Karoline Kollmann, Alessandro Fatica, Pablo Menendez, Evgenia Shishkova, Rachel E. Rau, Biola M. Javierre, Joshua Coon, Qi Chen, Eric L. Van Nostrand, Jose L. Sardina, Florian Grebien, Bruno Di Stefano","doi":"10.1038/s41556-024-01489-6","DOIUrl":"10.1038/s41556-024-01489-6","url":null,"abstract":"Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and future therapeutic interventions. Kodali, Proietti et al. report that increased numbers of P-bodies in leukaemia cells account for sequestration and prevention of tumour-suppressive mRNAs from being translated, which could be targeted as a potential intervention in myeloid leukaemia.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 10","pages":"1745-1758"},"PeriodicalIF":17.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013807","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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