Pub Date : 2024-07-18DOI: 10.1038/s41556-024-01460-5
Olivier Saulnier, Jamie Zagozewski, Lisa Liang, Liam D. Hendrikse, Paul Layug, Victor Gordon, Kimberly A. Aldinger, Parthiv Haldipur, Stephanie Borlase, Ludivine Coudière-Morrison, Ting Cai, Emma Martell, Naomi M. Gonzales, Gareth Palidwor, Christopher J. Porter, Stéphane Richard, Tanveer Sharif, Kathleen J. Millen, Brad W. Doble, Michael D. Taylor, Tamra E. Werbowetski-Ogilvie
OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein–protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among the OTX2-regulated differentially spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumour growth and enhances survival in vivo. These findings identify OTX2-mediated alternative splicing as a major determinant of cell fate decisions that drive group 3 MB progression. Werbowetski-Ogilvie, Taylor and colleagues report a noncanonical role for OTX2 in regulating alternative splicing and controlling a stem cell and pro-tumorigenic splicing program in group 3 medulloblastoma.
{"title":"A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing","authors":"Olivier Saulnier, Jamie Zagozewski, Lisa Liang, Liam D. Hendrikse, Paul Layug, Victor Gordon, Kimberly A. Aldinger, Parthiv Haldipur, Stephanie Borlase, Ludivine Coudière-Morrison, Ting Cai, Emma Martell, Naomi M. Gonzales, Gareth Palidwor, Christopher J. Porter, Stéphane Richard, Tanveer Sharif, Kathleen J. Millen, Brad W. Doble, Michael D. Taylor, Tamra E. Werbowetski-Ogilvie","doi":"10.1038/s41556-024-01460-5","DOIUrl":"10.1038/s41556-024-01460-5","url":null,"abstract":"OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein–protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among the OTX2-regulated differentially spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumour growth and enhances survival in vivo. These findings identify OTX2-mediated alternative splicing as a major determinant of cell fate decisions that drive group 3 MB progression. Werbowetski-Ogilvie, Taylor and colleagues report a noncanonical role for OTX2 in regulating alternative splicing and controlling a stem cell and pro-tumorigenic splicing program in group 3 medulloblastoma.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01460-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141724014","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 : 2024-07-15DOI: 10.1038/s41556-024-01464-1
Annemarie Schwab, Zhigang Rao, Jie Zhang, André Gollowitzer, Katharina Siebenkäs, Nino Bindel, Elisabetta D’Avanzo, Ruthger van Roey, Yussuf Hajjaj, Ece Özel, Isabell Armstark, Leonhard Bereuter, Fengting Su, Julia Grander, Ehsan Bonyadi Rad, Arwin Groenewoud, Felix B. Engel, George W. Bell, Whitney S. Henry, José Pedro Friedmann Angeli, Marc P. Stemmler, Simone Brabletz, Andreas Koeberle, Thomas Brabletz
Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial–mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis sensitivity preferentially in high-Zeb1-expressing cancer cells. Our data are of potential translational relevance and suggest a combination of ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1. Schwab, Rao et al. report that Zeb1 mediates enhanced ferroptosis sensitivity in cancer cells after EMT activation, associated with altered expression of selected lipogenic enzymes and an subsequent increase in the PUFA:MUFA ratio.
{"title":"Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition","authors":"Annemarie Schwab, Zhigang Rao, Jie Zhang, André Gollowitzer, Katharina Siebenkäs, Nino Bindel, Elisabetta D’Avanzo, Ruthger van Roey, Yussuf Hajjaj, Ece Özel, Isabell Armstark, Leonhard Bereuter, Fengting Su, Julia Grander, Ehsan Bonyadi Rad, Arwin Groenewoud, Felix B. Engel, George W. Bell, Whitney S. Henry, José Pedro Friedmann Angeli, Marc P. Stemmler, Simone Brabletz, Andreas Koeberle, Thomas Brabletz","doi":"10.1038/s41556-024-01464-1","DOIUrl":"10.1038/s41556-024-01464-1","url":null,"abstract":"Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial–mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis sensitivity preferentially in high-Zeb1-expressing cancer cells. Our data are of potential translational relevance and suggest a combination of ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1. Schwab, Rao et al. report that Zeb1 mediates enhanced ferroptosis sensitivity in cancer cells after EMT activation, associated with altered expression of selected lipogenic enzymes and an subsequent increase in the PUFA:MUFA ratio.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01464-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618238","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 : 2024-07-15DOI: 10.1038/s41556-024-01461-4
Jiechao Zhou, Yang ‘an Chuang, Javier Redding-Ochoa, Rongzhen Zhang, Alexander J. Platero, Alexander H. Barrett, Juan C. Troncoso, Paul F. Worley, Wenchi Zhang
Multiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. Here, we report a RING-in-between-RING-type E3 ligase, TRIAD3A, that functions as an autophagy adaptor for tau. TRIAD3A(RNF216) is an essential gene with mutations causing age-progressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyses mixed K11/K63 polyubiquitin chains and self-assembles into liquid–liquid phase separated (LLPS) droplets. Tau is ubiquitinated and accumulates within TRIAD3A LLPS droplets and, via LC3 interacting regions, targets tau for autophagic degradation. Unexpectedly, tau sequestered within TRIAD3A droplets rapidly converts to fibrillar aggregates without the transitional liquid phase of tau. In vivo studies show that TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and a disease-associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis and increases pathological tau spreading. In human Alzheimer disease brain, TRIAD3A co-localizes with tau amyloid in multiple histological forms, suggesting a role in tau proteostasis. TRIAD3A is an autophagic adaptor that utilizes E3 ligase and LLPS as a mechanism to capture cargo and appears especially relevant to neurodegenerative diseases. Zhou et al. show that the E3 ubiquitin ligase TRIAD3A assembles into liquid–liquid phase-separated droplets that contain tau and promote conversion to fibrillar aggregates and tau autophagic degradation.
多种神经退行性疾病的特征是 tau 蛋白质的异常积累。在这里，我们报告了一种 RING-in-between-RING 型 E3 连接酶 TRIAD3A，它可作为 tau 的自噬适配体发挥作用。TRIAD3A(RNF216)是一个重要基因，其突变可导致年龄进行性神经退行性变。我们的研究发现，TRIAD3A E3连接酶能催化混合的K11/K63多泛素链，并自组装成液相-液相分离（LLPS）液滴。Tau被泛素化并聚集在TRIAD3A LLPS液滴中，并通过LC3相互作用区将tau作为自噬降解的靶标。意想不到的是，螯合在TRIAD3A液滴中的tau会迅速转化为纤维状聚集体，而不会出现tau的过渡液相。体内研究表明，TRIAD3A 可减少磷酸化 tau 在一种 tauopathy 小鼠模型中的积累，而与疾病相关的 TRIAD3A 基因突变会增加磷酸化 tau 的积累，加剧胶质病变并增加病理 tau 的扩散。在人类阿尔茨海默病大脑中，TRIAD3A以多种组织学形式与tau淀粉样蛋白共定位，表明其在tau蛋白稳态中发挥作用。TRIAD3A是一种自噬适配体，利用E3连接酶和LLPS作为捕获货物的机制，似乎与神经退行性疾病特别相关。
{"title":"The autophagy adaptor TRIAD3A promotes tau fibrillation by nested phase separation","authors":"Jiechao Zhou, Yang ‘an Chuang, Javier Redding-Ochoa, Rongzhen Zhang, Alexander J. Platero, Alexander H. Barrett, Juan C. Troncoso, Paul F. Worley, Wenchi Zhang","doi":"10.1038/s41556-024-01461-4","DOIUrl":"10.1038/s41556-024-01461-4","url":null,"abstract":"Multiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. Here, we report a RING-in-between-RING-type E3 ligase, TRIAD3A, that functions as an autophagy adaptor for tau. TRIAD3A(RNF216) is an essential gene with mutations causing age-progressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyses mixed K11/K63 polyubiquitin chains and self-assembles into liquid–liquid phase separated (LLPS) droplets. Tau is ubiquitinated and accumulates within TRIAD3A LLPS droplets and, via LC3 interacting regions, targets tau for autophagic degradation. Unexpectedly, tau sequestered within TRIAD3A droplets rapidly converts to fibrillar aggregates without the transitional liquid phase of tau. In vivo studies show that TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and a disease-associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis and increases pathological tau spreading. In human Alzheimer disease brain, TRIAD3A co-localizes with tau amyloid in multiple histological forms, suggesting a role in tau proteostasis. TRIAD3A is an autophagic adaptor that utilizes E3 ligase and LLPS as a mechanism to capture cargo and appears especially relevant to neurodegenerative diseases. Zhou et al. show that the E3 ubiquitin ligase TRIAD3A assembles into liquid–liquid phase-separated droplets that contain tau and promote conversion to fibrillar aggregates and tau autophagic degradation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618239","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 : 2024-07-12DOI: 10.1038/s41556-024-01459-y
Ruiqi Cai, Ori Scott, Gang Ye, Trieu Le, Ekambir Saran, Whijin Kwon, Subothan Inpanathan, Blayne A. Sayed, Roberto J. Botelho, Amra Saric, Stefan Uderhardt, Spencer A. Freeman
Polymers are endocytosed and hydrolysed by lysosomal enzymes to generate transportable solutes. While the transport of diverse organic solutes across the plasma membrane is well studied, their necessary ongoing efflux from the endocytic fluid into the cytosol is poorly appreciated by comparison. Myeloid cells that employ specialized types of endocytosis, that is, phagocytosis and macropinocytosis, are highly dependent on such transport pathways to prevent the build-up of hydrostatic pressure that otherwise offsets lysosomal dynamics including vesiculation, tubulation and fission. Without undergoing rupture, we found that lysosomes incurring this pressure owing to defects in solute efflux, are unable to retain luminal Na+, which collapses its gradient with the cytosol. This cation ‘leak’ is mediated by pressure-sensitive channels resident to lysosomes and leads to the inhibition of mTORC1, which is normally activated by Na+-coupled amino acid transporters driven by the Na+ gradient. As a consequence, the transcription factors TFEB/TFE3 are made active in macrophages with distended lysosomes. In addition to their role in lysosomal biogenesis, TFEB/TFE3 activation causes the release of MCP-1/CCL2. In catabolically stressed tissues, defects in efflux of solutes from the endocytic pathway leads to increased monocyte recruitment. Here we propose that macrophages respond to a pressure-sensing pathway on lysosomes to orchestrate lysosomal biogenesis as well as myeloid cell recruitment. Cai et al. show that, in lysosomes under hydrostatic pressure in macrophages, lysosomal mechanosensitive channels cause a cation leak. This leads to the inhibition of mTORC1, activation of TFEB/TFE3 and release of monocyte chemoattractant proteins.
{"title":"Pressure sensing of lysosomes enables control of TFEB responses in macrophages","authors":"Ruiqi Cai, Ori Scott, Gang Ye, Trieu Le, Ekambir Saran, Whijin Kwon, Subothan Inpanathan, Blayne A. Sayed, Roberto J. Botelho, Amra Saric, Stefan Uderhardt, Spencer A. Freeman","doi":"10.1038/s41556-024-01459-y","DOIUrl":"10.1038/s41556-024-01459-y","url":null,"abstract":"Polymers are endocytosed and hydrolysed by lysosomal enzymes to generate transportable solutes. While the transport of diverse organic solutes across the plasma membrane is well studied, their necessary ongoing efflux from the endocytic fluid into the cytosol is poorly appreciated by comparison. Myeloid cells that employ specialized types of endocytosis, that is, phagocytosis and macropinocytosis, are highly dependent on such transport pathways to prevent the build-up of hydrostatic pressure that otherwise offsets lysosomal dynamics including vesiculation, tubulation and fission. Without undergoing rupture, we found that lysosomes incurring this pressure owing to defects in solute efflux, are unable to retain luminal Na+, which collapses its gradient with the cytosol. This cation ‘leak’ is mediated by pressure-sensitive channels resident to lysosomes and leads to the inhibition of mTORC1, which is normally activated by Na+-coupled amino acid transporters driven by the Na+ gradient. As a consequence, the transcription factors TFEB/TFE3 are made active in macrophages with distended lysosomes. In addition to their role in lysosomal biogenesis, TFEB/TFE3 activation causes the release of MCP-1/CCL2. In catabolically stressed tissues, defects in efflux of solutes from the endocytic pathway leads to increased monocyte recruitment. Here we propose that macrophages respond to a pressure-sensing pathway on lysosomes to orchestrate lysosomal biogenesis as well as myeloid cell recruitment. Cai et al. show that, in lysosomes under hydrostatic pressure in macrophages, lysosomal mechanosensitive channels cause a cation leak. This leads to the inhibition of mTORC1, activation of TFEB/TFE3 and release of monocyte chemoattractant proteins.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597641","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}
Migrasomes are organelles that are generated by migrating cells. Here we report the key role of neutrophil-derived migrasomes in haemostasis. We found that a large number of neutrophil-derived migrasomes exist in the blood of mice and humans. Compared with neutrophil cell bodies and platelets, these migrasomes adsorb and enrich coagulation factors on the surface. Moreover, they are highly enriched with adhesion molecules, which enable them to preferentially accumulate at sites of injury, where they trigger platelet activation and clot formation. Depletion of neutrophils, or genetic reduction of the number of these migrasomes, significantly decreases platelet plug formation and impairs coagulation. These defects can be rescued by intravenous injection of purified neutrophil-derived migrasomes. Our study reveals neutrophil-derived migrasomes as a previously unrecognized essential component of the haemostasis system, which may shed light on the cause of various coagulation disorders and open therapeutic possibilities. Jiang et al. document an abundance of neutrophil-derived migrasomes in the blood of mice and humans and show that migrasomes are enriched in coagulation factors, accumulate at sites of injury and trigger platelet activation and clot formation.
{"title":"Neutrophil-derived migrasomes are an essential part of the coagulation system","authors":"Dong Jiang, Lin Jiao, Qing Li, Renxiang Xie, Haohao Jia, ShiHui Wang, Yining Chen, Siyuan Liu, Dandan Huang, Jiajia Zheng, Wenhao Song, Ying Li, JianFeng Chen, Jinsong Li, Binwu Ying, Li Yu","doi":"10.1038/s41556-024-01440-9","DOIUrl":"10.1038/s41556-024-01440-9","url":null,"abstract":"Migrasomes are organelles that are generated by migrating cells. Here we report the key role of neutrophil-derived migrasomes in haemostasis. We found that a large number of neutrophil-derived migrasomes exist in the blood of mice and humans. Compared with neutrophil cell bodies and platelets, these migrasomes adsorb and enrich coagulation factors on the surface. Moreover, they are highly enriched with adhesion molecules, which enable them to preferentially accumulate at sites of injury, where they trigger platelet activation and clot formation. Depletion of neutrophils, or genetic reduction of the number of these migrasomes, significantly decreases platelet plug formation and impairs coagulation. These defects can be rescued by intravenous injection of purified neutrophil-derived migrasomes. Our study reveals neutrophil-derived migrasomes as a previously unrecognized essential component of the haemostasis system, which may shed light on the cause of various coagulation disorders and open therapeutic possibilities. Jiang et al. document an abundance of neutrophil-derived migrasomes in the blood of mice and humans and show that migrasomes are enriched in coagulation factors, accumulate at sites of injury and trigger platelet activation and clot formation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01440-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597640","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 : 2024-07-12DOI: 10.1038/s41556-024-01463-2
Bo Zhou, Zhi-hong Jiang, Meng-ran Dai, Yuan-li Ai, Li Xiao, Chuan-qi Zhong, Liu-Zheng Wu, Qi-tao Chen, Hang-zi Chen, Qiao Wu
Gasdermin (GSDM) family proteins, known as the executors of pyroptosis, undergo protease-mediated cleavage before inducing pyroptosis. We here discovered a form of pyroptosis mediated by full-length (FL) GSDME without proteolytic cleavage. Intense ultraviolet-C irradiation-triggered DNA damage activates nuclear PARP1, leading to extensive formation of poly(ADP-ribose) (PAR) polymers. These PAR polymers are released to the cytoplasm, where they activate PARP5 to facilitate GSDME PARylation, resulting in a conformational change in GSDME that relieves autoinhibition. Moreover, ultraviolet-C irradiation promotes cytochrome c-catalysed cardiolipin peroxidation to elevate lipid reactive oxygen species, which is then sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARylation and oxidation of FL-GSDME, synergistically promoting pyroptotic cell death. Overall, the present findings elucidate an unreported mechanism underlying the cleavage-independent function of GSDME in executing cell death, further enriching the paradigms and understanding of FL-GSDME-mediated pyroptosis. Zhou, Jiang, Dai et al report that upon ultraviolet-C radiation, full-length GSDME can induce pyroptosis without cleavage, likely due to conformational change and oxidative oligomerization after increased PARylation and mitochondrial lipid ROS levels.
{"title":"Full-length GSDME mediates pyroptosis independent from cleavage","authors":"Bo Zhou, Zhi-hong Jiang, Meng-ran Dai, Yuan-li Ai, Li Xiao, Chuan-qi Zhong, Liu-Zheng Wu, Qi-tao Chen, Hang-zi Chen, Qiao Wu","doi":"10.1038/s41556-024-01463-2","DOIUrl":"10.1038/s41556-024-01463-2","url":null,"abstract":"Gasdermin (GSDM) family proteins, known as the executors of pyroptosis, undergo protease-mediated cleavage before inducing pyroptosis. We here discovered a form of pyroptosis mediated by full-length (FL) GSDME without proteolytic cleavage. Intense ultraviolet-C irradiation-triggered DNA damage activates nuclear PARP1, leading to extensive formation of poly(ADP-ribose) (PAR) polymers. These PAR polymers are released to the cytoplasm, where they activate PARP5 to facilitate GSDME PARylation, resulting in a conformational change in GSDME that relieves autoinhibition. Moreover, ultraviolet-C irradiation promotes cytochrome c-catalysed cardiolipin peroxidation to elevate lipid reactive oxygen species, which is then sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARylation and oxidation of FL-GSDME, synergistically promoting pyroptotic cell death. Overall, the present findings elucidate an unreported mechanism underlying the cleavage-independent function of GSDME in executing cell death, further enriching the paradigms and understanding of FL-GSDME-mediated pyroptosis. Zhou, Jiang, Dai et al report that upon ultraviolet-C radiation, full-length GSDME can induce pyroptosis without cleavage, likely due to conformational change and oxidative oligomerization after increased PARylation and mitochondrial lipid ROS levels.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597638","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 : 2024-07-11DOI: 10.1038/s41556-024-01454-3
Fátima Gebauer
The role of RNA in preserving the integrity and dynamics of membrane-bound organelles remains largely unexplored. A study now identifies the Golgi-resident protein GM130 as an RNA-binding protein that scaffolds the Golgi ribbon in a polyadenylated-RNA-dependent manner.
{"title":"RNA glues it all","authors":"Fátima Gebauer","doi":"10.1038/s41556-024-01454-3","DOIUrl":"10.1038/s41556-024-01454-3","url":null,"abstract":"The role of RNA in preserving the integrity and dynamics of membrane-bound organelles remains largely unexplored. A study now identifies the Golgi-resident protein GM130 as an RNA-binding protein that scaffolds the Golgi ribbon in a polyadenylated-RNA-dependent manner.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141584269","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 : 2024-07-11DOI: 10.1038/s41556-024-01447-2
Yijun Zhang, Joachim Seemann
The mammalian Golgi is composed of stacks that are laterally connected into a continuous ribbon-like structure. The integrity and function of the ribbon is disrupted under stress conditions, but the molecular mechanisms remain unclear. Here we show that the ribbon is maintained by biomolecular condensates of RNA and the Golgi matrix protein GM130 (GOLGA2). We identify GM130 as a membrane-bound RNA-binding protein, which directly recruits RNA and associated RNA-binding proteins to the Golgi membrane. Acute degradation of RNA or GM130 in cells disrupts the ribbon. Under stress conditions, RNA dissociates from GM130 and the ribbon is disjointed, but after the cells recover from stress the ribbon is restored. When overexpressed in cells, GM130 forms RNA-dependent liquid-like condensates. GM130 contains an intrinsically disordered domain at its amino terminus, which binds RNA to induce liquid–liquid phase separation. These co-condensates are sufficient to link purified Golgi membranes, reconstructing lateral linking of stacks into a ribbon-like structure. Together, these studies show that RNA acts as a structural biopolymer that together with GM130 maintains the integrity of the Golgi ribbon. Zhang and Seemann show that GM130 forms a complex with RNA-binding proteins. RNA binding of GM130 induces liquid–liquid phase separation and these co-condensates function to link the Golgi ribbon.
{"title":"RNA scaffolds the Golgi ribbon by forming condensates with GM130","authors":"Yijun Zhang, Joachim Seemann","doi":"10.1038/s41556-024-01447-2","DOIUrl":"10.1038/s41556-024-01447-2","url":null,"abstract":"The mammalian Golgi is composed of stacks that are laterally connected into a continuous ribbon-like structure. The integrity and function of the ribbon is disrupted under stress conditions, but the molecular mechanisms remain unclear. Here we show that the ribbon is maintained by biomolecular condensates of RNA and the Golgi matrix protein GM130 (GOLGA2). We identify GM130 as a membrane-bound RNA-binding protein, which directly recruits RNA and associated RNA-binding proteins to the Golgi membrane. Acute degradation of RNA or GM130 in cells disrupts the ribbon. Under stress conditions, RNA dissociates from GM130 and the ribbon is disjointed, but after the cells recover from stress the ribbon is restored. When overexpressed in cells, GM130 forms RNA-dependent liquid-like condensates. GM130 contains an intrinsically disordered domain at its amino terminus, which binds RNA to induce liquid–liquid phase separation. These co-condensates are sufficient to link purified Golgi membranes, reconstructing lateral linking of stacks into a ribbon-like structure. Together, these studies show that RNA acts as a structural biopolymer that together with GM130 maintains the integrity of the Golgi ribbon. Zhang and Seemann show that GM130 forms a complex with RNA-binding proteins. RNA binding of GM130 induces liquid–liquid phase separation and these co-condensates function to link the Golgi ribbon.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141584271","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}
Currently, the dynamic accessible elements that determine regulatory programs responsible for the unique identity and function of each cell type during zebrafish embryogenesis lack detailed study. Here we present SPATAC-seq: a split-pool ligation-based assay for transposase-accessible chromatin using sequencing. Using SPATAC-seq, we profiled chromatin accessibility in more than 800,000 individual nuclei across 20 developmental stages spanning the sphere stage to the early larval protruding mouth stage. Using this chromatin accessibility map, we identified 604 cell states and inferred their developmental relationships. We also identified 959,040 candidate cis-regulatory elements (cCREs) and delineated development-specific cCREs, as well as transcription factors defining diverse cell identities. Importantly, enhancer reporter assays confirmed that the majority of tested cCREs exhibited robust enhanced green fluorescent protein expression in restricted cell types or tissues. Finally, we explored gene regulatory programs that drive pigment and notochord cell differentiation. Our work provides a valuable open resource for exploring driver regulators of cell fate decisions in zebrafish embryogenesis. In two independent studies, Sun, Liu et al. and Sun et al. develop SPATAC-seq to map the chromatin accessibility landscape of zebrafish embryogenesis and mouse organogenesis, respectively, and identify transcription regulators that determine cell fate.
{"title":"Mapping the chromatin accessibility landscape of zebrafish embryogenesis at single-cell resolution by SPATAC-seq","authors":"Keyong Sun, Xin Liu, Runda Xu, Chang Liu, Anming Meng, Xun Lan","doi":"10.1038/s41556-024-01449-0","DOIUrl":"10.1038/s41556-024-01449-0","url":null,"abstract":"Currently, the dynamic accessible elements that determine regulatory programs responsible for the unique identity and function of each cell type during zebrafish embryogenesis lack detailed study. Here we present SPATAC-seq: a split-pool ligation-based assay for transposase-accessible chromatin using sequencing. Using SPATAC-seq, we profiled chromatin accessibility in more than 800,000 individual nuclei across 20 developmental stages spanning the sphere stage to the early larval protruding mouth stage. Using this chromatin accessibility map, we identified 604 cell states and inferred their developmental relationships. We also identified 959,040 candidate cis-regulatory elements (cCREs) and delineated development-specific cCREs, as well as transcription factors defining diverse cell identities. Importantly, enhancer reporter assays confirmed that the majority of tested cCREs exhibited robust enhanced green fluorescent protein expression in restricted cell types or tissues. Finally, we explored gene regulatory programs that drive pigment and notochord cell differentiation. Our work provides a valuable open resource for exploring driver regulators of cell fate decisions in zebrafish embryogenesis. In two independent studies, Sun, Liu et al. and Sun et al. develop SPATAC-seq to map the chromatin accessibility landscape of zebrafish embryogenesis and mouse organogenesis, respectively, and identify transcription regulators that determine cell fate.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557192","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 : 2024-07-08DOI: 10.1038/s41556-024-01435-6
Keyong Sun, Xin Liu, Xun Lan
Organogenesis is a highly complex and precisely regulated process. Here we profiled the chromatin accessibility in >350,000 cells derived from 13 mouse embryos at four developmental stages from embryonic day (E) 10.5 to E13.5 by SPATAC-seq in a single experiment. The resulting atlas revealed the status of 830,873 candidate cis-regulatory elements in 43 major cell types. By integrating the chromatin accessibility atlas with the previous transcriptomic dataset, we characterized cis-regulatory sequences and transcription factors associated with cell fate commitment, such as Nr5a2 in the development of gastrointestinal tract, which was preliminarily supported by the in vivo experiment in zebrafish. Finally, we integrated this atlas with the previous single-cell chromatin accessibility dataset from 13 adult mouse tissues to delineate the developmental stage-specific gene regulatory programmes within and across different cell types and identify potential molecular switches throughout lineage development. This comprehensive dataset provides a foundation for exploring transcriptional regulation in organogenesis. In two independent studies, Sun, Liu et al. and Sun et al. develop SPATAC-seq to map the chromatin accessibility landscape of zebrafish embryogenesis and mouse organogenesis, respectively, and identify transcription regulators that determine cell fate.
{"title":"A single-cell atlas of chromatin accessibility in mouse organogenesis","authors":"Keyong Sun, Xin Liu, Xun Lan","doi":"10.1038/s41556-024-01435-6","DOIUrl":"10.1038/s41556-024-01435-6","url":null,"abstract":"Organogenesis is a highly complex and precisely regulated process. Here we profiled the chromatin accessibility in >350,000 cells derived from 13 mouse embryos at four developmental stages from embryonic day (E) 10.5 to E13.5 by SPATAC-seq in a single experiment. The resulting atlas revealed the status of 830,873 candidate cis-regulatory elements in 43 major cell types. By integrating the chromatin accessibility atlas with the previous transcriptomic dataset, we characterized cis-regulatory sequences and transcription factors associated with cell fate commitment, such as Nr5a2 in the development of gastrointestinal tract, which was preliminarily supported by the in vivo experiment in zebrafish. Finally, we integrated this atlas with the previous single-cell chromatin accessibility dataset from 13 adult mouse tissues to delineate the developmental stage-specific gene regulatory programmes within and across different cell types and identify potential molecular switches throughout lineage development. This comprehensive dataset provides a foundation for exploring transcriptional regulation in organogenesis. In two independent studies, Sun, Liu et al. and Sun et al. develop SPATAC-seq to map the chromatin accessibility landscape of zebrafish embryogenesis and mouse organogenesis, respectively, and identify transcription regulators that determine cell fate.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":null,"pages":null},"PeriodicalIF":17.3,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557137","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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