Pub Date : 2025-11-17DOI: 10.1038/s41556-025-01810-x
August F. Williams, David A. G. Gervasio, Claire E. Turkal, Anna E. Stuhlfire, Michael X. Wang, Brandon E. Mauch, Rhea Plawat, Ariel H. Nguyen, Michelle H. Paw, Mehrshad Hairani, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page, Matthew J. Hangauer
Oncogene-targeted cancer therapies can provide deep responses but frequently suffer from acquired resistance. Therapeutic approaches to treat tumours that have acquired drug resistance are complicated by continual tumour evolution and multiple co-occurring resistance mechanisms. Rather than treating resistance after it emerges, it may be possible to prevent it by inhibiting the adaptive processes that initiate resistance, but these are poorly understood. Here we report that residual cancer persister cells that survive oncogene-targeted therapy are growth arrested by drug stress-induced intrinsic type I interferon signalling. To escape growth arrest, persister cells leverage apoptotic machinery to transcriptionally suppress interferon-stimulated genes (ISGs). Mechanistically, persister cells sublethally engage apoptotic caspases to activate DNA endonuclease DNA fragmentation factor B (also known as caspase-activated DNase), which induces DNA damage, mutagenesis and stress response factor activating transcription factor 3 (ATF3). ATF3 limits activator protein 1-mediated ISG expression sufficiently to allow persister cell regrowth. Persister cells deficient in DNA fragmentation factor B or ATF3 exhibit high ISG expression and are consequently unable to regrow. Therefore, sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment. Williams et al. report a growth arrest mechanism in residual cancer persister cells through targeted therapy-induced upregulation of type I interferon signalling, which is negatively regulated by apoptotic DNA endonuclease DFFB to allow tumour relapse.
{"title":"DNA fragmentation factor B suppresses interferon to enable cancer persister cell regrowth","authors":"August F. Williams, David A. G. Gervasio, Claire E. Turkal, Anna E. Stuhlfire, Michael X. Wang, Brandon E. Mauch, Rhea Plawat, Ariel H. Nguyen, Michelle H. Paw, Mehrshad Hairani, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page, Matthew J. Hangauer","doi":"10.1038/s41556-025-01810-x","DOIUrl":"10.1038/s41556-025-01810-x","url":null,"abstract":"Oncogene-targeted cancer therapies can provide deep responses but frequently suffer from acquired resistance. Therapeutic approaches to treat tumours that have acquired drug resistance are complicated by continual tumour evolution and multiple co-occurring resistance mechanisms. Rather than treating resistance after it emerges, it may be possible to prevent it by inhibiting the adaptive processes that initiate resistance, but these are poorly understood. Here we report that residual cancer persister cells that survive oncogene-targeted therapy are growth arrested by drug stress-induced intrinsic type I interferon signalling. To escape growth arrest, persister cells leverage apoptotic machinery to transcriptionally suppress interferon-stimulated genes (ISGs). Mechanistically, persister cells sublethally engage apoptotic caspases to activate DNA endonuclease DNA fragmentation factor B (also known as caspase-activated DNase), which induces DNA damage, mutagenesis and stress response factor activating transcription factor 3 (ATF3). ATF3 limits activator protein 1-mediated ISG expression sufficiently to allow persister cell regrowth. Persister cells deficient in DNA fragmentation factor B or ATF3 exhibit high ISG expression and are consequently unable to regrow. Therefore, sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment. Williams et al. report a growth arrest mechanism in residual cancer persister cells through targeted therapy-induced upregulation of type I interferon signalling, which is negatively regulated by apoptotic DNA endonuclease DFFB to allow tumour relapse.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2143-2151"},"PeriodicalIF":19.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01810-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531628","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 : 2025-11-17DOI: 10.1038/s41556-025-01836-1
Dario F. De Jesus, Zijie Zhang, Natalie K. Brown, Xiaolu Li, Ling Xiao, Jiang Hu, Matthew J. Gaffrey, Garrett Fogarty, Sevim Kahraman, Jiangbo Wei, Giorgio Basile, Tariq M. Rana, Clayton Mathews, Alvin C. Powers, Audrey V. Parent, Mark A. Atkinson, Sirano Dhe-Paganon, Decio L. Eizirik, Wei-Jun Qian, Chuan He, Rohit N. Kulkarni
{"title":"Author Correction: Redox regulation of m6A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes","authors":"Dario F. De Jesus, Zijie Zhang, Natalie K. Brown, Xiaolu Li, Ling Xiao, Jiang Hu, Matthew J. Gaffrey, Garrett Fogarty, Sevim Kahraman, Jiangbo Wei, Giorgio Basile, Tariq M. Rana, Clayton Mathews, Alvin C. Powers, Audrey V. Parent, Mark A. Atkinson, Sirano Dhe-Paganon, Decio L. Eizirik, Wei-Jun Qian, Chuan He, Rohit N. Kulkarni","doi":"10.1038/s41556-025-01836-1","DOIUrl":"10.1038/s41556-025-01836-1","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"208-208"},"PeriodicalIF":19.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01836-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536156","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 : 2025-11-11DOI: 10.1038/s41556-025-01800-z
Deborah Fass, Carolyn S. Sevier
Phase separation is a mechanism for non-organellar macromolecule segregation typical in the cell cytosol and nucleus. Two recent studies revealed functional phase separation within the endoplasmic reticulum, where calcium-mediated condensates co-ordinate chaperones and disulfide catalysts to enhance secretory protein production.
{"title":"Young secretory proteins go through a phase","authors":"Deborah Fass, Carolyn S. Sevier","doi":"10.1038/s41556-025-01800-z","DOIUrl":"10.1038/s41556-025-01800-z","url":null,"abstract":"Phase separation is a mechanism for non-organellar macromolecule segregation typical in the cell cytosol and nucleus. Two recent studies revealed functional phase separation within the endoplasmic reticulum, where calcium-mediated condensates co-ordinate chaperones and disulfide catalysts to enhance secretory protein production.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1887-1888"},"PeriodicalIF":19.1,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487115","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}
In mammals, DNA methylation is re-established after implantation following post-fertilization global erasure. Yet, the underlying mechanism remains elusive. Here we investigate H3K36me2 reprogramming in mouse early development and its role in post-implantation DNA methylation re-establishment. In oocytes, H3K36me2 accumulates in gene bodies upon transcription silencing and partially persists to the eight-cell stage. De novo H3K36me2 occurs at enhancers after zygotic genome activation, before spreading genome-wide after implantation, except on the inactive X chromosome. Mutation of the H3K36me2 methyltransferase NSD1 compromises global DNA methylation after implantation preferentially in extra-embryonic lineages and that at methylation-prone promoters, including those of germline-specific genes. However, DNA methylation establishment partially bypasses H3K36me2 through upregulated DNMT3B, a ‘leaky’ H3K36me2/3 reader. This contrasts with DNMT3A, which strictly requires H3K36me2/3 for DNA methylation through its PWWP domain. Finally, DNA methylation valleys escape de novo DNA methylation via PRC1/H2AK119ub1-mediated H3K36me2 exclusion. Thus, H3K36me2 reprogramming regulates lineage- and locus-specific post-implantation DNA methylation establishment. Lu, Wang et al. profile H3K36me2 throughout oocyte-to-embryo transition, pre-implantation and early post-implantation development and report a role for H3K36me2 in post-implantation embryos to re-establish lineage-specific DNA methylation.
{"title":"Reprogramming of H3K36me2 guides lineage-specific post-implantation de novo DNA methylation","authors":"Xukun Lu, Lijuan Wang, Bofeng Liu, Xiaoyu Hu, Zhengmao Wang, Ling Liu, Guang Yu, Lijun Dong, Feng Kong, Qiang Fan, Yu Zhang, Wei Xie","doi":"10.1038/s41556-025-01805-8","DOIUrl":"10.1038/s41556-025-01805-8","url":null,"abstract":"In mammals, DNA methylation is re-established after implantation following post-fertilization global erasure. Yet, the underlying mechanism remains elusive. Here we investigate H3K36me2 reprogramming in mouse early development and its role in post-implantation DNA methylation re-establishment. In oocytes, H3K36me2 accumulates in gene bodies upon transcription silencing and partially persists to the eight-cell stage. De novo H3K36me2 occurs at enhancers after zygotic genome activation, before spreading genome-wide after implantation, except on the inactive X chromosome. Mutation of the H3K36me2 methyltransferase NSD1 compromises global DNA methylation after implantation preferentially in extra-embryonic lineages and that at methylation-prone promoters, including those of germline-specific genes. However, DNA methylation establishment partially bypasses H3K36me2 through upregulated DNMT3B, a ‘leaky’ H3K36me2/3 reader. This contrasts with DNMT3A, which strictly requires H3K36me2/3 for DNA methylation through its PWWP domain. Finally, DNA methylation valleys escape de novo DNA methylation via PRC1/H2AK119ub1-mediated H3K36me2 exclusion. Thus, H3K36me2 reprogramming regulates lineage- and locus-specific post-implantation DNA methylation establishment. Lu, Wang et al. profile H3K36me2 throughout oocyte-to-embryo transition, pre-implantation and early post-implantation development and report a role for H3K36me2 in post-implantation embryos to re-establish lineage-specific DNA methylation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 12","pages":"2128-2142"},"PeriodicalIF":19.1,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484917","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}
The endoplasmic reticulum (ER) plays crucial roles in maintaining protein quality control and regulating dynamic Ca2+ storage in eukaryotic cells. However, the proteostasis system involved in ER-mediated protein quality control has not been fully characterized. Here we show that Ca2+ triggers the condensation of PDIA6, an ER-resident disulfide isomerase and molecular chaperone, into quality control granules. In contrast to the condensation mechanism observed for proteins containing low-complexity domains, our results indicate that transient but specific electrostatic interactions occur between the first and the third folded thioredoxin-like domains of PDIA6. We further show that the PDIA6 condensates recruit proinsulin, thereby accelerating the oxidative proinsulin folding and suppressing the proinsulin aggregation inside quality control granules, essential for secretion of insulin. Lee et al. show that Ca²⁺ triggers condensates enriched with PDIA6, an ER-resident disulfide isomerase and chaperone, along with other protein disulfide isomerase family proteins and some chaperones that in turn enhance folding of proinsulin.
{"title":"Ca2+-driven PDIA6 biomolecular condensation ensures proinsulin folding","authors":"Young-Ho Lee, Tomohide Saio, Mai Watabe, Motonori Matsusaki, Shingo Kanemura, Yuxi Lin, Taro Mannen, Tsubura Kuramochi, Yuka Kamada, Katsuya Iuchi, Michiko Tajiri, Kotono Suzuki, Yan Li, Yunseok Heo, Kotone Ishii, Kenta Arai, Kazunori Ban, Mayuko Hashimoto, Shuichiro Oshita, Satoshi Ninagawa, Yoshikazu Hattori, Hiroyuki Kumeta, Airu Takeuchi, Shinji Kajimoto, Hiroya Abe, Eiichiro Mori, Takahiro Muraoka, Takakazu Nakabayashi, Satoko Akashi, Tsukasa Okiyoneda, Michele Vendruscolo, Kenji Inaba, Masaki Okumura","doi":"10.1038/s41556-025-01794-8","DOIUrl":"10.1038/s41556-025-01794-8","url":null,"abstract":"The endoplasmic reticulum (ER) plays crucial roles in maintaining protein quality control and regulating dynamic Ca2+ storage in eukaryotic cells. However, the proteostasis system involved in ER-mediated protein quality control has not been fully characterized. Here we show that Ca2+ triggers the condensation of PDIA6, an ER-resident disulfide isomerase and molecular chaperone, into quality control granules. In contrast to the condensation mechanism observed for proteins containing low-complexity domains, our results indicate that transient but specific electrostatic interactions occur between the first and the third folded thioredoxin-like domains of PDIA6. We further show that the PDIA6 condensates recruit proinsulin, thereby accelerating the oxidative proinsulin folding and suppressing the proinsulin aggregation inside quality control granules, essential for secretion of insulin. Lee et al. show that Ca²⁺ triggers condensates enriched with PDIA6, an ER-resident disulfide isomerase and chaperone, along with other protein disulfide isomerase family proteins and some chaperones that in turn enhance folding of proinsulin.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1952-1964"},"PeriodicalIF":19.1,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01794-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484919","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 : 2025-11-10DOI: 10.1038/s41556-025-01825-4
Sangbum Park, David G. Gonzalez, Boris Guirao, Jonathan D. Boucher, Katie Cockburn, Edward D. Marsh, Kailin R. Mesa, Samara Brown, Panteleimon Rompolas, Ann M. Haberman, Yohanns Bellaïche, Valentina Greco
{"title":"Author Correction: Tissue-scale coordination of cellular behaviour promotes epidermal wound repair in live mice","authors":"Sangbum Park, David G. Gonzalez, Boris Guirao, Jonathan D. Boucher, Katie Cockburn, Edward D. Marsh, Kailin R. Mesa, Samara Brown, Panteleimon Rompolas, Ann M. Haberman, Yohanns Bellaïche, Valentina Greco","doi":"10.1038/s41556-025-01825-4","DOIUrl":"10.1038/s41556-025-01825-4","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"208-208"},"PeriodicalIF":19.1,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01825-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484920","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 : 2025-11-06DOI: 10.1038/s41556-025-01796-6
Daniel Besser, Sina Bartfeld, Stefanie Mahler
The German Stem Cell Network (GSCN) connects science, society and policy to advance stem cell research. Since 2013, it has promoted innovation, ethics and public engagement. Recognizing Europe’s need for stronger collaboration, the GSCN aims to build a pan-European network to enhance research and translation, and to support young scientists.
{"title":"Bridging science, society and policy with the German Stem Cell Network","authors":"Daniel Besser, Sina Bartfeld, Stefanie Mahler","doi":"10.1038/s41556-025-01796-6","DOIUrl":"10.1038/s41556-025-01796-6","url":null,"abstract":"The German Stem Cell Network (GSCN) connects science, society and policy to advance stem cell research. Since 2013, it has promoted innovation, ethics and public engagement. Recognizing Europe’s need for stronger collaboration, the GSCN aims to build a pan-European network to enhance research and translation, and to support young scientists.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1877-1880"},"PeriodicalIF":19.1,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1038/s41556-025-01792-w
Yuanzhuo Zhou, Kohei Asai, Hirohisa Kyogoku, Tomoya S. Kitajima
Chromosome mis-segregation during meiosis in oocytes causes miscarriages and congenital diseases. Ageing-associated premature chromosome separation is a major cause of mis-segregation. Effective prevention of premature chromosome separation has not yet been achieved. Here we design protein-based artificial kinetochores that act as decoys to prevent premature chromosome separation. Designed artificial kinetochore-like decoys are submicroscale clusters of NDC80-NUF2-tethered protein particles that can establish a biorientation-like state by competing with chromosomal kinetochores for HURP-decorated microtubules. This competition reduces excessive bipolar microtubule pulling forces exerted on chromosomes, thereby effectively preventing premature chromosome separation during meiosis I and II in aged mouse oocytes. These effects suppress egg aneuploidy. This study provides a decoy strategy with biocompatible artificial kinetochores to prevent ageing-associated meiotic errors in oocytes. Zhou et al. design protein-based artificial kinetochore constructs as decoys to prevent premature chromosomal separation in aged oocytes. These constructs compete with chromosomal kinetochores, reducing excessive bipolar microtubule pulling forces.
{"title":"Designing protein-based artificial kinetochores as decoys to prevent meiotic errors in oocytes","authors":"Yuanzhuo Zhou, Kohei Asai, Hirohisa Kyogoku, Tomoya S. Kitajima","doi":"10.1038/s41556-025-01792-w","DOIUrl":"10.1038/s41556-025-01792-w","url":null,"abstract":"Chromosome mis-segregation during meiosis in oocytes causes miscarriages and congenital diseases. Ageing-associated premature chromosome separation is a major cause of mis-segregation. Effective prevention of premature chromosome separation has not yet been achieved. Here we design protein-based artificial kinetochores that act as decoys to prevent premature chromosome separation. Designed artificial kinetochore-like decoys are submicroscale clusters of NDC80-NUF2-tethered protein particles that can establish a biorientation-like state by competing with chromosomal kinetochores for HURP-decorated microtubules. This competition reduces excessive bipolar microtubule pulling forces exerted on chromosomes, thereby effectively preventing premature chromosome separation during meiosis I and II in aged mouse oocytes. These effects suppress egg aneuploidy. This study provides a decoy strategy with biocompatible artificial kinetochores to prevent ageing-associated meiotic errors in oocytes. Zhou et al. design protein-based artificial kinetochore constructs as decoys to prevent premature chromosomal separation in aged oocytes. These constructs compete with chromosomal kinetochores, reducing excessive bipolar microtubule pulling forces.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"2007-2018"},"PeriodicalIF":19.1,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01792-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434234","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 : 2025-10-31DOI: 10.1038/s41556-025-01801-y
Eliana Ibrahimi, Brooke N. Wolford
Statistical thinking is a core part of solid, trustworthy biology. However, many studies still include insufficient sample sizes, have poor experimental design or select an incorrect statistical method for the hypothesis being tested. Here we present ten statistical tips for cell biology.
{"title":"Ten essential tips for robust statistics in cell biology","authors":"Eliana Ibrahimi, Brooke N. Wolford","doi":"10.1038/s41556-025-01801-y","DOIUrl":"10.1038/s41556-025-01801-y","url":null,"abstract":"Statistical thinking is a core part of solid, trustworthy biology. However, many studies still include insufficient sample sizes, have poor experimental design or select an incorrect statistical method for the hypothesis being tested. Here we present ten statistical tips for cell biology.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1884-1886"},"PeriodicalIF":19.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-31DOI: 10.1038/s41556-025-01789-5
Shan Lu, Sitao Zhang, Spencer Oung, Jolene K. Diedrich, Peng Han, Olatz Arnold-Garcia, Takuya Ohkubo, Olubankole Aladesuyi Arogundade, Sonia Vazquez-Sanchez, Ke Zhang, John Ravits, John R. Yates III, Don W. Cleveland
In multiple neurodegenerative diseases, the RNA-binding protein TDP-43 forms cytoplasmic aggregates of distinct morphologies, including skein-like, small rounded granular and large spherical inclusions. Here, whereas the N-terminal self-oligomerization domain regulates TDP-43 demixing into cytoplasmic droplets, inhibition of N-terminal self-oligomerization domain-mediated oligomerization is shown to promote the formation of skein-like inclusions. Utilizing proximity labelling–mass spectrometry, cellular stresses are shown to induce TDP-43 association with actin-binding proteins that include filamins and α-actinin. Small interfering RNA-mediated reduction of filamin in Drosophila ameliorates cell loss from cytoplasmic TDP-43, consistent with the filamin–TDP-43 interaction enhancing cytotoxicity. TDP-43’s association with actin-binding proteins is mediated by BAG3, a HSP70 family nucleotide exchange factor that regulates the proteostasis of actin-binding proteins. BAG2, another HSP70 nucleotide exchange factor, facilitates the formation of small, rounded TDP-43 inclusions. We demonstrate that both TDP-43 self-oligomerization and its binding partners, including HSP70 and cochaperones BAG2 and BAG3, drive the formation of the different types of TDP-43 inclusion. Lu et al. show that, under proteotoxic stress, TDP-43 inclusions of skein-like morphology are guided by the chaperone HSP70 and its nucleotide exchange factor BAG3 to induce TDP-43 co-aggregation with F-actin-bound actin-binding proteins.
{"title":"TDP-43 skein-like inclusions are formed by BAG3- and HSP70-guided co-aggregation with actin-binding proteins","authors":"Shan Lu, Sitao Zhang, Spencer Oung, Jolene K. Diedrich, Peng Han, Olatz Arnold-Garcia, Takuya Ohkubo, Olubankole Aladesuyi Arogundade, Sonia Vazquez-Sanchez, Ke Zhang, John Ravits, John R. Yates III, Don W. Cleveland","doi":"10.1038/s41556-025-01789-5","DOIUrl":"10.1038/s41556-025-01789-5","url":null,"abstract":"In multiple neurodegenerative diseases, the RNA-binding protein TDP-43 forms cytoplasmic aggregates of distinct morphologies, including skein-like, small rounded granular and large spherical inclusions. Here, whereas the N-terminal self-oligomerization domain regulates TDP-43 demixing into cytoplasmic droplets, inhibition of N-terminal self-oligomerization domain-mediated oligomerization is shown to promote the formation of skein-like inclusions. Utilizing proximity labelling–mass spectrometry, cellular stresses are shown to induce TDP-43 association with actin-binding proteins that include filamins and α-actinin. Small interfering RNA-mediated reduction of filamin in Drosophila ameliorates cell loss from cytoplasmic TDP-43, consistent with the filamin–TDP-43 interaction enhancing cytotoxicity. TDP-43’s association with actin-binding proteins is mediated by BAG3, a HSP70 family nucleotide exchange factor that regulates the proteostasis of actin-binding proteins. BAG2, another HSP70 nucleotide exchange factor, facilitates the formation of small, rounded TDP-43 inclusions. We demonstrate that both TDP-43 self-oligomerization and its binding partners, including HSP70 and cochaperones BAG2 and BAG3, drive the formation of the different types of TDP-43 inclusion. Lu et al. show that, under proteotoxic stress, TDP-43 inclusions of skein-like morphology are guided by the chaperone HSP70 and its nucleotide exchange factor BAG3 to induce TDP-43 co-aggregation with F-actin-bound actin-binding proteins.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 11","pages":"1925-1937"},"PeriodicalIF":19.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145404894","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：