EMBO Journal最新文献

Molecular mechanism of condensin I activation by KIF4A.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-12-17 DOI: 10.1038/s44318-024-00340-w

Erin E Cutts, Damla Tetiker, Eugene Kim, Luis Aragon

引用次数: 0

A nuclear protein quality control system for elimination of nucleolus-related inclusions.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-12-17 DOI: 10.1038/s44318-024-00333-9

Lorène Brunello, Jolanta Polanowska, Léo Le Tareau, Chantal Maghames, Virginie Georget, Charlotte Guette, Karima Chaoui, Stéphanie Balor, Marie-Françoise O'Donohue, Marie-Pierre Bousquet, Pierre-Emmanuel Gleizes, Dimitris P Xirodimas

{"title":"A nuclear protein quality control system for elimination of nucleolus-related inclusions.","authors":"Lorène Brunello, Jolanta Polanowska, Léo Le Tareau, Chantal Maghames, Virginie Georget, Charlotte Guette, Karima Chaoui, Stéphanie Balor, Marie-Françoise O'Donohue, Marie-Pierre Bousquet, Pierre-Emmanuel Gleizes, Dimitris P Xirodimas","doi":"10.1038/s44318-024-00333-9","DOIUrl":"https://doi.org/10.1038/s44318-024-00333-9","url":null,"abstract":"The identification of pathways that control elimination of protein inclusions is essential to understand the cellular response to proteotoxicity, particularly in the nuclear compartment, for which our knowledge is limited. We report that stress-induced nuclear inclusions related to the nucleolus are eliminated upon stress alleviation during the recovery period. This process is independent of autophagy/lysosome and CRM1-mediated nuclear export pathways, but strictly depends on the ubiquitin-activating E1 enzyme, UBA1, and on nuclear proteasomes that are recruited into the formed inclusions. UBA1 activity is essential only for the recovery process but dispensable for nuclear inclusion formation. Furthermore, the E3 ligase HUWE1 and HSP70 are components of the ubiquitin/chaperone systems that promote inclusion elimination. The recovery process also requires RNA Pol I-dependent production of the lncRNA IGS42 during stress. IGS42 localises within the formed inclusions and promotes their elimination by preserving the mobility of resident proteins. These findings reveal a protein quality control system that operates within the nucleus for the elimination of stress-induced nucleolus-related inclusions.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848317","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}

引用次数: 0

Molecular mechanism targeting condensin for chromosome condensation. 以凝集素为染色体凝聚靶标的分子机制

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-12-17 DOI: 10.1038/s44318-024-00336-6

Menglu Wang, Daniel Robertson, Juan Zou, Christos Spanos, Juri Rappsilber, Adele L Marston

{"title":"Molecular mechanism targeting condensin for chromosome condensation.","authors":"Menglu Wang, Daniel Robertson, Juan Zou, Christos Spanos, Juri Rappsilber, Adele L Marston","doi":"10.1038/s44318-024-00336-6","DOIUrl":"https://doi.org/10.1038/s44318-024-00336-6","url":null,"abstract":"Genomes are organised into DNA loops by the Structural Maintenance of Chromosomes (SMC) proteins. SMCs establish functional chromosomal sub-domains for DNA repair, gene expression and chromosome segregation, but how SMC activity is specifically targeted is unclear. Here, we define the molecular mechanism targeting the condensin SMC complex to specific chromosomal regions in budding yeast. A conserved pocket on the condensin HAWK subunit Ycg1 binds to chromosomal receptors carrying a related motif, CR1. In early mitosis, CR1 motifs in receptors Sgo1 and Lrs4 recruit condensin to pericentromeres and rDNA, to facilitate sister kinetochore biorientation and rDNA condensation, respectively. We additionally find that chromosome arm condensation begins as sister kinetochores come under tension, in a manner dependent on the Ycg1 pocket. We propose that multiple CR1-containing proteins recruit condensin to chromosomes and identify several additional candidates based on their sequence. Overall, we uncover the molecular mechanism that targets condensin to functionalise chromosomal domains to achieve accurate chromosome segregation during mitosis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847853","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}

引用次数: 0

qTAG: an adaptable plasmid scaffold for CRISPR-based endogenous tagging.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-12-12 DOI: 10.1038/s44318-024-00337-5

Reuben Philip, Amit Sharma, Laura Matellan, Anna C Erpf, Wen-Hsin Hsu, Johnny M Tkach, Haley D M Wyatt, Laurence Pelletier

{"title":"qTAG: an adaptable plasmid scaffold for CRISPR-based endogenous tagging.","authors":"Reuben Philip, Amit Sharma, Laura Matellan, Anna C Erpf, Wen-Hsin Hsu, Johnny M Tkach, Haley D M Wyatt, Laurence Pelletier","doi":"10.1038/s44318-024-00337-5","DOIUrl":"https://doi.org/10.1038/s44318-024-00337-5","url":null,"abstract":"Endogenous tagging enables the study of proteins within their native regulatory context, typically using CRISPR to insert tag sequences directly into the gene sequence. Here, we introduce qTAG, a collection of repair cassettes that makes endogenous tagging more accessible. The cassettes support N- and C-terminal tagging with commonly used selectable markers and feature restriction sites for easy modification. Lox sites also enable the removal of the marker gene after successful integration. We demonstrate the utility of qTAG with a range of diverse tags for applications in fluorescence imaging, proximity labeling, epitope tagging, and targeted protein degradation. The system includes novel tags like mStayGold, offering enhanced brightness and photostability for live-cell imaging of native protein dynamics. Additionally, we explore alternative cassette designs for conditional expression tagging, selectable knockout tagging, and safe-harbor expression. The plasmid collection is available through Addgene, featuring ready-to-use constructs for common subcellular markers and tagging cassettes to target genes of interest. The qTAG system will serve as an open resource for researchers to adapt and tailor their own experiments.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819793","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}

引用次数: 0

Cyclin-dependent kinase inhibitor p18 regulates lineage transitions of excitatory neurons, astrocytes, and interneurons in the mouse cortex. 细胞周期蛋白依赖性激酶抑制剂p18调控小鼠大脑皮层兴奋性神经元、星形胶质细胞和中间神经元的谱系转换

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-12-12 DOI: 10.1038/s44318-024-00325-9

Wonyoung Lee, Byunghee Kang, Hyo-Min Kim, Tsuyoshi Ishida, Minkyung Shin, Misato Iwashita, Masahiro Nitta, Aki Shiraishi, Hiroshi Kiyonari, Koichiro Shimoya, Kazuto Masamoto, Tae-Young Roh, Yoichi Kosodo

{"title":"Cyclin-dependent kinase inhibitor p18 regulates lineage transitions of excitatory neurons, astrocytes, and interneurons in the mouse cortex.","authors":"Wonyoung Lee, Byunghee Kang, Hyo-Min Kim, Tsuyoshi Ishida, Minkyung Shin, Misato Iwashita, Masahiro Nitta, Aki Shiraishi, Hiroshi Kiyonari, Koichiro Shimoya, Kazuto Masamoto, Tae-Young Roh, Yoichi Kosodo","doi":"10.1038/s44318-024-00325-9","DOIUrl":"https://doi.org/10.1038/s44318-024-00325-9","url":null,"abstract":"Neural stem cells (NSCs) can give rise to both neurons and glia, but the regulatory mechanisms governing their differentiation transitions remain incompletely understood. Here, we address the role of cyclin-dependent kinase inhibitors (CDKIs) in the later stages of dorsal cortical development. We find that the CDKIs p18 and p27 are upregulated at the onset of astrocyte generation. Acute manipulation of p18 and p27 levels shows that CDKIs modulate lineage switching between upper-layer neurons and astrocytes at the transitional stage. We generate a conditional knock-in mouse model to induce p18 in NSCs. The transcriptomic deconvolution of microdissected tissue reveals that increased levels of p18 promote glial cell development and activate Delta-Notch signaling. Furthermore, we show that p18 upregulates the homeobox transcription factor Dlx2 to subsequently induce the differentiation of olfactory bulb interneurons while reducing the numbers of upper-layer neurons and astrocytes at the perinatal stage. Clonal analysis using transposon-based reporters reveals that the transition from the astrocyte to the interneuron lineage is potentiated by p18 at the single-cell level. In sum, our study reports a function of p18 in determining the developmental boundaries among different cellular lineages arising sequentially from NSCs in the dorsal cortex.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819785","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}

引用次数: 0

SNARE mimicry by the CD225 domain of IFITM3 enables regulation of homotypic late endosome fusion.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-12-09 DOI: 10.1038/s44318-024-00334-8

Kazi Rahman, Isaiah Wilt, Abigail A Jolley, Bhabadeb Chowdhury, Siddhartha A K Datta, Alex A Compton

{"title":"SNARE mimicry by the CD225 domain of IFITM3 enables regulation of homotypic late endosome fusion.","authors":"Kazi Rahman, Isaiah Wilt, Abigail A Jolley, Bhabadeb Chowdhury, Siddhartha A K Datta, Alex A Compton","doi":"10.1038/s44318-024-00334-8","DOIUrl":"https://doi.org/10.1038/s44318-024-00334-8","url":null,"abstract":"The CD225/Dispanin superfamily contains membrane proteins that regulate vesicular transport and membrane fusion events required for neurotransmission, glucose transport, and antiviral immunity. However, how the CD225 domain controls membrane trafficking has remained unknown. Here we show that the CD225 domain contains a SNARE-like motif that enables interaction with cellular SNARE fusogens. Proline-rich transmembrane protein 2 (PRRT2) encodes a SNARE-like motif that enables interaction with neuronal SNARE proteins; mutations in this region disrupt SNARE binding and are linked to neurological disease. Another CD225 member, interferon-induced transmembrane protein 3 (IFITM3), protects cells against influenza A virus infection. IFITM3 interacts with SNARE proteins that mediate late endosome-late endosome (homotypic) fusion and late endosome-lysosome (heterotypic) fusion. IFITM3 binds to syntaxin 7 (STX7) in cells and in vitro, and mutations that abrogate STX7 binding cause loss of antiviral activity against influenza A virus. Mechanistically, IFITM3 disrupts assembly of the SNARE complex controlling homotypic fusion and accelerates the trafficking of endosomal cargo to lysosomes. Our results suggest that SNARE modulation plays a previously unrecognized role in the diverse functions performed by CD225 proteins.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142803274","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}

引用次数: 0

Histone methyltransferases MLL2 and SETD1A/B play distinct roles in H3K4me3 deposition during the transition from totipotency to pluripotency.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-12-05 DOI: 10.1038/s44318-024-00329-5

Jingjing Zhang, Qiaoran Sun, Liang Liu, Shichun Yang, Xia Zhang, Yi-Liang Miao, Xin Liu

{"title":"Histone methyltransferases MLL2 and SETD1A/B play distinct roles in H3K4me3 deposition during the transition from totipotency to pluripotency.","authors":"Jingjing Zhang, Qiaoran Sun, Liang Liu, Shichun Yang, Xia Zhang, Yi-Liang Miao, Xin Liu","doi":"10.1038/s44318-024-00329-5","DOIUrl":"https://doi.org/10.1038/s44318-024-00329-5","url":null,"abstract":"In early mammalian embryogenesis, a shift from non-canonical histone H3 lysine 4 trimethylation (H3K4me3) linked to transcriptional repression to canonical H3K4me3 indicating active promoters occurs during zygotic genome activation (ZGA). However, the mechanisms and roles of these H3K4me3 states in embryogenesis remain poorly understood. Our research reveals that the histone methyltransferase MLL2 is responsible for installing H3K4me3 (both non-canonical and canonical) in totipotent embryos, while a transition to SETD1A/B-deposited H3K4me3 occurs in pluripotent embryos. Interestingly, MLL2-mediated H3K4me3 operates independently of transcription, fostering a relaxed chromatin state conducive to totipotency rather than directly influencing transcription. Conversely, SETD1A/B-mediated H3K4me3, which depends on transcription, is crucial for facilitating expression of genes essential for pluripotency and pre-implantation development. Our findings highlight the role of the H3K4me3 transition, mediated by an MLL2-to-SETD1A/B relay mechanism, in the regulation of transition from totipotency to pluripotency during early embryogenesis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787650","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}

引用次数: 0

How J-chain ensures the assembly of immunoglobulin IgM pentamers.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-12-04 DOI: 10.1038/s44318-024-00317-9

Chiara Giannone, Xenia Mess, Ruiming He, Maria Rita Chelazzi, Annika Mayer, Anush Bakunts, Tuan Nguyen, Yevheniia Bushman, Andrea Orsi, Benedikt Gansen, Massimo Degano, Johannes Buchner, Roberto Sitia

{"title":"How J-chain ensures the assembly of immunoglobulin IgM pentamers.","authors":"Chiara Giannone, Xenia Mess, Ruiming He, Maria Rita Chelazzi, Annika Mayer, Anush Bakunts, Tuan Nguyen, Yevheniia Bushman, Andrea Orsi, Benedikt Gansen, Massimo Degano, Johannes Buchner, Roberto Sitia","doi":"10.1038/s44318-024-00317-9","DOIUrl":"https://doi.org/10.1038/s44318-024-00317-9","url":null,"abstract":"Polymeric IgM immunoglobulins have high avidity for antigen and complement, and dominate primary antibody responses. They are produced either as assemblies of six µ2L2 subunits (i.e., hexamers), or as pentamers of two µ2L2 subunits and an additional protein termed J-chain (JC), which allows transcytosis across epithelia. The molecular mechanism of IgM assembly with the desired stoichiometry remained unknown. Here, we show in vitro and in cellula that JC outcompetes the sixth IgM subunit during assembly. Before insertion into IgM, JC exists as an ensemble of largely unstructured, protease-sensitive species with heterogeneous, non-native disulfide bonds. The J-chain interacts with the hydrophobic β-sheets selectively exposed by nascent pentamers. Completion of an amyloid-like core triggers JC folding and drives disulfide rearrangements that covalently stabilize JC-containing pentamers. In cells, the quality control factor ERp44 surveys IgM assembly and prevents the secretion of aberrant conformers. This mechanism allows the efficient production of high-avidity IgM for systemic or mucosal immunity.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781753","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}

引用次数: 0

Kinesin-like motor protein KIF23 maintains neural stem and progenitor cell pools in the developing cortex.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-12-04 DOI: 10.1038/s44318-024-00327-7

Sharmin Naher, Kenji Iemura, Satoshi Miyashita, Mikio Hoshino, Kozo Tanaka, Shinsuke Niwa, Jin-Wu Tsai, Takako Kikkawa, Noriko Osumi

{"title":"Kinesin-like motor protein KIF23 maintains neural stem and progenitor cell pools in the developing cortex.","authors":"Sharmin Naher, Kenji Iemura, Satoshi Miyashita, Mikio Hoshino, Kozo Tanaka, Shinsuke Niwa, Jin-Wu Tsai, Takako Kikkawa, Noriko Osumi","doi":"10.1038/s44318-024-00327-7","DOIUrl":"https://doi.org/10.1038/s44318-024-00327-7","url":null,"abstract":"Accurate mitotic division of neural stem and progenitor cells (NSPCs) is crucial for the coordinated generation of progenitors and mature neurons, which determines cortical size and structure. While mutations in the kinesin-like motor protein KIF23 gene have been recently linked to microcephaly in humans, the underlying mechanisms remain elusive. Here, we explore the pivotal role of KIF23 in embryonic cortical development. We characterize the dynamic expression of KIF23 in the cortical NSPCs of mice, ferrets, and humans during embryonic neurogenesis. Knockdown of Kif23 in mice results in precocious neurogenesis and neuronal apoptosis, attributed to an accelerated cell cycle exit, likely resulting from disrupted mitotic spindle orientation and impaired cytokinesis. Additionally, KIF23 depletion perturbs the apical surface structure of NSPCs by affecting the localization of apical junction proteins. We further demonstrate that the phenotypes induced by Kif23 knockdown are rescued by introducing wild-type human KIF23, but not by a microcephaly-associated variant. Our findings unveil a previously unexplored role of KIF23 in neural stem and progenitor cell maintenance via regulating spindle orientation and apical structure in addition to cytokinesis, shedding light on microcephaly pathogenesis.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781754","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}

引用次数: 0

FOXP1 phosphorylation antagonizes its O-GlcNAcylation in regulating ATR activation in response to replication stress.

IF 9.4 1区生物学

EMBO Journal Pub Date : 2024-12-02 DOI: 10.1038/s44318-024-00323-x

Xuefei Zhu, Congwen Gao, Bin Peng, Jingwei Xue, Donghui Xia, Liu Yang, Jiexiang Zhang, Xinrui Gao, Yilin Hu, Shixian Lin, Peng Gong, Xingzhi Xu

引用次数: 0