Nature Cell Biology最新文献_第10页

Direct observation of translational activation by a ribonucleoprotein granule 直接观察核糖核蛋白颗粒的翻译激活过程

IF 17.3 1区生物学

Nature Cell Biology Pub Date : 2024-07-04 DOI: 10.1038/s41556-024-01452-5

Ruoyu Chen, William Stainier, Jeremy Dufourt, Mounia Lagha, Ruth Lehmann

{"title":"Direct observation of translational activation by a ribonucleoprotein granule","authors":"Ruoyu Chen, William Stainier, Jeremy Dufourt, Mounia Lagha, Ruth Lehmann","doi":"10.1038/s41556-024-01452-5","DOIUrl":"10.1038/s41556-024-01452-5","url":null,"abstract":"Biomolecular condensates organize biochemical processes at the subcellular level and can provide spatiotemporal regulation within a cell. Among these, ribonucleoprotein (RNP) granules are storage hubs for translationally repressed mRNA. Whether RNP granules can also activate translation and how this could be achieved remains unclear. Here, using single-molecule imaging, we demonstrate that the germ cell-determining RNP granules in Drosophila embryos are sites for active translation of nanos mRNA. Nanos translation occurs preferentially at the germ granule surface with the 3′ UTR buried within the granule. Smaug, a cytosolic RNA-binding protein, represses nanos translation, which is relieved when Smaug is sequestered to the germ granule by the scaffold protein Oskar. Together, our findings uncover a molecular process by which RNP granules achieve localized protein synthesis through the compartmentalized loss of translational repression. Chen et al. perform single-molecule imaging of translation at ribonucleoprotein (RNP) granules. They show that RNP granule surfaces are sites of nanos mRNA translation, whereas the granule interior is translationally repressive.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 8","pages":"1322-1335"},"PeriodicalIF":17.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01452-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141521578","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}

引用次数: 0

Targeting specific DNA G-quadruplexes with CRISPR-guided G-quadruplex-binding proteins and ligands 利用 CRISPR 引导的 G-四联体结合蛋白和配体靶向特定 DNA G-四联体

IF 17.3 1区生物学

Nature Cell Biology Pub Date : 2024-07-03 DOI: 10.1038/s41556-024-01448-1

Geng Qin, Zhenqi Liu, Jie Yang, Xiaofeng Liao, Chuanqi Zhao, Jinsong Ren, Xiaogang Qu

{"title":"Targeting specific DNA G-quadruplexes with CRISPR-guided G-quadruplex-binding proteins and ligands","authors":"Geng Qin, Zhenqi Liu, Jie Yang, Xiaofeng Liao, Chuanqi Zhao, Jinsong Ren, Xiaogang Qu","doi":"10.1038/s41556-024-01448-1","DOIUrl":"10.1038/s41556-024-01448-1","url":null,"abstract":"Despite the demonstrated importance of DNA G-quadruplexes (G4s) in health and disease, technologies to readily manipulate specific G4 folding for functional analysis and therapeutic purposes are lacking. Here we employ G4-stabilizing protein/ligand in conjunction with CRISPR to selectively facilitate single or multiple targeted G4 folding within specific genomic loci. We demonstrate that fusion of nucleolin with a catalytically inactive Cas9 can specifically stabilize G4s in the promoter of oncogene MYC and muscle-associated gene Itga7 as well as telomere G4s, leading to cell proliferation arrest, inhibition of myoblast differentiation and cell senescence, respectively. Furthermore, CRISPR can confer intra-G4 selectivity to G4-binding compounds pyridodicarboxamide and pyridostatin. Compared with traditional G4 ligands, CRISPR-guided biotin-conjugated pyridodicarboxamide enables a more precise investigation into the biological functionality of de novo G4s. Our study provides insights that will enhance understanding of G4 functions and therapeutic interventions. Qin, Liu and colleagues develop a tool that combines CRISPR technology with G-quadruplex (G4)-stabilizing protein or ligand to specifically target DNA G4 structures. This tool provides better understanding of G4 functions and enables G4-based drug development.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 7","pages":"1212-1224"},"PeriodicalIF":17.3,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496032","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

Mechanistic insights into the basis of widespread RNA localization 从机理上洞察 RNA 广泛定位的基础

IF 17.3 1区生物学

Nature Cell Biology Pub Date : 2024-07-02 DOI: 10.1038/s41556-024-01444-5

Marina Chekulaeva

引用次数: 0

VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates VAMP2 在突触囊泡共缩物中合体α-突触核蛋白

IF 17.3 1区生物学

Nature Cell Biology Pub Date : 2024-07-01 DOI: 10.1038/s41556-024-01456-1

Chuchu Wang, Kai Zhang, Bin Cai, Jillian E. Haller, Kathryn E. Carnazza, Jiaojiao Hu, Chunyu Zhao, Zhiqi Tian, Xiao Hu, Daniel Hall, Jiali Qiang, Shouqiao Hou, Zhenying Liu, Jinge Gu, Yaoyang Zhang, Kim B. Seroogy, Jacqueline Burré, Yanshan Fang, Cong Liu, Axel T. Brunger, Dan Li, Jiajie Diao

{"title":"VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates","authors":"Chuchu Wang, Kai Zhang, Bin Cai, Jillian E. Haller, Kathryn E. Carnazza, Jiaojiao Hu, Chunyu Zhao, Zhiqi Tian, Xiao Hu, Daniel Hall, Jiali Qiang, Shouqiao Hou, Zhenying Liu, Jinge Gu, Yaoyang Zhang, Kim B. Seroogy, Jacqueline Burré, Yanshan Fang, Cong Liu, Axel T. Brunger, Dan Li, Jiajie Diao","doi":"10.1038/s41556-024-01456-1","DOIUrl":"10.1038/s41556-024-01456-1","url":null,"abstract":"α-Synuclein (α-Syn) aggregation is closely associated with Parkinson’s disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. However, the underlying structural and molecular mechanisms are uncertain and it is not known whether this function affects the pathological aggregation of α-Syn. Here we show that the juxtamembrane region of vesicle-associated membrane protein 2 (VAMP2)—a component of the SNARE complex that resides on SVs—directly interacts with the carboxy-terminal region of α-Syn through charged residues to regulate α-Syn’s function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase of SVs, α-Syn and other components. Moreover, VAMP2 binding protects α-Syn against forming aggregation-prone oligomers and fibrils in these condensates. Our results suggest a molecular mechanism that maintains α-Syn’s function and prevents its pathological amyloid aggregation, the failure of which may lead to Parkinson’s disease. Agarwal et al. and Wang et al. show that vesicle-associated membrane protein 2 (VAMP2) interacts with and regulates alpha-synuclein biomolecular condensation, affecting α-synuclein function, which may prevent pathological amyloid aggregation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 8","pages":"1287-1295"},"PeriodicalIF":17.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475333","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

VAMP2 regulates phase separation of α-synuclein VAMP2 调节α-突触核蛋白的相分离

IF 17.3 1区生物学

Nature Cell Biology Pub Date : 2024-07-01 DOI: 10.1038/s41556-024-01451-6

Aishwarya Agarwal, Aswathy Chandran, Farheen Raza, Irina-Maria Ungureanu, Christine Hilcenko, Katherine Stott, Nicholas A. Bright, Nobuhiro Morone, Alan J. Warren, Janin Lautenschläger

{"title":"VAMP2 regulates phase separation of α-synuclein","authors":"Aishwarya Agarwal, Aswathy Chandran, Farheen Raza, Irina-Maria Ungureanu, Christine Hilcenko, Katherine Stott, Nicholas A. Bright, Nobuhiro Morone, Alan J. Warren, Janin Lautenschläger","doi":"10.1038/s41556-024-01451-6","DOIUrl":"10.1038/s41556-024-01451-6","url":null,"abstract":"α-Synuclein (αSYN), a pivotal synaptic protein implicated in synucleinopathies such as Parkinson’s disease and Lewy body dementia, undergoes protein phase separation. We reveal that vesicle-associated membrane protein 2 (VAMP2) orchestrates αSYN phase separation both in vitro and in cells. Electrostatic interactions, specifically mediated by VAMP2 via its juxtamembrane domain and the αSYN C-terminal region, drive phase separation. Condensate formation is specific for R-SNARE VAMP2 and dependent on αSYN lipid membrane binding. Our results delineate a regulatory mechanism for αSYN phase separation in cells. Furthermore, we show that αSYN condensates sequester vesicles and attract complexin-1 and -2, thus supporting a role in synaptic physiology and pathophysiology. Agarwal et al. show that vesicle-associated membrane protein 2 interacts with and regulates α-synuclein biomolecular condensation, affecting α-synuclein function, which may prevent pathological amyloid aggregation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 8","pages":"1296-1308"},"PeriodicalIF":17.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01451-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475208","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}

引用次数: 0

Ras suppression potentiates rear actomyosin contractility-driven cell polarization and migration 抑制 Ras 可增强后部肌动蛋白收缩力驱动的细胞极化和迁移

IF 17.3 1区生物学

Nature Cell Biology Pub Date : 2024-07-01 DOI: 10.1038/s41556-024-01453-4

Yiyan Lin, Dhiman Sankar Pal, Parijat Banerjee, Tatsat Banerjee, Guanghui Qin, Yu Deng, Jane Borleis, Pablo A. Iglesias, Peter N. Devreotes

{"title":"Ras suppression potentiates rear actomyosin contractility-driven cell polarization and migration","authors":"Yiyan Lin, Dhiman Sankar Pal, Parijat Banerjee, Tatsat Banerjee, Guanghui Qin, Yu Deng, Jane Borleis, Pablo A. Iglesias, Peter N. Devreotes","doi":"10.1038/s41556-024-01453-4","DOIUrl":"10.1038/s41556-024-01453-4","url":null,"abstract":"Ras has been extensively studied as a promoter of cell proliferation, whereas few studies have explored its role in migration. To investigate the direct and immediate effects of Ras activity on cell motility or polarity, we focused on RasGAPs, C2GAPB in Dictyostelium amoebae and RASAL3 in HL-60 neutrophils and macrophages. In both cellular systems, optically recruiting the respective RasGAP to the cell front extinguished pre-existing protrusions and changed migration direction. However, when these respective RasGAPs were recruited uniformly to the membrane, cells polarized and moved more rapidly, whereas targeting to the back exaggerated these effects. These unexpected outcomes of attenuating Ras activity naturally had strong, context-dependent consequences for chemotaxis. The RasGAP-mediated polarization depended critically on myosin II activity and commenced with contraction at the cell rear, followed by sustained mTORC2-dependent actin polymerization at the front. These experimental results were captured by computational simulations in which Ras levels control front- and back-promoting feedback loops. The discovery that inhibiting Ras activity can produce counterintuitive effects on cell migration has important implications for future drug-design strategies targeting oncogenic Ras. Lin, Pal, et al. report a role for localized activation of Ras activity in promoting cell polarity and motility.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 7","pages":"1062-1076"},"PeriodicalIF":17.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475331","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

Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3 Kmt2c 或 Kmt2d 的缺失通过 KDM6A 依赖性上调 MMP3 推动脑转移

IF 17.3 1区生物学

Nature Cell Biology Pub Date : 2024-06-26 DOI: 10.1038/s41556-024-01446-3

Marco Seehawer, Zheqi Li, Jun Nishida, Pierre Foidart, Andrew H. Reiter, Ernesto Rojas-Jimenez, Marie-Anne Goyette, Pengze Yan, Shaunak Raval, Miguel Munoz Gomez, Paloma Cejas, Henry W. Long, Malvina Papanastasiou, Kornelia Polyak

{"title":"Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3","authors":"Marco Seehawer, Zheqi Li, Jun Nishida, Pierre Foidart, Andrew H. Reiter, Ernesto Rojas-Jimenez, Marie-Anne Goyette, Pengze Yan, Shaunak Raval, Miguel Munoz Gomez, Paloma Cejas, Henry W. Long, Malvina Papanastasiou, Kornelia Polyak","doi":"10.1038/s41556-024-01446-3","DOIUrl":"10.1038/s41556-024-01446-3","url":null,"abstract":"KMT2C and KMT2D, encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C-mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone–lysine N-methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3. Taken together, we identified the KDM6A–matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC. Seehawer et al. show that deletion of Kmt2c or Kmt2d promotes brain metastasis in mouse models of triple-negative breast cancer due to altered KDM6A activity and upregulated MMP3 expression, which may constitute a potential therapeutic target.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 7","pages":"1165-1175"},"PeriodicalIF":17.3,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01446-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453096","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}

引用次数: 0

Publisher Correction: Cell-intrinsic and microenvironmental determinants of metastatic colonization 出版商更正：转移性定植的细胞内在因素和微环境决定因素。

IF 17.3 1区生物学

Nature Cell Biology Pub Date : 2024-06-26 DOI: 10.1038/s41556-024-01458-z

Arthur W. Lambert, Yun Zhang, Robert A. Weinberg

引用次数: 0

A dual role of ERGIC-localized Rabs in TMED10-mediated unconventional protein secretion ERGIC定位的Rabs在TMED10介导的非常规蛋白质分泌中发挥双重作用

IF 17.3 1区生物学

Nature Cell Biology Pub Date : 2024-06-26 DOI: 10.1038/s41556-024-01445-4

Yuxin Sun, Xuan Tao, Yaping Han, Xubo Lin, Rui Tian, Haodong Wang, Pei Chang, Qiming Sun, Liang Ge, Min Zhang

{"title":"A dual role of ERGIC-localized Rabs in TMED10-mediated unconventional protein secretion","authors":"Yuxin Sun, Xuan Tao, Yaping Han, Xubo Lin, Rui Tian, Haodong Wang, Pei Chang, Qiming Sun, Liang Ge, Min Zhang","doi":"10.1038/s41556-024-01445-4","DOIUrl":"10.1038/s41556-024-01445-4","url":null,"abstract":"Cargo translocation across membranes is a crucial aspect of secretion. In conventional secretion signal peptide-equipped proteins enter the endoplasmic reticulum (ER), whereas a subset of cargo lacking signal peptides translocate into the ER–Golgi intermediate compartment (ERGIC) in a process called unconventional protein secretion (UcPS). The regulatory events at the ERGIC in UcPS are unclear. Here we reveal the involvement of ERGIC-localized small GTPases, Rab1 (Rab1A and Rab1B) and Rab2A, in regulating UcPS cargo transport via TMED10 on the ERGIC. Rab1 enhances TMED10 translocator activity, promoting cargo translocation into the ERGIC, whereas Rab2A, in collaboration with KIF5B, regulates ERGIC compartmentalization, establishing a UcPS-specific compartment. This study highlights the pivotal role of ERGIC-localized Rabs in governing cargo translocation and specifying the ERGIC’s function in UcPS. Sun, Tao, Han et al. identify the Rabs involved in unconventional protein secretion mediated by TMED10 and in ER–Golgi intermediate compartment organization.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 7","pages":"1077-1092"},"PeriodicalIF":17.3,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141452949","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

Ferroptosis-like cell death promotes and prolongs inflammation in Drosophila 类铁蛋白酶细胞死亡促进并延长果蝇的炎症反应

IF 17.3 1区生物学

Nature Cell Biology Pub Date : 2024-06-25 DOI: 10.1038/s41556-024-01450-7

Andrew J. Davidson, Rosalind Heron, Jyotirekha Das, Michael Overholtzer, Will Wood

{"title":"Ferroptosis-like cell death promotes and prolongs inflammation in Drosophila","authors":"Andrew J. Davidson, Rosalind Heron, Jyotirekha Das, Michael Overholtzer, Will Wood","doi":"10.1038/s41556-024-01450-7","DOIUrl":"10.1038/s41556-024-01450-7","url":null,"abstract":"Ferroptosis is a distinct form of necrotic cell death caused by overwhelming lipid peroxidation, and emerging evidence indicates a major contribution to organ damage in multiple pathologies. However, ferroptosis has not yet been visualized in vivo due to a lack of specific probes, which has severely limited the study of how the immune system interacts with ferroptotic cells and how this process contributes to inflammation. Consequently, whether ferroptosis has a physiological role has remained a key outstanding question. Here we identify a distinct, ferroptotic-like, necrotic cell death occurring in vivo during wounding of the Drosophila embryo using live imaging. We further demonstrate that macrophages rapidly engage these necrotic cells within the embryo but struggle to engulf them, leading to prolonged, frustrated phagocytosis and frequent corpse disintegration. Conversely, suppression of the ferroptotic programme during wounding delays macrophage recruitment to the injury site, pointing to conflicting roles for ferroptosis during inflammation in vivo. Davidson et al. visualize ferroptosis-like cell death using three-colour live imaging in vivo and demonstrate its role in triggering macrophage recruitment but delaying resolution of inflammation during wounding in the Drosophila embryo.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"26 9","pages":"1535-1544"},"PeriodicalIF":17.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-024-01450-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141448384","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}

引用次数: 0