EMBO Journal最新文献_第8页

Elongator is a microtubule polymerase selective for polyglutamylated tubulin. 伸长酶是一种选择性聚谷氨酰化微管的微管聚合酶。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-01-15 DOI: 10.1038/s44318-024-00358-0

Vicente J Planelles-Herrero, Mariya Genova, Lara K Krüger, Alice Bittleston, Kerrie E McNally, Tomos E Morgan, Gianluca Degliesposti, Maria M Magiera, Carsten Janke, Emmanuel Derivery

{"title":"Elongator is a microtubule polymerase selective for polyglutamylated tubulin.","authors":"Vicente J Planelles-Herrero, Mariya Genova, Lara K Krüger, Alice Bittleston, Kerrie E McNally, Tomos E Morgan, Gianluca Degliesposti, Maria M Magiera, Carsten Janke, Emmanuel Derivery","doi":"10.1038/s44318-024-00358-0","DOIUrl":"10.1038/s44318-024-00358-0","url":null,"abstract":"Elongator is a tRNA-modifying complex that regulates protein translation. Recently, a moonlighting function of Elongator has been identified in regulating the polarization of the microtubule cytoskeleton during asymmetric cell division. Elongator induces symmetry breaking of the anaphase midzone by selectively stabilizing microtubules on one side of the spindle, contributing to the downstream polarized segregation of cell-fate determinants, and therefore to cell fate determination. Here, we investigate how Elongator controls microtubule dynamics. Elongator binds both to the tip of microtubules and to free GTP-tubulin heterodimers using two different subcomplexes, Elp123 and Elp456, respectively. We show that these activities must be coupled for Elongator to decrease the tubulin critical concentration for microtubule elongation. As a consequence, Elongator increases the growth speed and decreases the catastrophe rate of microtubules. Surprisingly, the Elp456 subcomplex binds to tubulin tails and has strong selectivity towards polyglutamylated tubulin. Hence, microtubules assembled by Elongator become selectively enriched with polyglutamylated tubulin, as observed in vitro, in mouse and Drosophila cell lines, as well as in vivo in Drosophila Sensory Organ Precursor cells. Therefore, Elongator rewrites the tubulin code of growing microtubules, placing it at the core of cytoskeletal dynamics and polarization during asymmetric cell division.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1322-1353"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015691","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

Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state. 类器官模型揭示了肺泡祖细胞状态的致瘤潜能。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-02-10 DOI: 10.1038/s44318-025-00376-6

Jingyun Li, Susanna M Dang, Shreoshi Sengupta, Paul Schurmann, Antonella F M Dost, Aaron L Moye, Maria F Trovero, Sidrah Ahmed, Margherita Paschini, Preetida J Bhetariya, Roderick Bronson, Shannan J Ho Sui, Carla F Kim

{"title":"Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state.","authors":"Jingyun Li, Susanna M Dang, Shreoshi Sengupta, Paul Schurmann, Antonella F M Dost, Aaron L Moye, Maria F Trovero, Sidrah Ahmed, Margherita Paschini, Preetida J Bhetariya, Roderick Bronson, Shannan J Ho Sui, Carla F Kim","doi":"10.1038/s44318-025-00376-6","DOIUrl":"10.1038/s44318-025-00376-6","url":null,"abstract":"Cancers display cellular, genetic and epigenetic heterogeneity, complicating disease modeling. Multiple cell states defined by gene expression have been described in lung adenocarcinoma (LUAD). However, the functional contributions of cell state and the regulatory programs that control chromatin and gene expression in the early stages of tumor initiation are not well understood. Using single-cell RNA and ATAC sequencing in Kras/p53-driven tumor organoids, we identified two major cellular states: one more closely resembling alveolar type 2 (AT2) cells (SPC-high), and the other with epithelial-mesenchymal-transition (EMT)-associated gene expression (Hmga2-high). Each state exhibited distinct transcription factor networks, with SPC-high cells associated with TFs regulating AT2 fate and Hmga2-high cells enriched in Wnt- and NFκB-related TFs. CD44 was identified as a marker for the Hmga2-high state, enabling functional comparison of the two populations. Organoid assays and orthotopic transplantation revealed that SPC-high, CD44-negative cells exhibited higher tumorigenic potential within the lung microenvironment. These findings highlight the utility of organoids in understanding chromatin regulation in early tumorigenesis and identifying novel early-stage therapeutic targets in Kras-driven LUAD.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1804-1828"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392425","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

Modulation of tumor inflammatory signaling and drug sensitivity by CMTM4. CMTM4对肿瘤炎症信号和药物敏感性的调节。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-02-13 DOI: 10.1038/s44318-024-00330-y

Yitian Xu, Kyeongah Kang, Brian A Coakley, Samuel Eisenstein, Arshiya Parveen, Sunny Mai, Yuan Shuo Wang, Junjun Zheng, Debasish Boral, Junhua Mai, William Pan, Licheng Zhang, Stuart A Aaronson, Bingliang Fang, Celia Divino, Bin Zhang, Won-Min Song, Mien-Chie Hung, Ping-Ying Pan, Shu-Hsia Chen

{"title":"Modulation of tumor inflammatory signaling and drug sensitivity by CMTM4.","authors":"Yitian Xu, Kyeongah Kang, Brian A Coakley, Samuel Eisenstein, Arshiya Parveen, Sunny Mai, Yuan Shuo Wang, Junjun Zheng, Debasish Boral, Junhua Mai, William Pan, Licheng Zhang, Stuart A Aaronson, Bingliang Fang, Celia Divino, Bin Zhang, Won-Min Song, Mien-Chie Hung, Ping-Ying Pan, Shu-Hsia Chen","doi":"10.1038/s44318-024-00330-y","DOIUrl":"10.1038/s44318-024-00330-y","url":null,"abstract":"Although inflammation has been widely associated with cancer development, how it affects the outcomes of immunotherapy and chemotherapy remains incompletely understood. Here, we show that CKLF-like MARVEL transmembrane domain-containing member 4 (CMTM4) is highly expressed in multiple human and murine cancer types including Lewis lung carcinoma, triple-negative mammary cancer and melanoma. In lung carcinoma, loss of CMTM4 significantly reduces tumor growth and impairs NF-κB, mTOR, and PI3K/Akt pathway activation. Furthermore, we demonstrate that CMTM4 can regulate epidermal growth factor (EGF) signaling post-translationally by promoting EGFR recycling and preventing its Rab-dependent degradation. Consequently, CMTM4 knockout sensitizes human lung tumor cells to EGFR inhibitors. In addition, CMTM4 knockout tumors stimulated with EGF show a decreased ability to produce inflammatory cytokines including granulocyte colony-stimulating factor (G-CSF), leading to decreased recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and therefore establishing a less suppressive tumor immune environment in both lung and mammary cancers. We also present evidence indicating that CMTM4-targeting siRNA-loaded liposomes reduce lung tumor growth in vivo and prolong animal survival. Knockout of CMTM4 enhances immune checkpoint blockade or chemotherapy to further reduce lung tumor growth. These data suggest that CMTM4 represents a novel target for the inhibition of tumor inflammation, and improvement of the immune response and tumor drug sensitivity.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1866-1883"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416153","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

Proteogenomic analysis reveals adaptive strategies for alleviating the consequences of aneuploidy in cancer. 蛋白质基因组学分析揭示了减轻癌症非整倍体后果的适应性策略。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-02-10 DOI: 10.1038/s44318-025-00372-w

Jan-Eric Bökenkamp, Kristina Keuper, Stefan Redel, Karen Barthel, Leah Johnson, Amelie Becker, Angela Wieland, Markus Räschle, Zuzana Storchová

{"title":"Proteogenomic analysis reveals adaptive strategies for alleviating the consequences of aneuploidy in cancer.","authors":"Jan-Eric Bökenkamp, Kristina Keuper, Stefan Redel, Karen Barthel, Leah Johnson, Amelie Becker, Angela Wieland, Markus Räschle, Zuzana Storchová","doi":"10.1038/s44318-025-00372-w","DOIUrl":"10.1038/s44318-025-00372-w","url":null,"abstract":"Aneuploidy is prevalent in cancer and associates with fitness advantage and poor patient prognosis. Yet, experimentally induced aneuploidy initially leads to adverse effects and impaired proliferation, suggesting that cancer cells must adapt to aneuploidy. We performed in vitro evolution of cells with extra chromosomes and obtained cell lines with improved proliferation and gene expression changes congruent with changes in aneuploid cancers. Integrated analysis of cancer multi-omics data and model cells revealed increased expression of DNA replicative and repair factors, reduced genomic instability, and reduced lysosomal degradation. We identified E2F4 and FOXM1 as transcription factors strongly associated with adaptation to aneuploidy in vitro and in cancers and validated this finding. The adaptation to aneuploidy also coincided with specific copy number aberrations that correlate with poor patient prognosis. Chromosomal engineering mimicking these aberrations improved aneuploid cell proliferation, while loss of previously present extra chromosomes impaired it. The identified common adaptation strategies suggest replication stress, genomic instability, and lysosomal stress as common liabilities of aneuploid cancers.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1829-1865"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392433","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

Arginine: at the crossroads of nitrogen metabolism. 精氨酸：处于氮代谢的十字路口。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-02-07 DOI: 10.1038/s44318-025-00379-3

Tak Shun Fung, Keun Woo Ryu, Craig B Thompson

{"title":"Arginine: at the crossroads of nitrogen metabolism.","authors":"Tak Shun Fung, Keun Woo Ryu, Craig B Thompson","doi":"10.1038/s44318-025-00379-3","DOIUrl":"10.1038/s44318-025-00379-3","url":null,"abstract":"L-arginine is the most nitrogen-rich amino acid, acting as a key precursor for the synthesis of nitrogen-containing metabolites and an essential intermediate in the clearance of excess nitrogen. Arginine's side chain possesses a guanidino group which has unique biochemical properties, and plays a primary role in nitrogen excretion (urea), cellular signaling (nitric oxide) and energy buffering (phosphocreatine). The post-translational modification of protein-incorporated arginine by guanidino-group methylation also contributes to epigenetic gene control. Most human cells do not synthesize sufficient arginine to meet demand and are dependent on exogenous arginine. Thus, dietary arginine plays an important role in maintaining health, particularly upon physiologic stress. How cells adapt to changes in extracellular arginine availability is unclear, mostly because nearly all tissue culture media are supplemented with supraphysiologic levels of arginine. Evidence is emerging that arginine-deficiency can influence disease progression. Here, we review new insights into the importance of arginine as a metabolite, emphasizing the central role of mitochondria in arginine synthesis/catabolism and the recent discovery that arginine can act as a signaling molecule regulating gene expression and organelle dynamics.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1275-1293"},"PeriodicalIF":9.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371138","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

Decoding host-microbe interactions with engineered human organoids. 解码宿主-微生物与人类类器官的相互作用。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 Epub Date: 2025-02-21 DOI: 10.1038/s44318-025-00387-3

Lucas A Meirelles, Alexandre Persat

引用次数: 0

Author Correction: An extrinsic motor directs chromatin loop formation by cohesin. 作者更正：外部马达通过内聚蛋白指导染色质环的形成。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-03-01 DOI: 10.1038/s44318-024-00341-9

Thomas M Guérin, Christopher Barrington, Georgii Pobegalov, Maxim I Molodtsov, Frank Uhlmann

引用次数: 0

Francesco Amaldi (1939-2024) - a pioneer in RNA research. 弗朗西斯科·阿马尔迪（1939-2024）——RNA研究的先驱。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-27 DOI: 10.1038/s44318-025-00388-2

Irene Bozzoni

引用次数: 0

The barley MLA13-AVR_A13 heterodimer reveals principles for immunoreceptor recognition of RNase-like powdery mildew effectors. 大麦MLA13-AVRA13异源二聚体揭示了rase样白粉病效应物的免疫受体识别原理。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-13 DOI: 10.1038/s44318-025-00373-9

Aaron W Lawson, Andrea Flores-Ibarra, Yu Cao, Chunpeng An, Ulla Neumann, Monika Gunkel, Isabel M L Saur, Jijie Chai, Elmar Behrmann, Paul Schulze-Lefert

{"title":"The barley MLA13-AVRA13 heterodimer reveals principles for immunoreceptor recognition of RNase-like powdery mildew effectors.","authors":"Aaron W Lawson, Andrea Flores-Ibarra, Yu Cao, Chunpeng An, Ulla Neumann, Monika Gunkel, Isabel M L Saur, Jijie Chai, Elmar Behrmann, Paul Schulze-Lefert","doi":"10.1038/s44318-025-00373-9","DOIUrl":"10.1038/s44318-025-00373-9","url":null,"abstract":"Co-evolution between cereals and pathogenic grass powdery mildew fungi is exemplified by sequence diversification of an allelic series of barley resistance genes encoding Mildew Locus A (MLA) nucleotide-binding leucine-rich repeat (NLR) immunoreceptors with an N-terminal coiled-coil domain (CNLs). Each immunoreceptor recognises a matching, strain-specific powdery mildew effector encoded by an avirulence gene (AVRa). We present here the cryo-EM structure of barley MLA13 in complex with its cognate effector AVRA13-1. The effector adopts an RNase-like fold when bound to MLA13 in planta, similar to crystal structures of other RNase-like AVRA effectors unbound to receptors. AVRA13-1 interacts via its basal loops with MLA13 C-terminal leucine-rich repeats (LRRs) and the central winged helix domain (WHD). Co-expression of structure-guided MLA13 and AVRA13-1 substitution variants show that the receptor-effector interface plays an essential role in mediating immunity-associated plant cell death. Furthermore, by combining structural information from the MLA13-AVRA13-1 heterocomplex with sequence alignments of other MLA receptors, we engineered a single amino acid substitution in MLA7 that enables expanded effector detection of AVRA13-1 and the virulent variant AVRA13-V2. In contrast to the pentameric conformation of previously reported effector-activated CNL resistosomes, MLA13 was purified and resolved as a stable heterodimer from an in planta expression system. Our study suggests a common structural principle for RNase-like effector binding to MLAs and highlights the utility of structure-guided engineering of plant immune receptors for broadening their pathogen effector recognition capabilities.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416158","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

Specialized pericyte subtypes in the pulmonary capillaries. 肺毛细血管中特化的周细胞亚型。

IF 9.4 1区生物学

EMBO Journal Pub Date : 2025-02-01 Epub Date: 2025-01-13 DOI: 10.1038/s44318-024-00349-1

Timothy Klouda, Yunhye Kim, Seung-Han Baek, Mantu Bhaumik, Yan Li, Yu Liu, Joseph C Wu, Benjamin A Raby, Vinicio de Jesus Perez, Ke Yuan

{"title":"Specialized pericyte subtypes in the pulmonary capillaries.","authors":"Timothy Klouda, Yunhye Kim, Seung-Han Baek, Mantu Bhaumik, Yan Li, Yu Liu, Joseph C Wu, Benjamin A Raby, Vinicio de Jesus Perez, Ke Yuan","doi":"10.1038/s44318-024-00349-1","DOIUrl":"10.1038/s44318-024-00349-1","url":null,"abstract":"Pericytes are essential for capillary stability and homeostasis, with impaired pericyte function linked to diseases like pulmonary arterial hypertension. Investigating pericyte biology has been challenging due to the lack of specific markers, making it difficult to distinguish pericytes from other stromal cells. Using bioinformatic analysis and RNAscope, we identified Higd1b as a unique gene marker for pericytes and subsequently generated a knock-in mouse line, Higd1b-CreERT2, that accurately labels pericytes in the lung and heart. Single-cell RNA sequencing revealed two distinct Higd1b+ pericyte subtypes: while Type 1 pericytes support capillary homeostasis, Type 2 pericytes accumulate in arterioles, and co-express smooth muscle markers and higher levels of vimentin under hypoxic conditions. Lastly, healthy human lung pericytes with upregulation of vimentin exhibited increased adhesion, migration, and higher expression levels of the smooth muscle marker SM22 in vitro. These findings highlight the specialization of pulmonary pericytes and their contribution to vascular remodeling during hypoxia-induced pulmonary hypertension.","PeriodicalId":50533,"journal":{"name":"EMBO Journal","volume":" ","pages":"1074-1106"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980590","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