Cell reports最新文献_第10页

Olfactory projection neuron rewiring in the brain of an ecological specialist. 一位生态专家大脑中的嗅觉投射神经元重新布线。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-04-25 DOI: 10.1016/j.celrep.2025.115615

Benedikt R Dürr, Enrico Bertolini, Suguru Takagi, Justine Pascual, Liliane Abuin, Giovanna Lucarelli, Richard Benton, Thomas O Auer

{"title":"Olfactory projection neuron rewiring in the brain of an ecological specialist.","authors":"Benedikt R Dürr, Enrico Bertolini, Suguru Takagi, Justine Pascual, Liliane Abuin, Giovanna Lucarelli, Richard Benton, Thomas O Auer","doi":"10.1016/j.celrep.2025.115615","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115615","url":null,"abstract":"Animal behaviors can differ greatly between closely related species. These behavioral changes are frequently linked to sensory system modifications, but central brain cell-type alterations might also be involved. Here, we develop advanced genetic tools to compare homologous central neurons in Drosophila sechellia, an ecological specialist, with the generalist Drosophila melanogaster. Through systematic morphological analysis of olfactory projection neurons (PNs), we reveal that the global anatomy of these second-order neurons is conserved. However, high-resolution, quantitative comparisons identify a striking case of convergent rewiring of PNs in two olfactory pathways critical for D. sechellia's host location. Calcium imaging and labeling of pre-synaptic sites in these evolved D. sechellia PNs indicate that species-specific connections with third-order partners are formed. This work demonstrates that peripheral sensory evolution is accompanied by selective wiring changes in the central brain to facilitate ecological specialization and paves the way to compare other cell types throughout the nervous system.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115615"},"PeriodicalIF":7.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968474","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

Mitochondrial Ca²⁺ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity. 线粒体Ca2+通过调节上皮细胞的可塑性控制胰腺癌的生长和转移。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-04-24 DOI: 10.1016/j.celrep.2025.115627

Jillian S Weissenrieder, Jessica Peura, Usha Paudel, Nikita Bhalerao, Natalie Weinmann, Calvin Johnson, Maximilian Wengyn, Rebecca Drager, Emma Elizabeth Furth, Karl Simin, Marcus Ruscetti, Ben Z Stanger, Anil K Rustgi, Jason R Pitarresi, J Kevin Foskett

{"title":"Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.","authors":"Jillian S Weissenrieder, Jessica Peura, Usha Paudel, Nikita Bhalerao, Natalie Weinmann, Calvin Johnson, Maximilian Wengyn, Rebecca Drager, Emma Elizabeth Furth, Karl Simin, Marcus Ruscetti, Ben Z Stanger, Anil K Rustgi, Jason R Pitarresi, J Kevin Foskett","doi":"10.1016/j.celrep.2025.115627","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115627","url":null,"abstract":"Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in patients with PDAC. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced the expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF-β. Snail re-expression and TGF-β treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115627"},"PeriodicalIF":7.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978199","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

Transcriptional landscape and chromatin accessibility reveal key regulators for liver regenerative initiation and organoid formation. 转录景观和染色质可及性揭示了肝脏再生起始和类器官形成的关键调节因子。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-04-24 DOI: 10.1016/j.celrep.2025.115633

Jiabei Lian, Yachun An, Wenjing Wei, Yao Lu, Xiyu Zhang, Gongping Sun, Haiyang Guo, Longjin Xu, Xuena Chen, Huili Hu

{"title":"Transcriptional landscape and chromatin accessibility reveal key regulators for liver regenerative initiation and organoid formation.","authors":"Jiabei Lian, Yachun An, Wenjing Wei, Yao Lu, Xiyu Zhang, Gongping Sun, Haiyang Guo, Longjin Xu, Xuena Chen, Huili Hu","doi":"10.1016/j.celrep.2025.115633","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115633","url":null,"abstract":"Liver regeneration is a well-organized and phase-restricted process that involves chromatin remodeling and transcriptional alterations. However, the specific transcription factors (TFs) that act as key \"switches\" to initiate hepatocyte regeneration and organoid formation remain unclear. Comprehensive integration of RNA sequencing and ATAC sequencing reveals that ATF3 representing \"Initiation_on\" TF and ONECUT2 representing \"Initiation_off\" TF transiently modulate the occupancy of target promoters to license liver cells for regeneration. Knockdown of Atf3 or overexpression of Onecut2 not only reduces organoid formation but also delays tissue-damage repair after PHx or CCl4 treatment. Mechanistically, we demonstrate that ATF3 binds to the promoter of Slc7a5 to activate mTOR signals while the Hmgcs1 promoter loses ONECUT2 binding to facilitate regenerative initiation. The results identify the mechanism for initiating regeneration and reveal the remodeling of transcriptional landscapes and chromatin accessibility, thereby providing potential therapeutic targets for liver diseases with regenerative defects.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115633"},"PeriodicalIF":7.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967271","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

Piezo1 balances the osteogenic-tenogenic plasticity of periosteal progenitor cells through the YAP pathway. Piezo1通过YAP通路平衡骨膜祖细胞的成骨-肌腱可塑性。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-04-24 DOI: 10.1016/j.celrep.2025.115630

Lijun Wang, Qian Ren, Shuqin Chen, Lixiang Lou, Xuye Hu, Wenhui Xing, Jinlong Suo, Jun Sun, Matthew B Greenblatt, Heng Feng, Weiguo Zou

{"title":"Piezo1 balances the osteogenic-tenogenic plasticity of periosteal progenitor cells through the YAP pathway.","authors":"Lijun Wang, Qian Ren, Shuqin Chen, Lixiang Lou, Xuye Hu, Wenhui Xing, Jinlong Suo, Jun Sun, Matthew B Greenblatt, Heng Feng, Weiguo Zou","doi":"10.1016/j.celrep.2025.115630","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115630","url":null,"abstract":"The extremity tendons and bones are derived from limb bud mesenchyme, which eventually becomes cells of different tissues. Despite their common origin, it was widely believed that tenocytes and skeletal cells are distinct lineages without interconversion. However, we found that periosteal skeletal progenitor cells could transform between osteogenic and tenogenic commitment. SCX can label the periosteal progenitor cell population. Loss of Piezo1 arrests the periosteal progenitor cells in a progenitor state. Piezo1 deficiency leads to upregulation of Scx expression due to the inhibited YAP nuclear localization. Loss of Piezo1 showed increased tenogenic marker genes and decreased osteogenic marker genes. The periosteal progenitor cells can regenerate the injured tendon more robustly when Piezo1 is absent. Taken together, our data reveal that periosteal SCX+ progenitor cells compromise the osteogenic ability and acquire the tenocyte-biased lineage commitment after loss of Piezo1, providing a strategy to modulate the periosteal progenitor cells for tissue regeneration.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115630"},"PeriodicalIF":7.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969936","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

Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice. 衰老小鼠单核细胞源性小胶质细胞积累引起的克隆造血相关运动障碍。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-04-24 DOI: 10.1016/j.celrep.2025.115609

Jung-Seok Kim, Sébastien Trzebanski, Sun-Hye Shin, Lior Schori, Gal Ronit Frumer Friedman, Noa Chapal Ilani, Aditee Kadam, Rocio Vicario, Oliver Aust, Polina Bugaeva, Sylwia Piatek, Laura Kate Ismajli, Christian Johannes Hoffmann, Marina Scheller, Sigalit Boura-Halfon, Nathali Kaushansky, Ofra Golani, Aryeh Solomon, Zhaoyuan Liu, Lukas Amann, Philipp Böhm-Sturm, Stefan Paul Koch, Nikolaus Wenger, Florent Ginhoux, Marco Prinz, Roi Avraham, Christoph Harms, Frederic Geissmann, Carsten Müller-Tidow, Stefan Uderhardt, Ivan Milenkovic, Liran Shlush, Steffen Jung

{"title":"Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.","authors":"Jung-Seok Kim, Sébastien Trzebanski, Sun-Hye Shin, Lior Schori, Gal Ronit Frumer Friedman, Noa Chapal Ilani, Aditee Kadam, Rocio Vicario, Oliver Aust, Polina Bugaeva, Sylwia Piatek, Laura Kate Ismajli, Christian Johannes Hoffmann, Marina Scheller, Sigalit Boura-Halfon, Nathali Kaushansky, Ofra Golani, Aryeh Solomon, Zhaoyuan Liu, Lukas Amann, Philipp Böhm-Sturm, Stefan Paul Koch, Nikolaus Wenger, Florent Ginhoux, Marco Prinz, Roi Avraham, Christoph Harms, Frederic Geissmann, Carsten Müller-Tidow, Stefan Uderhardt, Ivan Milenkovic, Liran Shlush, Steffen Jung","doi":"10.1016/j.celrep.2025.115609","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115609","url":null,"abstract":"Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their hematopoietic stem cell (HSC) derivation, monocyte-derived microglia (MoMg) are unlike yolk-sac-derived cells, targets of clonal hematopoiesis (CH). Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human CH variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can cause brain pathology.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115609"},"PeriodicalIF":7.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969809","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

Myeloid-lineage-specific membrane protein LRRC25 suppresses immunity in solid tumor and is a potential cancer immunotherapy checkpoint target. 髓系特异性膜蛋白LRRC25在实体瘤中抑制免疫，是一个潜在的癌症免疫治疗检查点靶点。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-04-24 DOI: 10.1016/j.celrep.2025.115631

Guorong Zhang, Hanzhi Yu, Jingjing Liu, Ge Dong, Zhigang Cai

{"title":"Myeloid-lineage-specific membrane protein LRRC25 suppresses immunity in solid tumor and is a potential cancer immunotherapy checkpoint target.","authors":"Guorong Zhang, Hanzhi Yu, Jingjing Liu, Ge Dong, Zhigang Cai","doi":"10.1016/j.celrep.2025.115631","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115631","url":null,"abstract":"Leucine-rich repeat containing 25 (LRRC25), a type I membrane protein, is specifically expressed in myeloid cells including neutrophils and macrophages. The anti-inflammatory role of LRRC25 was suggested in a few pathogenic models. However, its role in cancer immunity has not been interrogated. Here, we demonstrate that LRRC25 is robustly expressed in tumor-associated macrophages (TAMs). Lrrc25 deficiency in the tumor microenvironment (TME) suppresses growth of multiple murine tumor models by reprogramming TAMs toward an anti-tumor phenotype and thereby enhancing infiltration and activation of CD8+ T cells. The Nox2-ROS-Nlrp3-Il1β pathway is elevated in Lrrc25-deficient TAMs. Furthermore, a human myeloid cell line or mice with loss of Lrrc25 appear normal, indicating that LRRC25 is a safe immune target. Our results suggest that as an unappreciated immune checkpoint for tumor immunotherapy, the myeloid-specific membrane protein LRRC25 orchestrates the activity of TAMs via the canonical Nlrp3-IL1β inflammatory pathway and influences CD8+ T cell chemotaxis to the TME.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115631"},"PeriodicalIF":7.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962847","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

Regulation of translation elongation and integrated stress response in heat-shocked neurons. 热休克神经元翻译延伸和综合应激反应的调控。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-04-24 DOI: 10.1016/j.celrep.2025.115639

Caitlin M Seluzicki, Milad Razavi-Mohseni, Fulya Türker, Priyal Patel, Boyang Hua, Michael A Beer, Loyal Goff, Seth S Margolis

{"title":"Regulation of translation elongation and integrated stress response in heat-shocked neurons.","authors":"Caitlin M Seluzicki, Milad Razavi-Mohseni, Fulya Türker, Priyal Patel, Boyang Hua, Michael A Beer, Loyal Goff, Seth S Margolis","doi":"10.1016/j.celrep.2025.115639","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115639","url":null,"abstract":"Neurons deviate from a canonical heat shock response (HSR). Here, we revealed that neuronal adaptation to heat shock accompanies a brake on mRNA translation, slowed elongating ribosomes, phosphorylation of eukaryotic elongation factor-2 (p-eEF2), and suppressed the integrated stress response (ISR). Returning neurons to control temperature within 1 h of starting heat shock was necessary for survival and allowed for restored translation following dephosphorylation of eEF2. Subsequent to recovery, neurons briefly activated the ISR and were sensitive to the ISR inhibitor ISRIB, which enhanced protein synthesis and survival. Ribosome profiling and RNA sequencing (RNA-seq) identified newly synthesized and existing transcripts associated with ribosomes during heat shock. Preservation of these transcripts for translation during recovery was in part mediated by p-eEF2 and slowed ribosomes. Our work supports a neuronal heat shock model of a partially suspended state of translation poised for rapid reversal if recovery becomes an option and provides insight into regulation between the HSR and the ISR.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115639"},"PeriodicalIF":7.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974613","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 neurofibromin induces inflammatory macrophage phenotypic switch and retinal neovascularization via GLUT1 activation. 神经纤维蛋白缺失通过GLUT1激活诱导炎性巨噬细胞表型转换和视网膜新生血管形成。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-04-24 DOI: 10.1016/j.celrep.2025.115625

Yusra Zaidi, Rebekah Tritz, Nida Zaidi, Faisal Nabi, Syed Adeel H Zaidi, Abdelhakim Morsy, Valerie Harris, Rilee Racine, Farlyn Z Hudson, Zsuzsanna Bordan, Simone Kennard, Robert Batori, Yuqing Huo, Gabor Csanyi, Eric J Belin de Chantemèle, Kecheng Lei, Nicholas M Boulis, David J Fulton, Rizwan Hasan Khan, Ruth B Caldwell, Brian K Stansfield

{"title":"Loss of neurofibromin induces inflammatory macrophage phenotypic switch and retinal neovascularization via GLUT1 activation.","authors":"Yusra Zaidi, Rebekah Tritz, Nida Zaidi, Faisal Nabi, Syed Adeel H Zaidi, Abdelhakim Morsy, Valerie Harris, Rilee Racine, Farlyn Z Hudson, Zsuzsanna Bordan, Simone Kennard, Robert Batori, Yuqing Huo, Gabor Csanyi, Eric J Belin de Chantemèle, Kecheng Lei, Nicholas M Boulis, David J Fulton, Rizwan Hasan Khan, Ruth B Caldwell, Brian K Stansfield","doi":"10.1016/j.celrep.2025.115625","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115625","url":null,"abstract":"Persons with neurofibromatosis type 1 (NF1) exhibit enhanced glucose metabolism, which is replicated in Nf1-mutant mice. Inflammatory macrophages invest NF1-associated tumors, and targeting macrophages appears efficacious in NF1 models. Inflammatory macrophages rely on glycolysis to generate ATP; thus, identifying whether neurofibromin, the protein encoded by NF1, controls glucose metabolism in macrophages is therapeutically compelling. Using neurofibromin-deficient macrophages and macrophage-specific Nf1-knockout mice, we demonstrate that neurofibromin complexes with glucose transporter-1 (GLUT1) to restrain its activity and that loss of neurofibromin permits Akt2 to facilitate GLUT1 translocation to the membrane. In turn, glucose internalization and glycolysis are upregulated and provoke reparative (MIL4) macrophages to undergo an inflammatory phenotypic switch. Inflammatory MLPSIFNγ macrophages and inflammatory-like MIL4 macrophages invest the perivascular stroma of tumors and induce pathologic angiogenesis in macrophage-specific Nf1-knockout mice. These studies identify a mechanism for the enhanced glycolysis associated with NF1 and provide a novel therapeutic target for NF1.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115625"},"PeriodicalIF":7.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955037","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

Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of LSD1 and OXPHOS. 杂合子Kmt2d缺失减少增强子，使髓母细胞瘤细胞容易受到LSD1和OXPHOS的联合抑制。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-04-24 DOI: 10.1016/j.celrep.2025.115619

Shilpa S Dhar, Calena Brown, Ali Rizvi, Lauren Reed, Sivareddy Kotla, Constantin Zod, Janak Abraham, Jun-Ichi Abe, Veena Rajaram, Kaifu Chen, Min Gyu Lee

{"title":"Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of LSD1 and OXPHOS.","authors":"Shilpa S Dhar, Calena Brown, Ali Rizvi, Lauren Reed, Sivareddy Kotla, Constantin Zod, Janak Abraham, Jun-Ichi Abe, Veena Rajaram, Kaifu Chen, Min Gyu Lee","doi":"10.1016/j.celrep.2025.115619","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115619","url":null,"abstract":"The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in many cancers, including medulloblastoma (MB). Notably, heterozygous KMT2D loss frequently occurs in MB and other cancers. However, its oncogenic role remains largely uncharacterized. Here, we show that heterozygous Kmt2d loss in murine cerebellar regions promotes MB genesis driven by heterozygous loss of the MB-suppressor gene Ptch via the upregulation of tumor-promoting programs (e.g., oxidative phosphorylation [OXPHOS]). Downregulation of the transcription-repressive tumor suppressor NCOR2 by heterozygous Kmt2d loss, along with Ptch+/--increased MYCN, upregulated tumor-promoting genes. Heterozygous Kmt2d loss substantially diminished enhancer marks (H3K4me1 and H3K27ac) and the H3K4me3 signature, including those for Ncor2. Combinatory pharmacological inhibition of the enhancer-decommissioning H3K4 demethylase LSD1 and OXPHOS significantly reduced the tumorigenicity of MB cells bearing heterozygous Kmt2d loss. Our findings suggest the molecular and epigenetic pathogenesis underlying the MB-promoting effect of heterozygous KMT2D loss.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115619"},"PeriodicalIF":7.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955355","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

High-confidence glycosomal membrane protein inventory unveils trypanosomal peroxin PEX15. 高可信度的糖体膜蛋白清单揭示了锥虫体过氧化物PEX15。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-04-24 DOI: 10.1016/j.celrep.2025.115614

Chethan K Krishna, Hirak Das, Lisa Hohnen, Wolfgang Schliebs, Silke Oeljeklaus, Bettina Warscheid, Vishal C Kalel, Ralf Erdmann

{"title":"High-confidence glycosomal membrane protein inventory unveils trypanosomal peroxin PEX15.","authors":"Chethan K Krishna, Hirak Das, Lisa Hohnen, Wolfgang Schliebs, Silke Oeljeklaus, Bettina Warscheid, Vishal C Kalel, Ralf Erdmann","doi":"10.1016/j.celrep.2025.115614","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115614","url":null,"abstract":"Trypanosomatid parasite infections cause Chagas disease, human African trypanosomiasis, and leishmaniasis, affecting over 12 million people worldwide. Glycosomes, the peroxisome-related organelles of trypanosomes, are essential for survival, making their metabolic functions and biogenesis mediated by peroxins (PEXs) suitable drug targets. We report a comprehensive protein inventory of glycosomal membranes, defined through advanced subcellular membrane protein profiling combined with quantitative mass spectrometry and including 28 high-confidence glycosomal membrane proteins. We validate four previously unknown glycosomal membrane proteins, including a tail-anchored protein, which we show to be the long-sought Trypanosoma PEX15. Despite low sequence similarity, Trypanosoma PEX15 exhibits structural and topological similarities with its yeast and human counterparts, and it is essential for glycosome biogenesis and parasite survival. Considering the low degree of conservation with its human counterpart, PEX15 is a promising target for drug development. This inventory is an important resource for characterizing glycosome biology and therapeutic development.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115614"},"PeriodicalIF":7.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961362","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