Cell reports最新文献_第2页

The deubiquitinase Rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26S proteasome. 去泛素酶Rpn11作为变构泛素传感器，促进26S蛋白酶体与底物的结合。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-05-22 DOI: 10.1016/j.celrep.2025.115736

Zaw Min Htet, Ken C Dong, Andreas Martin

{"title":"The deubiquitinase Rpn11 functions as an allosteric ubiquitin sensor to promote substrate engagement by the 26S proteasome.","authors":"Zaw Min Htet, Ken C Dong, Andreas Martin","doi":"10.1016/j.celrep.2025.115736","DOIUrl":"10.1016/j.celrep.2025.115736","url":null,"abstract":"The 26S proteasome is the major compartmental protease in eukaryotic cells, responsible for the ATP-dependent turnover of obsolete, damaged, or misfolded proteins that are delivered for degradation through attached ubiquitin modifications. Besides targeting substrates to the proteasome, ubiquitin was recently shown to promote degradation initiation by modulating proteasome conformational switching, yet the underlying mechanisms are unknown. Here, we use biochemical, mutational, and single-molecule fluorescence resonance energy transfer (FRET)-based approaches to show that the proteasomal deubiquitinase Rpn11 functions as an allosteric sensor and facilitates the early steps of degradation. After substrate recruitment to the proteasome, ubiquitin binding to Rpn11 interferes with conformation-specific interactions of the ubiquitin receptor subunit Rpn10, thereby stabilizing the proteasome's engagement-competent state and expediting substrate insertion into the ATPase motor for mechanical translocation, unfolding, and Rpn11-mediated deubiquitination. These findings explain how modifications with poly-ubiquitin chains or multiple mono-ubiquitins allosterically promote substrate degradation and allow up to 4-fold faster turnover by the proteasome.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115736"},"PeriodicalIF":7.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136019","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

Heterologous prime-boost with an mRNA vaccine and an oncolytic virus enhances tumor regression through overcoming intratumoral immune suppression. mRNA疫苗和溶瘤病毒异种启动增强通过克服肿瘤内免疫抑制促进肿瘤消退。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-05-22 DOI: 10.1016/j.celrep.2025.115745

Kuan Zhang, Dong Zuo, Zhenglong Wang, Jun Ding, Jiang Xu, Yin Liu, Yu Zhong, William Jia

{"title":"Heterologous prime-boost with an mRNA vaccine and an oncolytic virus enhances tumor regression through overcoming intratumoral immune suppression.","authors":"Kuan Zhang, Dong Zuo, Zhenglong Wang, Jun Ding, Jiang Xu, Yin Liu, Yu Zhong, William Jia","doi":"10.1016/j.celrep.2025.115745","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115745","url":null,"abstract":"Therapeutic mRNA vaccines are limited in inducing tumor shrinkage in advanced cancers due to their inability to overcome immune-suppressive mechanisms within tumors. In this study, we developed an HPV-immunogen-expressing oncolytic virus (OV) using HSV-1 for HPV-related cancer treatment. A mouse syngeneic tumor model evaluates the effectiveness of intratumoral OV application for E6+E7+ tumors. Comparative analysis of OV and mRNA vaccines reveals distinct mechanisms in tumor treatment. Single-cell RNA sequencing and flow cytometry show that OV enhances cytotoxic T cell infiltration, polarizes neutrophils and macrophages toward anti-tumor phenotypes, and promotes immune activation within the tumor. In contrast, the mRNA vaccine more effectively activates peripheral antigen-specific T cell responses. A heterologous prime-boost strategy using the mRNA vaccine to prime systemic T cells, followed by OV therapy to direct these cells into the tumor, leads to significant tumor regression. This combination optimizes both systemic and intratumoral immune responses for advanced HPV-related cancers.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115745"},"PeriodicalIF":7.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136013","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

MePCE promotes homologous recombination through coordinating R-loop resolution at DNA double-stranded breaks. MePCE通过协调DNA双链断裂处的r环分解促进同源重组。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-05-22 DOI: 10.1016/j.celrep.2025.115740

Sravan K Devanathan, Yi-Ru Li, Samantha B Shelton, Joshuah Nguyen, Wei-Che Tseng, Nakul M Shah, Marvin Mercado, Kyle M Miller, Blerta Xhemalçe

{"title":"MePCE promotes homologous recombination through coordinating R-loop resolution at DNA double-stranded breaks.","authors":"Sravan K Devanathan, Yi-Ru Li, Samantha B Shelton, Joshuah Nguyen, Wei-Che Tseng, Nakul M Shah, Marvin Mercado, Kyle M Miller, Blerta Xhemalçe","doi":"10.1016/j.celrep.2025.115740","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115740","url":null,"abstract":"MePCE is a multifunctional protein that regulates the positive transcription elongation factor b (P-TEFb) partitioning between the nucleosol and chromatin. MePCE's role in sequestering P-TEFb in the nucleosol via the 7SK ribonuclear protein complex (RNPc) is clear, but its functions on chromatin remain obscure. We report that chromatin-associated MePCE interacts with R-loop processing and DNA repair factors. MePCE is recruited to DNA double-stranded breaks (DSBs), and MePCE depletion impairs DSB repair by homologous recombination (HR), decreases RAD51 loading, and enhances R-loop levels at AsiSI-induced DSBs at specific genomic locations. Besides decreasing specific R-loop processing factors and chromatin remodelers, MePCE depletion increases the interaction with R-loops of the other constitutive member of the 7SK RNPc, LARP7, which is degraded by BRCA1/BARD1 upon DSB. Overall, our results uncover dynamic regulation of the 7SK RNPc at DSBs during the DSB repair process and explain the recently observed synthetic lethality of MePCE and BRCA1 deficiency.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115740"},"PeriodicalIF":7.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136017","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

Division of labor among H3K4 methyltransferases defines distinct facets of homeostatic plasticity. H3K4甲基转移酶之间的分工定义了稳态可塑性的不同方面。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-05-21 DOI: 10.1016/j.celrep.2025.115746

Takao Tsukahara, Saini Kethireddy, Katherine M Bonefas, Alex Chen, Brendan L M Sutton, Kenjiro Bandow, Yali Dou, Shigeki Iwase, Michael A Sutton

{"title":"Division of labor among H3K4 methyltransferases defines distinct facets of homeostatic plasticity.","authors":"Takao Tsukahara, Saini Kethireddy, Katherine M Bonefas, Alex Chen, Brendan L M Sutton, Kenjiro Bandow, Yali Dou, Shigeki Iwase, Michael A Sutton","doi":"10.1016/j.celrep.2025.115746","DOIUrl":"10.1016/j.celrep.2025.115746","url":null,"abstract":"Heterozygous mutations in any of the six H3K4 methyltransferases (KMT2s) result in monogenic neurodevelopmental disorders, indicating non-redundant yet poorly understood roles of this enzyme family in neurodevelopment. However, the specific cellular role of KMT2 enzymes in the brain remains poorly understood, owing to the clear non-catalytic functions of each family member and the potential for functional redundancy in installing H3K4 methylation (H3K4me). Here, we identify an instructive role for H3K4me in controlling synapse function and a division of labor among the six KMT2 enzymes in regulating homeostatic synaptic scaling. Using RNAi screening, conditional genetics, small-molecule inhibitors, and transcriptional profiling, our data reveal that individual KMT2 enzymes have unique roles and operate in specific phases to control distinct facets of homeostatic scaling. Together, our results suggest that the expansion of this enzyme family in mammals is key to coupling fine-tuned gene expression changes to adaptive modifications of synaptic function.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115746"},"PeriodicalIF":7.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126942","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

PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation. pus10诱导的tRNA断裂影响反转录转座子驱动的炎症。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-05-21 DOI: 10.1016/j.celrep.2025.115735

Magdalena Madej, Phuong Cao Thi Ngoc, Sowndarya Muthukumar, Anna Konturek-Cieśla, Silvia Tucciarone, Alexandre Germanos, Christian Ashworth, Knut Kotarsky, Sudip Ghosh, Zhimeng Fan, Helena Fritz, Izei Pascual-Gonzalez, Alain Huerta, Nicola Guzzi, Anita Colazzo, Giulia Beneventi, Hang-Mao Lee, Maciej Cieśla, Christopher Douse, Hiroki Kato, Vinay Swaminathan, William W Agace, Ainara Castellanos-Rubio, Paolo Salomoni, David Bryder, Cristian Bellodi

{"title":"PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation.","authors":"Magdalena Madej, Phuong Cao Thi Ngoc, Sowndarya Muthukumar, Anna Konturek-Cieśla, Silvia Tucciarone, Alexandre Germanos, Christian Ashworth, Knut Kotarsky, Sudip Ghosh, Zhimeng Fan, Helena Fritz, Izei Pascual-Gonzalez, Alain Huerta, Nicola Guzzi, Anita Colazzo, Giulia Beneventi, Hang-Mao Lee, Maciej Cieśla, Christopher Douse, Hiroki Kato, Vinay Swaminathan, William W Agace, Ainara Castellanos-Rubio, Paolo Salomoni, David Bryder, Cristian Bellodi","doi":"10.1016/j.celrep.2025.115735","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115735","url":null,"abstract":"Pseudouridine synthases (PUSs) catalyze the isomerization of uridine (U)-to-pseudouridine (Ψ) and have emerging roles in development and disease. How PUSs adapt gene expression under stress remains mostly unexplored. We identify an unconventional role for the Ψ \"writer\" PUS10 impacting intracellular innate immunity. Using Pus10 knockout mice, we uncover cell-intrinsic upregulation of interferon (IFN) signaling, conferring resistance to inflammation in vivo. Pus10 loss alters tRNA-derived small RNAs (tdRs) abundance, perturbing translation and endogenous retroelements expression. These alterations promote proinflammatory RNA-DNA hybrids accumulation, potentially activating cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING). Supplementation with selected tdR pools partly rescues these effects through interactions with RNA processing factors that modulate immune responses, revealing a regulatory circuit that counteracts cell-intrinsic inflammation. By extension, we define a PUS10-specific molecular fingerprint linking its dysregulation to human autoimmune disorders, including inflammatory bowel diseases. Collectively, these findings establish PUS10 as a viral mimicry modulator, with broad implications for innate immune homeostasis and autoimmunity.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115735"},"PeriodicalIF":7.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126898","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

Hormonal regulation of primary root development. 初生根发育的激素调控。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-05-21 DOI: 10.1016/j.celrep.2025.115751

Michela De Nittis, Mirko De Vivo, Raffaele Dello Ioio, Sabrina Sabatini

引用次数: 0

Bioactive ketamine metabolite exerts in vivo neuroplastogenic effects to improve hippocampal function in a treatment-resistant depression model. 生物活性氯胺酮代谢物在体内发挥神经塑性作用，改善治疗抵抗性抑郁症模型的海马功能。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-05-21 DOI: 10.1016/j.celrep.2025.115743

Lace M Riggs, Sage Aronson, Ta-Chung M Mou, Edna F R Pereira, Scott M Thompson, Todd D Gould

{"title":"Bioactive ketamine metabolite exerts in vivo neuroplastogenic effects to improve hippocampal function in a treatment-resistant depression model.","authors":"Lace M Riggs, Sage Aronson, Ta-Chung M Mou, Edna F R Pereira, Scott M Thompson, Todd D Gould","doi":"10.1016/j.celrep.2025.115743","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115743","url":null,"abstract":"An acute increase in excitatory synaptic transmission contributes to the rapid antidepressant actions of neuroplastogens, including ketamine and its bioactive metabolite, (2R,6R)-hydroxynorketamine (HNK). It is hypothesized that drug-induced metaplastic changes in synaptic strength account for therapeutically relevant behavioral adaptations in vivo. Using the plasticity-deficient Wistar Kyoto model of treatment-resistant depression, we demonstrate that (2R,6R)-HNK potentiates glutamatergic transmission, promotes synaptic strength, restores long-term potentiation (LTP), and reverses deficits in hippocampal-dependent synaptic activity and behavior. (2R,6R)-HNK selectively potentiated CA1 pyramidal neuron activity during novelty exploration and restored Schaffer collateral-dependent spatial recognition memory. Prior experience with spatial learning partially occluded LTP in control rats, an effect mimicked in LTP-impaired rats in which spatial learning deficits were reversed by (2R,6R)-HNK. These findings demonstrate that (2R,6R)-HNK exerts rapid neuroplastogenic effects in vivo, which improve cognitive function and promote adaptive changes in synaptic strength at functionally impaired synapses.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115743"},"PeriodicalIF":7.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132253","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

A lncRNA-mediated metabolic rewiring of cell senescence. lncrna介导的细胞衰老的代谢重新布线。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-05-21 DOI: 10.1016/j.celrep.2025.115747

Elena Grossi, Francesco P Marchese, Jovanna González, Enrique Goñi, José Miguel Fernández-Justel, Alicia Amadoz, Nicolás Herranz, Leonor Puchades-Carrasco, Marta Montes, Maite Huarte

{"title":"A lncRNA-mediated metabolic rewiring of cell senescence.","authors":"Elena Grossi, Francesco P Marchese, Jovanna González, Enrique Goñi, José Miguel Fernández-Justel, Alicia Amadoz, Nicolás Herranz, Leonor Puchades-Carrasco, Marta Montes, Maite Huarte","doi":"10.1016/j.celrep.2025.115747","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115747","url":null,"abstract":"Despite not proliferating, senescent cells remain metabolically active to maintain the senescence program. However, the mechanisms behind this metabolic reprogramming are not well understood. We identify senescence-induced long noncoding RNA (sin-lncRNA), a previously uncharacterized long noncoding RNA (lncRNA), a key player in this response. While strongly activated in senescence by C/EBPβ, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with dihydrolipoamide S-succinyltransferase (DLST), it facilitates its mitochondrial localization. Depletion of sin-lncRNA causes DLST nuclear translocation, leading to transcriptional changes in oxidative phosphorylation (OXPHOS) genes. While not expressed in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells reduces oxygen consumption and increases extracellular acidification, sensitizing cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in senescence to maintain metabolic homeostasis, unveiling an RNA-dependent metabolic rewiring specific to senescent cells.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115747"},"PeriodicalIF":7.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132252","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

Glycerophospholipid metabolism licenses IgE-mediated mast cell degranulation. 甘油磷脂代谢允许ige介导的肥大细胞脱颗粒。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-05-20 DOI: 10.1016/j.celrep.2025.115742

Yaoyao Xia, Peng Bin, Youyou Zhou, Muyang Zhao, Jianglin Zhang, Weiming Zhong, Na Wang, Bingfeng Wang, Wenkai Ren

{"title":"Glycerophospholipid metabolism licenses IgE-mediated mast cell degranulation.","authors":"Yaoyao Xia, Peng Bin, Youyou Zhou, Muyang Zhao, Jianglin Zhang, Weiming Zhong, Na Wang, Bingfeng Wang, Wenkai Ren","doi":"10.1016/j.celrep.2025.115742","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115742","url":null,"abstract":"Immunoglobulin E (IgE) antibodies and mast cells have been extensively recognized to dictate the pathophysiology of anaphylaxis and allergic reactions; nevertheless, the pivotal cues driving IgE-mediated mast cell degranulation remain enigmatic. Here, we demonstrate that FcεRI aggregation-initiated p38α signaling stimulates Ets-1 transcription by recruitment of the SWI-SNF chromatin-remodeling complex, contributing to Pcyt1a expression and glycerophospholipid metabolism in IgE-stimulated mast cells. Most importantly, Pcyt1a-mediated glycerophospholipid metabolism facilitates mast cell degranulation through the limited macropinocytosis of FcεRI via altering H3K9me3 deposition at the promoter of Prkcd. Moreover, the metabolic cue functions as an instigator of allergic diseases (e.g., atopic dermatitis [AD]) according to preclinical findings of murine models, in silico analysis of human disease studies, and examination of clinical samples. In summary, our study establishes that lipid metabolism and signaling orchestrate mast cell activation and provides promising therapeutic targets for clinically tackling allergic diseases.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115742"},"PeriodicalIF":7.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118951","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

A platform of functional studies of ESCC-associated gene mutations identifies the roles of TGFBR2 in ESCC progression and metastasis. ESCC相关基因突变的功能研究平台确定了TGFBR2在ESCC进展和转移中的作用。

IF 7.5 1区生物学

Cell reports Pub Date : 2025-05-20 DOI: 10.1016/j.celrep.2025.115756

Jian Wang, Jiajia Du, Xiangmeng Luo, Linjie Guo, Yixin Liu, Jianfeng Zhou, Yang Zou, Zhenghao Lu, Xiangyu Pan, Xuelan Chen, Ailing Zhong, Xudong Wan, Lu Wang, Hongyu Liu, Siqi Dai, Shiyu Zhang, Xingyu Xiong, Ping Tan, Manli Wang, Baohong Wu, Qi Zhang, Yingjie Wang, Mengsha Zhang, Runda Lu, Huahang Lin, Yuan Li, Yaxin Li, Zongkai Han, Longqi Chen, Bing Hu, Yu Liu, Feifei Na, Chong Chen

引用次数: 0