EMBO Reports最新文献_第2页

In situ cell-surface conformation of the TCR-CD3 signaling complex. TCR-CD3 信号复合体的原位细胞表面构象。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-07 DOI: 10.1038/s44319-024-00314-3

Aswin Natarajan, Yogambigai Velmurugu, Manuel Becerra Flores, Fatoumatta Dibba, Saikiran Beesam, Sally Kikvadze, Xiaotian Wang, Wenjuan Wang, Tianqi Li, Hye Won Shin, Timothy Cardozo, Michelle Krogsgaard

{"title":"In situ cell-surface conformation of the TCR-CD3 signaling complex.","authors":"Aswin Natarajan, Yogambigai Velmurugu, Manuel Becerra Flores, Fatoumatta Dibba, Saikiran Beesam, Sally Kikvadze, Xiaotian Wang, Wenjuan Wang, Tianqi Li, Hye Won Shin, Timothy Cardozo, Michelle Krogsgaard","doi":"10.1038/s44319-024-00314-3","DOIUrl":"https://doi.org/10.1038/s44319-024-00314-3","url":null,"abstract":"The extracellular molecular organization of the individual CD3 subunits around the αβ T cell receptor (TCR) is critical for initiating T cell signaling. In this study, we incorporate photo-crosslinkers at specific sites within the TCRα, TCRβ, CD3δ, and CD3γ subunits. Through crosslinking and docking, we identify a CD3ε'-CD3γ-CD3ε-CD3δ arrangement situated around the αβTCR in situ within the cell surface environment. We demonstrate the importance of cholesterol in maintaining the stability of the complex and that the 'in situ' complex structure mirrors the structure from 'detergent-purified' complexes. In addition, mutations aimed at stabilizing extracellular TCR-CD3 interfaces lead to poor signaling, suggesting that subunit fluidity is indispensable for signaling. Finally, employing photo-crosslinking and CD3 tetramer assays, we show that the TCR-CD3 complex undergoes minimal subunit movements or reorientations upon interaction with activating antibodies and pMHC tetramers. This suggests an absence of 'inactive-active' conformational states in the TCR constant regions and the extracellular CD3 subunits, unlike the transmembrane regions of the complex. This study contributes a nuanced understanding of TCR signaling, which may inform the development of therapeutics for immune-related disorders.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602171","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

PTGS is dispensable for the initiation of epigenetic silencing of an active transposon in Arabidopsis. 在拟南芥中，PTGS对于启动活性转座子的表观遗传沉默是不可或缺的。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-07 DOI: 10.1038/s44319-024-00304-5

Marieke Trasser, Grégoire Bohl-Viallefond, Verónica Barragán-Borrero, Laura Diezma-Navas, Lukas Loncsek, Magnus Nordborg, Arturo Marí-Ordóñez

{"title":"PTGS is dispensable for the initiation of epigenetic silencing of an active transposon in Arabidopsis.","authors":"Marieke Trasser, Grégoire Bohl-Viallefond, Verónica Barragán-Borrero, Laura Diezma-Navas, Lukas Loncsek, Magnus Nordborg, Arturo Marí-Ordóñez","doi":"10.1038/s44319-024-00304-5","DOIUrl":"https://doi.org/10.1038/s44319-024-00304-5","url":null,"abstract":"Transposable elements (TEs) are repressed in plants through transcriptional gene silencing (TGS), maintained epigenetic silencing marks such as DNA methylation. However, the mechanisms by which silencing is first installed remain poorly understood in plants. Small interfering (si)RNAs and post-transcriptional gene silencing (PTGS) are believed to mediate the initiation of TGS by guiding the first deposition of DNA methylation. To determine how this silencing installation works, we took advantage of ÉVADÉ (EVD), an endogenous retroelement in Arabidopsis, able to recapitulate true de novo silencing with a sequence of PTGS followed by a TGS. To test whether PTGS is required for TGS, we introduce active EVD into RNA-DEPENDENT-RNA-POLYMERASE-6 (RDR6) mutants, an essential PTGS component. EVD activity and silencing are monitored across several generations. In the absence of PTGS, silencing of EVD is still achieved through installation of RNA-directed DNA methylation (RdDM). Our study shows that PTGS is dispensable for de novo EVD silencing. Although we cannot rule out that PTGS might facilitate TGS, or control TE activity, initiation of epigenetic silencing can take place in its absence.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602172","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

The USP12/46 deubiquitinases protect integrins from ESCRT-mediated lysosomal degradation. USP12/46 去泛素酶保护整合素免受 ESCRT 介导的溶酶体降解。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-06 DOI: 10.1038/s44319-024-00300-9

Kaikai Yu, Guan M Wang, Shiny Shengzhen Guo, Florian Bassermann, Reinhard Fässler

引用次数: 0

Reducing competition between msd and genomic DNA improves retron editing efficiency. 减少 msd 与基因组 DNA 之间的竞争可提高 retron 编辑效率。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-05 DOI: 10.1038/s44319-024-00311-6

Yuyang Ni, Yifei Wang, Xinyu Shi, Fan Yu, Qingmin Ruan, Na Tian, Jin He, Xun Wang

{"title":"Reducing competition between msd and genomic DNA improves retron editing efficiency.","authors":"Yuyang Ni, Yifei Wang, Xinyu Shi, Fan Yu, Qingmin Ruan, Na Tian, Jin He, Xun Wang","doi":"10.1038/s44319-024-00311-6","DOIUrl":"https://doi.org/10.1038/s44319-024-00311-6","url":null,"abstract":"Retrons, found in bacteria and used for defense against phages, generate a unique molecule known as multicopy single-stranded DNA (msDNA). This msDNA mimics Okazaki fragments during DNA replication, making it a promising tool for targeted gene editing in prokaryotes. However, existing retron systems often exhibit suboptimal editing efficiency. Here, we identify the msd gene in Escherichia coli, which encodes the noncoding RNA template for msDNA synthesis and carries the homologous sequence of the target gene to be edited, as a critical bottleneck. Sequence homology causes the msDNA to bind to the msd gene, thereby reducing its efficiency in editing the target gene. To address this issue, we engineer a retron system that tailors msDNA to the leading strand of the plasmid containing the msd gene. This strategy minimizes msd gene editing and reduces competition with target genes, significantly increasing msDNA availability. Our optimized system achieves very high retron editing efficiency, enhancing performance and expanding the potential for in vivo techniques that rely on homologous DNA synthesis.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582495","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

Making contact away from home: a bacterial secreted effector mediates inter-organelle communication. 远离家乡建立联系：细菌分泌的效应物介导细胞器间的交流。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-05 DOI: 10.1038/s44319-024-00312-5

Rachel J Ende, Isabelle Derré

引用次数: 0

The L27 domain of MPP7 enhances TAZ-YY1 cooperation to renew muscle stem cells. MPP7的L27结构域增强了TAZ-YY1在更新肌肉干细胞方面的合作。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-04 DOI: 10.1038/s44319-024-00305-4

Anwen Shao, Joseph L Kissil, Chen-Ming Fan

引用次数: 0

PARP1 condensates differentially partition DNA repair proteins and enhance DNA ligation. PARP1 缩合物可对 DNA 修复蛋白进行不同的分区，并增强 DNA 连接。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-04 DOI: 10.1038/s44319-024-00285-5

Christopher Chin Sang, Gaelen Moore, Maria Tereshchenko, Hongshan Zhang, Michael L Nosella, Morgan Dasovich, T Reid Alderson, Anthony K L Leung, Ilya J Finkelstein, Julie D Forman-Kay, Hyun O Lee

{"title":"PARP1 condensates differentially partition DNA repair proteins and enhance DNA ligation.","authors":"Christopher Chin Sang, Gaelen Moore, Maria Tereshchenko, Hongshan Zhang, Michael L Nosella, Morgan Dasovich, T Reid Alderson, Anthony K L Leung, Ilya J Finkelstein, Julie D Forman-Kay, Hyun O Lee","doi":"10.1038/s44319-024-00285-5","DOIUrl":"10.1038/s44319-024-00285-5","url":null,"abstract":"Poly(ADP-ribose) polymerase 1 (PARP1) is one of the first responders to DNA damage and plays crucial roles in recruiting DNA repair proteins through its activity - poly(ADP-ribosyl)ation (PARylation). The enrichment of DNA repair proteins at sites of DNA damage has been described as the formation of a biomolecular condensate. However, it remains unclear how exactly PARP1 and PARylation contribute to the formation and organization of DNA repair condensates. Using recombinant human single-strand repair proteins in vitro, we find that PARP1 readily forms viscous biomolecular condensates in a DNA-dependent manner and that this depends on its three zinc finger (ZnF) domains. PARylation enhances PARP1 condensation in a PAR chain length-dependent manner and increases the internal dynamics of PARP1 condensates. DNA and single-strand break repair proteins XRCC1, LigIII, Polβ, and FUS partition in PARP1 condensates, although in different patterns. While Polβ and FUS are both homogeneously mixed within PARP1 condensates, FUS enrichment is greatly enhanced upon PARylation whereas Polβ partitioning is not. XRCC1 and LigIII display an inhomogeneous organization within PARP1 condensates; their enrichment in these multiphase condensates is enhanced by PARylation. Functionally, PARP1 condensates concentrate short DNA fragments, which correlates with PARP1 clusters compacting long DNA and bridging DNA ends. Furthermore, the presence of PARP1 condensates significantly promotes DNA ligation upon PARylation. These findings provide insight into how PARP1 condensation and PARylation regulate the assembly and biochemical activities of DNA repair factors, which may inform on how PARPs function in DNA repair foci and other PAR-driven condensates in cells.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575641","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

Severe fever with thrombocytopenia syndrome virus induces lactylation of m6A reader protein YTHDF1 to facilitate viral replication. 严重发热伴血小板减少综合征病毒诱导 m6A 读取蛋白 YTHDF1 乳化，以促进病毒复制。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-04 DOI: 10.1038/s44319-024-00310-7

Bingxin Liu, Xiaoyan Tian, Linrun Li, Rui Zhang, Jing Wu, Na Jiang, Meng Yuan, Deyan Chen, Airong Su, Shijie Xu, Zhiwei Wu

{"title":"Severe fever with thrombocytopenia syndrome virus induces lactylation of m6A reader protein YTHDF1 to facilitate viral replication.","authors":"Bingxin Liu, Xiaoyan Tian, Linrun Li, Rui Zhang, Jing Wu, Na Jiang, Meng Yuan, Deyan Chen, Airong Su, Shijie Xu, Zhiwei Wu","doi":"10.1038/s44319-024-00310-7","DOIUrl":"10.1038/s44319-024-00310-7","url":null,"abstract":"Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging infectious pathogen with a high fatality rate, is an enveloped tripartite segmented single-stranded negative-sense RNA virus. SFTSV infection is characterized by suppressed host innate immunity, proinflammatory cytokine storm, failure of B-cell immunity, and robust viral replication. m6A modification has been shown to play a role in viral infections. However, interactions between m6A modification and SFTSV infection remain poorly understood. Through MeRIP-seq, we identify m6A modifications on SFTSV RNA. We show that YTHDF1 can bind to m6A modification sites on SFTSV, decreasing the stability of SFTSV RNA and reducing the translation efficiency of SFTSV proteins. The SFTSV virulence factor NSs increases lactylation of YTHDF1 and YTHDF1 degradation, thus facilitating SFTSV replication. Our findings indicate that the SFTSV protein NSs induce lactylation to inhibit YTHDF1 as a countermeasure to host's YTHDF1-mediated degradation of m6A-marked viral mRNAs.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575644","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

Genetic linkage disequilibrium of deleterious mutations in threatened mammals. 受威胁哺乳动物中有害突变的遗传连锁不平衡。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-01 DOI: 10.1038/s44319-024-00307-2

Chunyan Hu, Gaoming Liu, Zhan Zhang, Qi Pan, Xiaoxiao Zhang, Weiqiang Liu, Zihao Li, Meng Li, Pingfen Zhu, Ting Ji, Paul A Garber, Xuming Zhou

{"title":"Genetic linkage disequilibrium of deleterious mutations in threatened mammals.","authors":"Chunyan Hu, Gaoming Liu, Zhan Zhang, Qi Pan, Xiaoxiao Zhang, Weiqiang Liu, Zihao Li, Meng Li, Pingfen Zhu, Ting Ji, Paul A Garber, Xuming Zhou","doi":"10.1038/s44319-024-00307-2","DOIUrl":"https://doi.org/10.1038/s44319-024-00307-2","url":null,"abstract":"The impact of negative selection against deleterious mutations in endangered species remains underexplored. Recent studies have measured mutation load by comparing the accumulation of deleterious mutations, however, this method is most effective when comparing within and between populations of phylogenetically closely related species. Here, we introduced new statistics, LDcor, and its standardized form nLDcor, which allows us to detect and compare global linkage disequilibrium of deleterious mutations across species using unphased genotypes. These statistics measure averaged pairwise standardized covariance and standardize mutation differences based on the standard deviation of alleles to reflect selection intensity. We then examined selection strength in the genomes of seven mammals. Tigers exhibited an over-dispersion of deleterious mutations, while gorillas, giant pandas, and golden snub-nosed monkeys displayed negative linkage disequilibrium. Furthermore, the distribution of deleterious mutations in threatened mammals did not reveal consistent trends. Our results indicate that these newly developed statistics could help us understand the genetic burden of threatened species.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563992","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

STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1. 尤文肉瘤中 STAG2 的缺失会改变增强子-启动子接触，这种改变既依赖于 EWS::FLI1 也独立于 EWS::FLI1。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-11-01 DOI: 10.1038/s44319-024-00303-6

Daniel Giménez-Llorente, Ana Cuadrado, María José Andreu, Inmaculada Sanclemente-Alamán, Maria Solé-Ferran, Miriam Rodríguez-Corsino, Ana Losada

{"title":"STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1.","authors":"Daniel Giménez-Llorente, Ana Cuadrado, María José Andreu, Inmaculada Sanclemente-Alamán, Maria Solé-Ferran, Miriam Rodríguez-Corsino, Ana Losada","doi":"10.1038/s44319-024-00303-6","DOIUrl":"https://doi.org/10.1038/s44319-024-00303-6","url":null,"abstract":"Cohesin complexes carrying STAG1 or STAG2 organize the genome into chromatin loops. STAG2 loss-of-function mutations promote metastasis in Ewing sarcoma, a pediatric cancer driven by the fusion transcription factor EWS::FLI1. We integrated transcriptomic data from patients and cellular models to identify a STAG2-dependent gene signature associated with worse prognosis. Subsequent genomic profiling and high-resolution chromatin interaction data from Capture Hi-C indicated that cohesin-STAG2 facilitates communication between EWS::FLI1-bound long GGAA repeats, presumably acting as neoenhancers, and their target promoters. Changes in CTCF-dependent chromatin contacts involving signature genes, unrelated to EWS::FLI1 binding, were also identified. STAG1 is unable to compensate for STAG2 loss and chromatin-bound cohesin is severely decreased, while levels of the processivity factor NIPBL remain unchanged, likely affecting DNA looping dynamics. These results illuminate how STAG2 loss modifies the chromatin interactome of Ewing sarcoma cells and provide a list of potential biomarkers and therapeutic targets.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563994","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