EMBO Reports最新文献

High CDC20 levels increase sensitivity of cancer cells to MPS1 inhibitors. 高CDC20水平会增加癌细胞对MPS1抑制剂的敏感性。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-21 DOI: 10.1038/s44319-024-00363-8

Siqi Zheng, Linoy Raz, Lin Zhou, Yael Cohen-Sharir, Ruifang Tian, Marica Rosaria Ippolito, Sara Gianotti, Ron Saad, Rene Wardenaar, Mathilde Broekhuis, Maria Suarez Peredo Rodriguez, Soraya Wobben, Anouk van den Brink, Petra Bakker, Stefano Santaguida, Floris Foijer, Uri Ben-David

{"title":"High CDC20 levels increase sensitivity of cancer cells to MPS1 inhibitors.","authors":"Siqi Zheng, Linoy Raz, Lin Zhou, Yael Cohen-Sharir, Ruifang Tian, Marica Rosaria Ippolito, Sara Gianotti, Ron Saad, Rene Wardenaar, Mathilde Broekhuis, Maria Suarez Peredo Rodriguez, Soraya Wobben, Anouk van den Brink, Petra Bakker, Stefano Santaguida, Floris Foijer, Uri Ben-David","doi":"10.1038/s44319-024-00363-8","DOIUrl":"https://doi.org/10.1038/s44319-024-00363-8","url":null,"abstract":"Spindle assembly checkpoint (SAC) inhibitors are a recently developed class of drugs, which perturb chromosome segregation during cell division, induce chromosomal instability (CIN), and eventually lead to cell death. The molecular features that determine cellular sensitivity to these drugs are not fully understood. We recently reported that aneuploid cancer cells are preferentially sensitive to SAC inhibition. Here we report that sensitivity to SAC inhibition by MPS1 inhibitors is largely driven by the expression of CDC20, a main mitotic activator of the anaphase-promoting complex (APC/C), and that the effect of CDC20 is larger than that of the APC/C itself. Mechanistically, we discovered that CDC20 depletion prolongs metaphase duration, diminishes mitotic errors, and reduces sensitivity to SAC inhibition. We found that aneuploid cells express higher basal levels of CDC20, which shortens the duration of metaphase and leads to multiple mitotic errors, resulting in increased long-term sensitivity to the additional CIN induced by SAC inhibition. Our findings propose high CDC20 expression as a molecular feature associated with the sensitivity to SAC inhibition therapy and as a potential aneuploidy-induced cellular vulnerability.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002266","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 controls that got out of control : How failed control experiments paved the way to transformative discoveries. 失控的控制：失败的控制实验如何为变革性的发现铺平道路。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-20 DOI: 10.1038/s44319-025-00369-w

André Schneider

引用次数: 0

Male sex determination maintains proteostasis and extends lifespan of daf-18/PTEN deficient C. elegans. 雄性性别决定维持daf-18/PTEN缺陷秀丽隐杆线虫的蛋白质平衡并延长其寿命。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-16 DOI: 10.1038/s44319-025-00368-x

Zhi Qu, Lu Zhang, Xue Yin, Fangzhou Dai, Wei Huang, Yutong Zhang, Dongyang Ran, Shanqing Zheng

{"title":"Male sex determination maintains proteostasis and extends lifespan of daf-18/PTEN deficient C. elegans.","authors":"Zhi Qu, Lu Zhang, Xue Yin, Fangzhou Dai, Wei Huang, Yutong Zhang, Dongyang Ran, Shanqing Zheng","doi":"10.1038/s44319-025-00368-x","DOIUrl":"https://doi.org/10.1038/s44319-025-00368-x","url":null,"abstract":"Although females typically have a survival advantage, those with PTEN functional abnormalities face a higher risk of developing tumors than males. However, the differences in how each sex responds to PTEN dysfunction have rarely been studied. We use Caenorhabditis elegans to investigate how male and hermaphrodite worms respond to dysfunction of the PTEN homolog daf-18. Our study reveals that male worms can counterbalance the negative effects of daf-18 deficiency, resulting in longer adult lifespan. The survival advantage depends on the loss of DAF-18 protein phosphatase activity, while its lipid phosphatase activity is dispensable. The deficiency in DAF-18 protein phosphatase activity leads to the failure of dephosphorylation of the endoplasmic reticulum membrane protein C18E9.2/SEC62, causing increased levels of unfolded and aggregated proteins in hermaphrodites. In contrast, males maintain proteostasis through a UNC-23/NEF-mediated protein ubiquitination and degradation process, providing them with a survival advantage. We find that sex determination is a key factor in regulating the differential expression of unc-23 between sexes in response to daf-18 loss. These findings highlight the unique role of the male sex determination pathway in regulating protein degradation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002268","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

Author Correction: PP4 is a γH2AX phosphatase required for recovery from the DNA damage checkpoint. 作者更正：PP4 是一种从 DNA 损伤检查点恢复所需的γH2AX 磷酸酶。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-14 DOI: 10.1038/s44319-024-00338-9

Shinichiro Nakada, Ginny I Chen, Anne-Claude Gingras, Daniel Durocher

引用次数: 0

CRISPR-Enabled Autonomous Transposable Element (CREATE) for RNA-based gene editing and delivery. CRISPR-Enabled Autonomous Transposable Element （CREATE）用于基于rna的基因编辑和传递。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-09 DOI: 10.1038/s44319-024-00364-7

Yuxiao Wang, Ruei-Zeng Lin, Meghan Harris, Bianca Lavayen, Neha Diwanji, Bruce McCreedy, Robert Hofmeister, Daniel Getts

引用次数: 0

Acidic pH can attenuate immune killing through inactivation of perforin. 酸性pH可以通过穿孔素失活来减弱免疫杀伤。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-09 DOI: 10.1038/s44319-024-00365-6

Adrian W Hodel, Jesse A Rudd-Schmidt, Tahereh Noori, Christopher J Lupton, Veronica C T Cheuk, Joseph A Trapani, Bart W Hoogenboom, Ilia Voskoboinik

{"title":"Acidic pH can attenuate immune killing through inactivation of perforin.","authors":"Adrian W Hodel, Jesse A Rudd-Schmidt, Tahereh Noori, Christopher J Lupton, Veronica C T Cheuk, Joseph A Trapani, Bart W Hoogenboom, Ilia Voskoboinik","doi":"10.1038/s44319-024-00365-6","DOIUrl":"https://doi.org/10.1038/s44319-024-00365-6","url":null,"abstract":"Cytotoxic lymphocytes are crucial to our immune system, primarily eliminating virus-infected or cancerous cells via perforin/granzyme killing. Perforin forms transmembrane pores in the plasma membrane, allowing granzymes to enter the target cell cytosol and trigger apoptosis. The prowess of cytotoxic lymphocytes to efficiently eradicate target cells has been widely harnessed in immunotherapies against haematological cancers. Despite efforts to achieve a similar outcome against solid tumours, the immunosuppressive and acidic tumour microenvironment poses a persistent obstacle. Using different types of effector cells, including therapeutically relevant anti-CD19 CAR T cells, we demonstrate that the acidic pH typically found in solid tumours hinders the efficacy of immune therapies by impeding perforin pore formation within the immunological synapse. A nanometre-scale study of purified recombinant perforin undergoing oligomerization reveals that pore formation is inhibited specifically by preventing the formation of a transmembrane β-barrel. The absence of perforin pore formation directly prevents target cell death. This finding uncovers a novel layer of immune effector inhibition that must be considered in the development of effective immunotherapies for solid tumours.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946446","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

OTUD6B regulates KIFC1-dependent centrosome clustering and breast cancer cell survival. OTUD6B调节kifc1依赖性中心体聚集和乳腺癌细胞存活。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-09 DOI: 10.1038/s44319-024-00361-w

Valeria E Marotta, Dorota Sabat-Pośpiech, Andrew B Fielding, Amy H Ponsford, Amanda Thomaz, Francesca Querques, Mark R Morgan, Ian A Prior, Judy M Coulson

{"title":"OTUD6B regulates KIFC1-dependent centrosome clustering and breast cancer cell survival.","authors":"Valeria E Marotta, Dorota Sabat-Pośpiech, Andrew B Fielding, Amy H Ponsford, Amanda Thomaz, Francesca Querques, Mark R Morgan, Ian A Prior, Judy M Coulson","doi":"10.1038/s44319-024-00361-w","DOIUrl":"https://doi.org/10.1038/s44319-024-00361-w","url":null,"abstract":"Cancer cells often display centrosome amplification, requiring the kinesin KIFC1/HSET for centrosome clustering to prevent multipolar spindles and cell death. In parallel siRNA screens of deubiquitinase enzymes, we identify OTUD6B as a positive regulator of KIFC1 expression that is required for centrosome clustering in triple-negative breast cancer (TNBC) cells. OTUD6B can localise to centrosomes and the mitotic spindle and interacts with KIFC1. In OTUD6B-deficient cells, we see increased KIFC1 polyubiquitination and premature KIFC1 degradation during mitosis. Depletion of OTUD6B increases multipolar spindles without inducing centrosome amplification. Phenotypic rescue is dependent on OTUD6B catalytic activity and evident upon KIFC1 overexpression. OTUD6B is commonly overexpressed in breast cancer, correlating with KIFC1 protein expression and worse patient survival. TNBC cells with centrosome amplification, but not normal breast epithelial cells, depend on OTUD6B to proliferate. Indeed CRISPR-Cas9 editing results in only OTUD6B-/+ TNBC cells which fail to divide and die. As a deubiquitinase that supports KIFC1 expression, allowing pseudo-bipolar cell division and survival of cancer cells with centrosome amplification, OTUD6B has potential as a novel target for cancer-specific therapies.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946543","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

Addendum: The history of GM crops in Italy. 附录：意大利转基因作物的历史。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-08 DOI: 10.1038/s44319-024-00359-4

Roberto Defez, Maria Chiara Errigo, Giulia Formici, Lucia Scaffardi, Eleonora Sirsi, Fabio Fornara, Vittoria Brambilla

引用次数: 0

Schizophrenia-related Xpo7 haploinsufficiency leads to behavioral and nuclear transport pathologies. 精神分裂症相关的Xpo7单倍不足导致行为和核转运病理。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-07 DOI: 10.1038/s44319-024-00362-9

Saori Toyoda, Masataka Kikuchi, Yoshifumi Abe, Kyosei Tashiro, Takehisa Handa, Shingo Katayama, Yukiko Motokawa, Kenji F Tanaka, Hidehiko Takahashi, Hiroki Shiwaku

{"title":"Schizophrenia-related Xpo7 haploinsufficiency leads to behavioral and nuclear transport pathologies.","authors":"Saori Toyoda, Masataka Kikuchi, Yoshifumi Abe, Kyosei Tashiro, Takehisa Handa, Shingo Katayama, Yukiko Motokawa, Kenji F Tanaka, Hidehiko Takahashi, Hiroki Shiwaku","doi":"10.1038/s44319-024-00362-9","DOIUrl":"https://doi.org/10.1038/s44319-024-00362-9","url":null,"abstract":"Recent genetic studies by the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) consortium have identified that protein-truncating variants of exportin 7 (XPO7) can increase the risk of schizophrenia (odds ratio, 28.1). Here we show that mice with Xpo7 haploinsufficiency (Xpo7+/- mice) present with cognitive and social behavioral impairments. Through proteome analysis using immunoprecipitation and frontal cortex nuclear isolation of Xpo7+/- mice, we identify 45 molecules interacting with Xpo7, including CutC, Rbfox3, and Gria3. Through single-nucleus RNA sequencing of the frontal cortex and striatum of Xpo7+/- mice differentiating between the onset and progressive stages, we also identify 284 gene expression changes that correlate with these stages. These genes encompass high-odds risk genes of schizophrenia identified by SCHEMA, including Gria3, Grin2A, Herc1, and Trio. Furthermore, our approach reveals 15 gene expression changes in the frontal cortex that correlate with the progressive stages. Our findings indicate the importance of investigating whether the interactions among the high-risk genes identified by SCHEMA contribute to a common schizophrenia pathology and underscore the significance of stage-dependent analysis.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946546","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

Dbi1 is an oxidoreductase and an assembly chaperone for mitochondrial inner membrane proteins. Dbi1是一种氧化还原酶，是线粒体内膜蛋白的组装伴侣。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-03 DOI: 10.1038/s44319-024-00349-6

Soraya Badrie, Kai Hell, Dejana Mokranjac

{"title":"Dbi1 is an oxidoreductase and an assembly chaperone for mitochondrial inner membrane proteins.","authors":"Soraya Badrie, Kai Hell, Dejana Mokranjac","doi":"10.1038/s44319-024-00349-6","DOIUrl":"https://doi.org/10.1038/s44319-024-00349-6","url":null,"abstract":"Import and assembly of mitochondrial proteins into multimeric complexes are essential for cellular function. Yet, many steps of these processes and the proteins involved remain unknown. Here, we identify a novel pathway for disulfide bond formation and assembly of mitochondrial inner membrane (IM) proteins. Dbi1, a previously uncharacterized IM protein, interacts with an unassembled pool of Tim17, the central subunit of the presequence translocase of the IM, and is upregulated in cells with increased levels of unassembled Tim17. In the absence of Dbi1, the conformation of the presequence translocase is affected and stability of Tim17 is reduced. Furthermore, Dbi1, through its conserved CxxC motif, is involved in the formation of the disulfide bond in Tim17 in a manner independent of the disulfide relay system, the major oxidation-driven protein import pathway into mitochondria. The substrate spectrum of Dbi1 is not limited to Tim17 but includes at least two more IM proteins, Tim22 and Cox20. We conclude that Dbi1 is a novel oxidoreductase in mitochondria which introduces disulfide bonds into IM proteins and chaperones their assembly into multimeric protein complexes.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925977","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