EMBO Reports最新文献_第5页

Using AI to prepare for academic interviews - don't trade authenticity for polish.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-17 DOI: 10.1038/s44319-025-00396-7

Shina Caroline Lynn Kamerlin, William C Ratcliff

引用次数: 0

LATS1/2 inactivation in the mammary epithelium drives the evolution of a tumor-associated niche.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-14 DOI: 10.1038/s44319-025-00370-3

Joseph G Kern, Lina Kroehling, Anthony J Spinella, Stefano Monti, Xaralabos Varelas

{"title":"LATS1/2 inactivation in the mammary epithelium drives the evolution of a tumor-associated niche.","authors":"Joseph G Kern, Lina Kroehling, Anthony J Spinella, Stefano Monti, Xaralabos Varelas","doi":"10.1038/s44319-025-00370-3","DOIUrl":"10.1038/s44319-025-00370-3","url":null,"abstract":"Basal-like breast cancers exhibit distinct cellular heterogeneity that contributes to disease pathology. In this study we used a genetic mouse model of basal-like breast cancer driven by epithelial-specific inactivation of the Hippo pathway-regulating LATS1 and LATS2 kinases to elucidate epithelial-stromal interactions. We demonstrate that basal-like carcinoma initiation in this model is accompanied by the accumulation of distinct cancer-associated fibroblasts and macrophages and dramatic extracellular matrix remodeling, phenocopying the stromal diversity observed in human triple-negative breast tumors. Dysregulated epithelial-stromal signals were observed, including those mediated by TGF-β, PDGF, and CSF. Autonomous activation of the transcriptional effector TAZ was observed in LATS1/2-deleted cells along with non-autonomous activation within the evolving tumor niche. We further show that inhibition of the YAP/TAZ-associated TEAD family of transcription factors blocks the development of the carcinomas and associated microenvironment. These observations demonstrate that carcinomas resulting from Hippo pathway dysregulation in the mammary epithelium are sufficient to drive cellular events that promote a basal-like tumor-associated niche and suggest that targeting dysregulated YAP/TAZ-TEAD activity may offer a therapeutic opportunity for basal-like mammary tumors.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1472-1503"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425189","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

Tafazzin regulates neutrophil maturation and inflammatory response.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-17 DOI: 10.1038/s44319-025-00393-w

Przemysław Zakrzewski, Christopher M Rice, Kathryn Fleming, Drinalda Cela, Sarah J Groves, Fernando M Ponce-Garcia, Willem Gibbs, Kiran Roberts, Tobias Pike, Douglas Strathdee, Eve Anderson, Angela H Nobbs, Ashley M Toye, Colin Steward, Borko Amulic

{"title":"Tafazzin regulates neutrophil maturation and inflammatory response.","authors":"Przemysław Zakrzewski, Christopher M Rice, Kathryn Fleming, Drinalda Cela, Sarah J Groves, Fernando M Ponce-Garcia, Willem Gibbs, Kiran Roberts, Tobias Pike, Douglas Strathdee, Eve Anderson, Angela H Nobbs, Ashley M Toye, Colin Steward, Borko Amulic","doi":"10.1038/s44319-025-00393-w","DOIUrl":"10.1038/s44319-025-00393-w","url":null,"abstract":"Barth syndrome (BTHS) is a rare genetic disease caused by mutations in the TAFAZZIN gene. It is characterized by neutropenia, cardiomyopathy and skeletal myopathy. Neutropenia in BTHS is associated with life-threatening infections, yet there is little understanding of the molecular and physiological causes of this phenomenon. We combined bone marrow analysis, CRISPR/Cas9 genome editing in hematopoietic stem cells and functional characterization of circulating BTHS patient neutrophils to investigate the role of TAFAZZIN in neutrophils and their progenitors. We demonstrate a partial cell intrinsic differentiation defect, along with a dysregulated neutrophil inflammatory response in BTHS, including elevated degranulation and formation of neutrophil extracellular traps (NETs) in response to calcium flux. Developmental and functional alterations in BTHS neutrophils are underpinned by perturbations in the unfolded protein response (UPR) signaling pathway, suggesting potential therapeutic avenues for targeting BTHS neutropenia.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1590-1619"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440038","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

DSTYK phosphorylates STING at late endosomes to promote STING signaling.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-20 DOI: 10.1038/s44319-025-00394-9

Hao Dong, Heng Zhang, Pu Song, Yuan Hu, Danying Chen

引用次数: 0

Immune cells adapt to confined environments in vivo to optimise nuclear plasticity for migration.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-06 DOI: 10.1038/s44319-025-00381-0

Tua Karling, Helen Weavers

{"title":"Immune cells adapt to confined environments in vivo to optimise nuclear plasticity for migration.","authors":"Tua Karling, Helen Weavers","doi":"10.1038/s44319-025-00381-0","DOIUrl":"10.1038/s44319-025-00381-0","url":null,"abstract":"Cells navigating in complex 3D microenvironments frequently encounter narrow spaces that physically challenge migration. While in vitro studies identified nuclear stiffness as a key rate-limiting factor governing the movement of many cell types through artificial constraints, how cells migrating in vivo respond dynamically to confinement imposed by local tissue architecture, and whether these encounters trigger molecular adaptations, is unclear. Here, we establish an innovative in vivo model for mechanistic analysis of nuclear plasticity as Drosophila immune cells transition into increasingly confined microenvironments. Integrating live in vivo imaging with molecular genetic analyses, we demonstrate how rapid molecular adaptation upon environmental confinement (including fine-tuning of the nuclear lamina) primes leukocytes for enhanced nuclear deformation while curbing damage (including rupture and micronucleation), ultimately accelerating movement through complex tissues. We find nuclear dynamics in vivo are further impacted by large organelles (phagosomes) and the plasticity of neighbouring cells, which themselves deform during leukocyte passage. The biomechanics of cell migration in vivo are thus shaped both by factors intrinsic to individual immune cells and the malleability of the surrounding microenvironment.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1238-1268"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11894099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364102","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

Natural variations of adolescent neurogenesis and anxiety predict the hierarchical status of adult inbred mice.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-01-23 DOI: 10.1038/s44319-025-00367-y

Fabio Grieco, Atik Balla, Thomas Larrieu, Nicolas Toni

{"title":"Natural variations of adolescent neurogenesis and anxiety predict the hierarchical status of adult inbred mice.","authors":"Fabio Grieco, Atik Balla, Thomas Larrieu, Nicolas Toni","doi":"10.1038/s44319-025-00367-y","DOIUrl":"10.1038/s44319-025-00367-y","url":null,"abstract":"Hierarchy provides a survival advantage to social animals in challenging circumstances. In mice, social dominance is associated with trait anxiety which is regulated by adult hippocampal neurogenesis. Here, we test whether adolescent hippocampal neurogenesis may regulate social dominance behavior in adulthood. We observe that adolescent individuals with higher trait anxiety and lower levels of hippocampal neurogenesis prior to the formation of a new group become dominants, suggesting that baseline adolescent neurogenesis predicts hierarchical status. This phenotype persists beyond social hierarchy stabilization. Experimentally reducing neurogenesis prior to the stabilization of social hierarchy in group-housed adolescent males increases the probability of mice to become dominant and increases anxiety. Finally, when innate dominance is assessed in socially isolated and anxiety-matched animals, mice with impaired neurogenesis display a dominant status toward strangers. Together, these results indicate that adolescent neurogenesis predicts and regulates hierarchical and situational dominance behavior along with anxiety-related behavior. These results provide a framework to study the mechanisms underlying social hierarchy and the dysregulation of dominance behavior in psychiatric diseases related to anxiety.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1440-1456"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028136","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

HSC70 coordinates COP9 signalosome and SCF ubiquitin ligase activity to enable a prompt stress response.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-06 DOI: 10.1038/s44319-025-00376-x

Shunsuke Nishimura, Hidetaka Kioka, Shan Ding, Hideyuki Hakui, Haruki Shinomiya, Kazuya Tanabe, Tatsuro Hitsumoto, Ken Matsuoka, Hisakazu Kato, Osamu Tsukamoto, Yoshihiro Asano, Seiji Takashima, Radoslav I Enchev, Yasushi Sakata

{"title":"HSC70 coordinates COP9 signalosome and SCF ubiquitin ligase activity to enable a prompt stress response.","authors":"Shunsuke Nishimura, Hidetaka Kioka, Shan Ding, Hideyuki Hakui, Haruki Shinomiya, Kazuya Tanabe, Tatsuro Hitsumoto, Ken Matsuoka, Hisakazu Kato, Osamu Tsukamoto, Yoshihiro Asano, Seiji Takashima, Radoslav I Enchev, Yasushi Sakata","doi":"10.1038/s44319-025-00376-x","DOIUrl":"10.1038/s44319-025-00376-x","url":null,"abstract":"The SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex plays a protective role against external stress, such as ultraviolet irradiation. The emergence of substrates activates SCF through neddylation, the covalent attachment of ubiquitin-like protein NEDD8 to CUL1. After substrate degradation, SCF is inactivated through deneddylation by COP9-signalosome (CSN), a solo enzyme that can deneddylate SCF. How the activity of CSN and SCF is coordinated within the cell is not fully understood. Here, we find that heat-shock cognate 70 (HSC70) chaperone coordinates SCF and CSN activation dependent on the neddylation status and substrate availability. Under basal conditions and low substrate availability, HCS70 directly enhances CSN deneddylation activity, thereby reducing SCF activity. Under SCF-activated conditions, HSC70 interacts with neddylated SCF and enhances its ubiquitination activity. The alternative interaction between HSC70 and CSN or neddylated SCF is regulated by the presence or absence of SCF substrates. The knockdown of HSC70 decreases SCF-mediated substrate ubiquitination, resulting in vulnerability against ultraviolet irradiation. Our work demonstrates the pivotal role of HSC70 in the alternative activation of CSN deneddylation and SCF substrate ubiquitination, which enables a prompt stress response.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1344-1366"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11894141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364099","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

Haploinsufficient phenotypes promote selection of PTEN and ARID1A-deficient clones in human colon.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-07 DOI: 10.1038/s44319-025-00373-0

Nefeli Skoufou-Papoutsaki, Sam Adler, Shenay Mehmed, Claire Tume, Cora Olpe, Edward Morrissey, Richard Kemp, Anne-Claire Girard, Elisa B Moutin, Chandra Sekhar Reddy Chilamakuri, Jodi L Miller, Cecilia Lindskog, Fabian Werle, Kate Marks, Francesca Perrone, Matthias Zilbauer, David S Tourigny, Douglas J Winton

{"title":"Haploinsufficient phenotypes promote selection of PTEN and ARID1A-deficient clones in human colon.","authors":"Nefeli Skoufou-Papoutsaki, Sam Adler, Shenay Mehmed, Claire Tume, Cora Olpe, Edward Morrissey, Richard Kemp, Anne-Claire Girard, Elisa B Moutin, Chandra Sekhar Reddy Chilamakuri, Jodi L Miller, Cecilia Lindskog, Fabian Werle, Kate Marks, Francesca Perrone, Matthias Zilbauer, David S Tourigny, Douglas J Winton","doi":"10.1038/s44319-025-00373-0","DOIUrl":"10.1038/s44319-025-00373-0","url":null,"abstract":"Cancer driver mutations are defined by their high prevalence in cancers and presumed rarity in normal tissues. However, recent studies show that positive selection in normal epithelia can increase the prevalence of some cancer drivers. To determine their true cancer-driving potential, it is essential to evaluate how frequent these mutations are in normal tissues and what are their phenotypes. Here, we explore the bioavailability of somatic variants by quantifying age-related mutational burdens in normal human colonic epithelium using immunodetection in FFPE samples (N = 181 patients). Positive selection of variants of tumour suppressor genes PTEN and ARID1A associates with monoallelic gene loss as confirmed by CRISPR/Cas9 mutagenesis and changes in their downstream effectors. Comparison of the mutational burden in normal tissue and colorectal cancers allows quantification of cancer driver potency based on relative representation. Additionally, immune exclusion, a cancer hallmark feature, is observed within ARID1A-deficient clones in histologically normal tissue. The behaviour resulting from haploinsufficiency of PTEN and ARID1A demonstrates how somatic mosaicism of tumour suppressors arises and can predispose to cancer initiation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1269-1289"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11893880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370602","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

Muskelin is a substrate adaptor of the highly regulated Drosophila embryonic CTLH E3 ligase.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-20 DOI: 10.1038/s44319-025-00397-6

Chloe A Briney, Jesslyn C Henriksen, Chenwei Lin, Lisa A Jones, Leif Benner, Addison B Rains, Roxana Gutierrez, Philip R Gafken, Olivia S Rissland

{"title":"Muskelin is a substrate adaptor of the highly regulated Drosophila embryonic CTLH E3 ligase.","authors":"Chloe A Briney, Jesslyn C Henriksen, Chenwei Lin, Lisa A Jones, Leif Benner, Addison B Rains, Roxana Gutierrez, Philip R Gafken, Olivia S Rissland","doi":"10.1038/s44319-025-00397-6","DOIUrl":"10.1038/s44319-025-00397-6","url":null,"abstract":"The maternal-to-zygotic transition (MZT) is a conserved developmental process where the maternally-derived protein and mRNA cache is replaced with newly made zygotic gene products. We have previously shown that in Drosophila the deposited RNA-binding proteins ME31B, Cup, and Trailer Hitch are ubiquitylated by the CTLH E3 ligase and cleared. However, the organization and regulation of the CTLH complex remain poorly understood in flies because Drosophila lacks an identifiable substrate adaptor, and the mechanisms restricting the degradation of ME31B and its cofactors to the MZT are unknown. Here, we show that the developmental regulation of the CTLH complex is multi-pronged, including transcriptional control by OVO and autoinhibition of the E3 ligase. One major regulatory target is the subunit Muskelin, which we demonstrate is a substrate adaptor for the Drosophila CTLH complex. Finally, we find that Muskelin has few targets beyond the three known RNA-binding proteins, showing exquisite target specificity. Thus, multiple levels of integrated regulation restrict the activity of the embryonic CTLH complex to early embryogenesis, during which time it regulates three important RNA-binding proteins.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1647-1669"},"PeriodicalIF":6.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467371","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

Structure of the MUC5AC VWD3 assembly responsible for the formation of net-like mucin polymers.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-27 DOI: 10.1038/s44319-025-00395-8

Sergio Trillo-Muyo, Anna Ermund, Gunnar C Hansson

引用次数: 0