EMBO Reports最新文献_第9页

The proximity-based protein interactome and regulatory logics of the transcription factor p65 NF-κB/RELA. 转录因子p65 NF-κB/RELA的邻近蛋白相互作用及其调控逻辑。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-03 DOI: 10.1038/s44319-024-00339-8

Lisa Leib, Jana Juli, Liane Jurida, Christin Mayr-Buro, Jasmin Priester, Hendrik Weiser, Stefanie Wirth, Simon Hanel, Daniel Heylmann, Axel Weber, M Lienhard Schmitz, Argyris Papantonis, Marek Bartkuhn, Jochen Wilhelm, Uwe Linne, Johanna Meier-Soelch, Michael Kracht

{"title":"The proximity-based protein interactome and regulatory logics of the transcription factor p65 NF-κB/RELA.","authors":"Lisa Leib, Jana Juli, Liane Jurida, Christin Mayr-Buro, Jasmin Priester, Hendrik Weiser, Stefanie Wirth, Simon Hanel, Daniel Heylmann, Axel Weber, M Lienhard Schmitz, Argyris Papantonis, Marek Bartkuhn, Jochen Wilhelm, Uwe Linne, Johanna Meier-Soelch, Michael Kracht","doi":"10.1038/s44319-024-00339-8","DOIUrl":"10.1038/s44319-024-00339-8","url":null,"abstract":"The protein interactome of p65/RELA, the most active subunit of the transcription factor (TF) NF-κB, has not been previously determined in living cells. Using p65-miniTurbo fusion proteins and biotin tagging, we identify >350 RELA interactors from untreated and IL-1α-stimulated cells, including many TFs (47% of all interactors) and >50 epigenetic regulators belonging to different classes of chromatin remodeling complexes. A comparison with the interactomes of two point mutants of p65 reveals that the interactions primarily require intact dimerization rather than DNA-binding properties. A targeted RNAi screen for 38 interactors and subsequent functional transcriptome and bioinformatics studies identify gene regulatory (sub)networks, each controlled by RELA in combination with one of the TFs ZBTB5, GLIS2, TFE3/TFEB, or S100A8/A9. The large, dynamic and versatile high-resolution interactome of RELA and its gene regulatory logics provides a rich resource and a new framework for explaining how RELA cooperativity determines gene expression patterns.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"1144-1183"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926559","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

Nuclear PD-L1 triggers tumour-associated inflammation upon DNA damage. 核PD-L1在DNA损伤时触发肿瘤相关炎症。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44319-024-00354-9

Naoe T Nihira, Wenwen Wu, Mitsue Hosoi, Yukiko Togashi, Shigeaki Sunada, Yasuo Miyoshi, Yoshio Miki, Tomohiko Ohta

{"title":"Nuclear PD-L1 triggers tumour-associated inflammation upon DNA damage.","authors":"Naoe T Nihira, Wenwen Wu, Mitsue Hosoi, Yukiko Togashi, Shigeaki Sunada, Yasuo Miyoshi, Yoshio Miki, Tomohiko Ohta","doi":"10.1038/s44319-024-00354-9","DOIUrl":"10.1038/s44319-024-00354-9","url":null,"abstract":"Immune checkpoint inhibitors against PD-1/PD-L1 are highly effective in immunologically hot tumours such as triple-negative breast cancer, wherein constitutive DNA damage promotes inflammation, while inducing PD-L1 expression to avoid attack by cytotoxic T cells. However, whether and how PD-L1 regulates the DNA damage response and inflammation remains unclear. Here, we show that nuclear PD-L1 activates the ATR-Chk1 pathway and induces proinflammatory chemocytokines upon genotoxic stress. PD-L1 interacts with ATR and is essential for Chk1 activation and chromatin binding. cGAS-STING and NF-κB activation in the late phase of the DNA damage response is inhibited by PD-L1 deletion or by inhibitors of ATR and Chk1. Consequently, the induction of proinflammatory chemocytokines at this stage is inhibited by deletion of PD-L1, but restored by the ATR activator Garcinone C. Inhibition of nuclear localisation by PD-L1 mutations or the HDAC2 inhibitor Santacruzamate A inhibits chemocytokine induction. Conversely, the p300 inhibitor C646, which accelerates PD-L1 nuclear localisation, promotes chemocytokine induction. These findings suggest that nuclear PD-L1 strengthens the properties of hot tumours and contributes to shaping the tumour microenvironment.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"635-655"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921084","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

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 : 2025-02-01 Epub 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":"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":"929-947"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850619/pdf/","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":"OA","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 : 2025-02-01 Epub 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":"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":"1003-1035"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850729/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RudLOV is an optically synchronized cargo transport method revealing unexpected effects of dynasore. RudLOV是一种光学同步的货物运输方式，显示出意想不到的王朝效应。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2024-12-10 DOI: 10.1038/s44319-024-00342-z

Tatsuya Tago, Takumi Ogawa, Yumi Goto, Kiminori Toyooka, Takuro Tojima, Akihiko Nakano, Takunori Satoh, Akiko K Satoh

{"title":"RudLOV is an optically synchronized cargo transport method revealing unexpected effects of dynasore.","authors":"Tatsuya Tago, Takumi Ogawa, Yumi Goto, Kiminori Toyooka, Takuro Tojima, Akihiko Nakano, Takunori Satoh, Akiko K Satoh","doi":"10.1038/s44319-024-00342-z","DOIUrl":"10.1038/s44319-024-00342-z","url":null,"abstract":"Live imaging of secretory cargoes is a powerful method for understanding the mechanisms of membrane trafficking. Inducing the synchronous release of cargoes from an organelle is key for enhancing microscopic observation. We developed an optical cargo-releasing method, 'retention using dark state of LOV2' (RudLOV), which enables precise spatial, temporal, and quantity control during cargo release. A limited amount of cargo-release using RudLOV is able to visualize cargo cisternal-movement and cargo-specific exit sites on the Golgi/trans-Golgi network. Moreover, by controlling the timing of cargo-release using RudLOV, we reveal the canonical and non-canonical effects of the well-known dynamin inhibitor dynasore, which inhibits early- but not late-Golgi transport and exits from the trans-Golgi network where dynamin-2 is active. Accumulation of COPI vesicles at the cis-side of the Golgi stacks in dynasore-treated cells suggests that dynasore targets COPI-uncoating/tethering/fusion machinery in the early-Golgi cisternae or endoplasmic reticulum but not in the late-Golgi cisternae. These results provide insight into the cisternal maturation of Golgi stacks.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"613-634"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806374","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

DYRK4 upregulates antiviral innate immunity by promoting IRF3 activation. DYRK4通过促进IRF3激活来上调抗病毒先天免疫。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2024-12-19 DOI: 10.1038/s44319-024-00352-x

Xianhuang Zeng, Jiaqi Xu, Jiaqi Liu, Yang Liu, Siqi Yang, Junsong Huang, Chengpeng Fan, Mingxiong Guo, Guihong Sun

引用次数: 0

miRNA-target complementarity in cnidarians resembles its counterpart in plants. 刺胞动物中的mirna靶点互补与植物中的mirna靶点互补相似。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44319-024-00350-z

Yael Admoni, Arie Fridrich, Paris K Weavers, Reuven Aharoni, Talya Razin, Miguel Salinas-Saavedra, Michal Rabani, Uri Frank, Yehu Moran

{"title":"miRNA-target complementarity in cnidarians resembles its counterpart in plants.","authors":"Yael Admoni, Arie Fridrich, Paris K Weavers, Reuven Aharoni, Talya Razin, Miguel Salinas-Saavedra, Michal Rabani, Uri Frank, Yehu Moran","doi":"10.1038/s44319-024-00350-z","DOIUrl":"10.1038/s44319-024-00350-z","url":null,"abstract":"microRNAs (miRNAs) are important post-transcriptional regulators that activate silencing mechanisms by annealing to mRNA transcripts. While plant miRNAs match their targets with nearly-full complementarity leading to mRNA cleavage, miRNAs in most animals require only a short sequence called 'seed' to inhibit target translation. Recent findings showed that miRNAs in cnidarians, early-branching metazoans, act similarly to plant miRNAs, by exhibiting full complementarity and target cleavage; however, it remained unknown if seed-based regulation was possible in cnidarians. Here, we investigate the miRNA-target complementarity requirements for miRNA activity in the cnidarian Nematostella vectensis. We show that bilaterian-like complementarity of seed-only or seed and supplementary 3' matches are insufficient for miRNA-mediated knockdown. Furthermore, miRNA-target mismatches in the cleavage site decrease knockdown efficiency. Finally, miRNA silencing of a target with three seed binding sites in the 3' untranslated region that mimics typical miRNA targeting was repressed in zebrafish but not in Nematostella and another cnidarian, Hydractinia symbiolongicarpus. Altogether, these results unravel striking similarities between plant and cnidarian miRNAs supporting a possible common evolutionary origin of miRNAs in plants and animals.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"836-859"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921065","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

RAGE is a key regulator of ductular reaction-mediated fibrosis during cholestasis. RAGE是胆汁淤积期间导管反应介导纤维化的关键调节因子。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44319-024-00356-7

Wai-Ling Macrina Lam, Gisela Gabernet, Tanja Poth, Melanie Sator-Schmitt, Morgana Barroso Oquendo, Bettina Kast, Sabrina Lohr, Aurora de Ponti, Lena Weiß, Martin Schneider, Dominic Helm, Karin Müller-Decker, Peter Schirmacher, Mathias Heikenwälder, Ursula Klingmüller, Doris Schneller, Fabian Geisler, Sven Nahnsen, Peter Angel

{"title":"RAGE is a key regulator of ductular reaction-mediated fibrosis during cholestasis.","authors":"Wai-Ling Macrina Lam, Gisela Gabernet, Tanja Poth, Melanie Sator-Schmitt, Morgana Barroso Oquendo, Bettina Kast, Sabrina Lohr, Aurora de Ponti, Lena Weiß, Martin Schneider, Dominic Helm, Karin Müller-Decker, Peter Schirmacher, Mathias Heikenwälder, Ursula Klingmüller, Doris Schneller, Fabian Geisler, Sven Nahnsen, Peter Angel","doi":"10.1038/s44319-024-00356-7","DOIUrl":"10.1038/s44319-024-00356-7","url":null,"abstract":"Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with an increased risk of fibrosis and liver failure. The receptor for advanced glycation end products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remain elusive. Here, we delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing and in vitro analyses, we reveal a role for BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Notch ligand Jagged1 is secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"880-907"},"PeriodicalIF":6.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921113","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

The dynamics of loss of heterozygosity events in genomes. 基因组中杂合性事件丢失的动力学。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1038/s44319-024-00353-w

Abhishek Dutta, Joseph Schacherer

引用次数: 0

Soul Men and Women-what must science do to regain public trust? 灵魂男女--科学必须做些什么才能重新赢得公众的信任？

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-01-01 Epub Date: 2024-11-20 DOI: 10.1038/s44319-024-00325-0

Arthur Caplan

引用次数: 0