EMBO Reports最新文献_第9页

O-GlcNAcylation mediates Wnt-stimulated bone formation by rewiring aerobic glycolysis. O-GlcNAcylation通过重新连接有氧糖酵解介导Wnt刺激的骨形成。

IF 7.7 1区生物学

EMBO Reports Pub Date : 2024-09-10 DOI: 10.1038/s44319-024-00237-z

Chengjia You,Fangyuan Shen,Puying Yang,Jingyao Cui,Qiaoyue Ren,Moyu Liu,Yujie Hu,Boer Li,Ling Ye,Yu Shi

{"title":"O-GlcNAcylation mediates Wnt-stimulated bone formation by rewiring aerobic glycolysis.","authors":"Chengjia You,Fangyuan Shen,Puying Yang,Jingyao Cui,Qiaoyue Ren,Moyu Liu,Yujie Hu,Boer Li,Ling Ye,Yu Shi","doi":"10.1038/s44319-024-00237-z","DOIUrl":"https://doi.org/10.1038/s44319-024-00237-z","url":null,"abstract":"Wnt signaling is an important target for anabolic therapies in osteoporosis. A sclerostin-neutralizing antibody (Scl-Ab), that blocks the Wnt signaling inhibitor (sclerostin), has been shown to promote bone mass in animal models and clinical studies. However, the cellular mechanisms by which Wnt signaling promotes osteogenesis remain to be further investigated. O-GlcNAcylation, a dynamic post-translational modification of proteins, controls multiple critical biological processes including transcription, translation, and cell fate determination. Here, we report that Wnt3a either induces O-GlcNAcylation rapidly via the Ca2+-PKA-Gfat1 axis, or increases it in a Wnt-β-catenin-dependent manner following prolonged stimulation. Importantly, we find O-GlcNAcylation indispensable for osteoblastogenesis both in vivo and in vitro. Genetic ablation of O-GlcNAcylation in the osteoblast-lineage diminishes bone formation and delays bone fracture healing in response to Wnt stimulation in vivo. Mechanistically, Wnt3a induces O-GlcNAcylation at Serine 174 of PDK1 to stabilize the protein, resulting in increased glycolysis and osteogenesis. These findings highlight O-GlcNAcylation as an important mechanism regulating Wnt-induced glucose metabolism and bone anabolism.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227579","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

O-GlcNAcylation in the osteoblast lineage-boosting the complexity of Wnt-stimulated bone formation. 成骨细胞谱系中的 O-GlcNAcylation 促进了 Wnt 刺激骨形成的复杂性。

IF 7.7 1区生物学

EMBO Reports Pub Date : 2024-09-10 DOI: 10.1038/s44319-024-00242-2

Sandra Pohl,Thorsten Schinke

引用次数: 0

Gene therapy for epilepsy targeting neuropeptide Y and its Y2 receptor to dentate gyrus granule cells. 针对齿状回颗粒细胞神经肽 Y 及其 Y2 受体的癫痫基因疗法。

IF 7.7 1区生物学

EMBO Reports Pub Date : 2024-09-09 DOI: 10.1038/s44319-024-00244-0

Stefano Cattaneo,Barbara Bettegazzi,Lucia Crippa,Laila Asth,Maria Regoni,Marie Soukupova,Silvia Zucchini,Alessio Cantore,Franca Codazzi,Flavia Valtorta,Michele Simonato

{"title":"Gene therapy for epilepsy targeting neuropeptide Y and its Y2 receptor to dentate gyrus granule cells.","authors":"Stefano Cattaneo,Barbara Bettegazzi,Lucia Crippa,Laila Asth,Maria Regoni,Marie Soukupova,Silvia Zucchini,Alessio Cantore,Franca Codazzi,Flavia Valtorta,Michele Simonato","doi":"10.1038/s44319-024-00244-0","DOIUrl":"https://doi.org/10.1038/s44319-024-00244-0","url":null,"abstract":"Gene therapy is emerging as an alternative option for individuals with drug-resistant focal epilepsy. Here, we explore the potential of a novel gene therapy based on Neuropeptide Y (NPY), a well-known endogenous anticonvulsant. We develop a lentiviral vector co-expressing NPY with its inhibitory receptor Y2 in which, for the first time, both transgenes are placed under the control of the minimal CamKIIa(0.4) promoter, biasing expression toward excitatory neurons and allowing autoregulation of neuronal excitability by Y2 receptor-mediated inhibition. Vector-induced NPY and Y2 expression and safety are first assessed in cultures of hippocampal neurons. In vivo experiments demonstrate efficient and nearly selective overexpression of both genes in granule cell mossy fiber terminals following vector administration in the dentate gyrus. Telemetry video-EEG monitoring reveals a reduction in the frequency and duration of seizures in the synapsin triple KO model. This study shows that targeting a small subset of neurons (hippocampal granule cells) with a combined overexpression of NPY and Y2 receptor is sufficient to reduce the occurrence of spontaneous seizures.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178892","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

SPIN1 facilitates chemoresistance and HR repair by promoting Tip60 binding to H3K9me3. SPIN1 通过促进 Tip60 与 H3K9me3 的结合，促进化疗抗性和 HR 修复。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-01 DOI: 10.1038/s44319-024-00219-1

Yukun Wang, Mengyao Li, Yuhan Chen, Yuhan Jiang, Ziyu Zhang, Zhenzhen Yan, Xiuhua Liu, Chen Wu

引用次数: 0

Identification of resistance mechanisms to small-molecule inhibition of TEAD-regulated transcription. 鉴定小分子抑制 TEAD 调控转录的抗性机制。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI: 10.1038/s44319-024-00217-3

Aishwarya Kulkarni, Varshini Mohan, Tracy T Tang, Leonard Post, Yih-Chih Chan, Murray Manning, Niko Thio, Benjamin L Parker, Mark A Dawson, Joseph Rosenbluh, Joseph Ha Vissers, Kieran F Harvey

{"title":"Identification of resistance mechanisms to small-molecule inhibition of TEAD-regulated transcription.","authors":"Aishwarya Kulkarni, Varshini Mohan, Tracy T Tang, Leonard Post, Yih-Chih Chan, Murray Manning, Niko Thio, Benjamin L Parker, Mark A Dawson, Joseph Rosenbluh, Joseph Ha Vissers, Kieran F Harvey","doi":"10.1038/s44319-024-00217-3","DOIUrl":"10.1038/s44319-024-00217-3","url":null,"abstract":"The Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors. By exploring gene expression programs of mutant cells, we find that MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ target genes. Consistent with this, combined inhibition of TEAD and the MAPK kinase MEK, synergistically blocks proliferation of multiple mesothelioma and lung cancer cell lines and more potently reduces the growth of patient-derived lung cancer xenografts in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893175","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

Inflated expectations: the strange craze for translational research on aging : Given existing confusion about the basic science of aging, why the high optimism in the private sector about the prospects of developing anti-aging treatments? 夸大的期望：衰老转化研究的奇怪热潮：既然衰老的基础科学存在困惑，为什么私营部门对开发抗衰老疗法的前景高度乐观？

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-16 DOI: 10.1038/s44319-024-00226-2

David Gems, Simon Okholm, Maёl Lemoine

引用次数: 0

Combination of AID2 and BromoTag expands the utility of degron-based protein knockdowns. AID2 与 BromoTag 的结合拓展了基于降解子的蛋白质敲除技术的用途。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-23 DOI: 10.1038/s44319-024-00224-4

Yuki Hatoyama, Moutushi Islam, Adam G Bond, Ken-Ichiro Hayashi, Alessio Ciulli, Masato T Kanemaki

{"title":"Combination of AID2 and BromoTag expands the utility of degron-based protein knockdowns.","authors":"Yuki Hatoyama, Moutushi Islam, Adam G Bond, Ken-Ichiro Hayashi, Alessio Ciulli, Masato T Kanemaki","doi":"10.1038/s44319-024-00224-4","DOIUrl":"10.1038/s44319-024-00224-4","url":null,"abstract":"Acute protein knockdown is a powerful approach to dissecting protein function in dynamic cellular processes. We previously reported an improved auxin-inducible degron system, AID2, but recently noted that its ability to induce degradation of some essential replication factors, such as ORC1 and CDC6, was not enough to induce lethality. Here, we present combinational degron technologies to control two proteins or enhance target depletion. For this purpose, we initially compare PROTAC-based degrons, dTAG and BromoTag, with AID2 to reveal their key features and then demonstrate control of cohesin and condensin with AID2 and BromoTag, respectively. We develop a double-degron system with AID2 and BromoTag to enhance target depletion and accelerate depletion kinetics and demonstrate that both ORC1 and CDC6 are pivotal for MCM loading. Finally, we show that co-depletion of ORC1 and CDC6 by the double-degron system completely suppresses DNA replication, and the cells enter mitosis with single-chromatid chromosomes, indicating that DNA replication is uncoupled from cell cycle control. Our combinational degron technologies will expand the application scope for functional analyses.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046469","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 septin cytoskeleton is required for plasma membrane repair. 质膜修复需要 septin 细胞骨架。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-07-05 DOI: 10.1038/s44319-024-00195-6

M Isabella Prislusky, Jonathan G T Lam, Viviana Ruiz Contreras, Marilynn Ng, Madeline Chamberlain, Sarika Pathak-Sharma, Madalyn Fields, Xiaoli Zhang, Amal O Amer, Stephanie Seveau

{"title":"The septin cytoskeleton is required for plasma membrane repair.","authors":"M Isabella Prislusky, Jonathan G T Lam, Viviana Ruiz Contreras, Marilynn Ng, Madeline Chamberlain, Sarika Pathak-Sharma, Madalyn Fields, Xiaoli Zhang, Amal O Amer, Stephanie Seveau","doi":"10.1038/s44319-024-00195-6","DOIUrl":"10.1038/s44319-024-00195-6","url":null,"abstract":"Plasma membrane repair is a fundamental homeostatic process of eukaryotic cells. Here, we report a new function for the conserved cytoskeletal proteins known as septins in the repair of cells perforated by pore-forming toxins or mechanical disruption. Using a silencing RNA screen, we identified known repair factors (e.g. annexin A2, ANXA2) and novel factors such as septin 7 (SEPT7) that is essential for septin assembly. Upon plasma membrane injury, the septin cytoskeleton is extensively redistributed to form submembranous domains arranged as knob and loop structures containing F-actin, myosin IIA, S100A11, and ANXA2. Formation of these domains is Ca2+-dependent and correlates with plasma membrane repair efficiency. Super-resolution microscopy revealed that septins and F-actin form intertwined filaments associated with ANXA2. Depletion of SEPT7 prevented ANXA2 recruitment and formation of submembranous actomyosin domains. However, ANXA2 depletion had no effect on domain formation. Collectively, our data support a novel septin-based mechanism for resealing damaged cells, in which the septin cytoskeleton plays a key structural role in remodeling the plasma membrane by promoting the formation of SEPT/F-actin/myosin IIA/ANXA2/S100A11 repair domains.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537727","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

Interactome of the HIV-1 proteome and human host RNA. HIV-1 蛋白质组与人类宿主 RNA 的相互作用组。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-09 DOI: 10.1038/s44319-024-00222-6

Tinus Schynkel, Willem van Snippenberg, Kimberly Verniers, Gwendolyn M Jang, Nevan J Krogan, Pieter Mestdagh, Linos Vandekerckhove, Wim Trypsteen

引用次数: 0

The sound of science : Data sonification has emerged as possible alternative to data visualization. 科学之声：数据声化已成为数据可视化的可能替代方案。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-19 DOI: 10.1038/s44319-024-00230-6

Lutz Bornmann

引用次数: 0