EMBO Reports最新文献

CaMKII suppresses proteotoxicity by phosphorylating BAG3 in response to proteasomal dysfunction. CaMKII 在蛋白酶体功能失调时通过磷酸化 BAG3 来抑制蛋白毒性。

IF 7.7 1区生物学

EMBO Reports Pub Date : 2024-09-11 DOI: 10.1038/s44319-024-00248-w

Chenliang Zhang,Huanji Xu,Qiulin Tang,Yichun Duan,Hongwei Xia,Huixi Huang,Di Ye,Feng Bi

{"title":"CaMKII suppresses proteotoxicity by phosphorylating BAG3 in response to proteasomal dysfunction.","authors":"Chenliang Zhang,Huanji Xu,Qiulin Tang,Yichun Duan,Hongwei Xia,Huixi Huang,Di Ye,Feng Bi","doi":"10.1038/s44319-024-00248-w","DOIUrl":"https://doi.org/10.1038/s44319-024-00248-w","url":null,"abstract":"Protein quality control serves as the primary defense mechanism for cells against proteotoxicity induced by proteasome dysfunction. While cells can limit the build-up of ubiquitinated misfolded proteins during proteasome inhibition, the precise mechanism is unclear. Here, we find that protein kinase Ca2+/Calmodulin (CaM)-dependent protein kinase II (CaMKII) maintains proteostasis during proteasome inhibition. We show that proteasome inhibition activates CaMKII, which phosphorylates B-cell lymphoma 2 (Bcl-2)-associated athanogene 3 (BAG3) at residues S173, S377, and S386. Phosphorylated BAG3 activates the heme-regulated inhibitor (HRI)- eukaryotic initiation factor-2α (eIF2α) signaling pathway, suppressing protein synthesis and the production of aggregated ubiquitinated misfolded proteins, ultimately mitigating the proteotoxic crisis. Inhibition of CaMKII exacerbates the accumulation of aggregated misfolded proteins and paraptosis induced by proteasome inhibitors. Based on these findings, we validate that combined targeting of proteasome and CaMKII accelerates tumor cell death and enhances the efficacy of proteasome inhibitors in tumor treatment. Our data unveil a new proteasomal inhibition-induced misfolded protein quality control mechanism and propose a novel therapeutic intervention for proteasome inhibitor-mediated tumor treatment.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":7.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178889","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

Terminal α1,2-fucosylation of glycosphingolipids by FUT1 is a key regulator in early cell-fate decisions. FUT1对糖磷脂的末端α1,2-岩藻糖基化是早期细胞命运决定的关键调节因子。

IF 7.7 1区生物学

EMBO Reports Pub Date : 2024-09-10 DOI: 10.1038/s44319-024-00243-1

Saray Chen,Dana Hayoun-Neeman,Michal Nagar,Sapir Pinyan,Limor Hadad,Liat Yaacobov,Lilach Alon,Liraz Efrat Shachar,Tair Swissa,Olga Kryukov,Orly Gershoni-Yahalom,Benyamin Rosental,Smadar Cohen,Rachel G Lichtenstein

{"title":"Terminal α1,2-fucosylation of glycosphingolipids by FUT1 is a key regulator in early cell-fate decisions.","authors":"Saray Chen,Dana Hayoun-Neeman,Michal Nagar,Sapir Pinyan,Limor Hadad,Liat Yaacobov,Lilach Alon,Liraz Efrat Shachar,Tair Swissa,Olga Kryukov,Orly Gershoni-Yahalom,Benyamin Rosental,Smadar Cohen,Rachel G Lichtenstein","doi":"10.1038/s44319-024-00243-1","DOIUrl":"https://doi.org/10.1038/s44319-024-00243-1","url":null,"abstract":"The embryonic cell surface is rich in glycosphingolipids (GSLs), which change during differentiation. The reasons for GSL subgroup variation during early embryogenesis remain elusive. By combining genomic approaches, flow cytometry, confocal imaging, and transcriptomic data analysis, we discovered that α1,2-fucosylated GSLs control the differentiation of human pluripotent cells (hPCs) into germ layer tissues. Overexpression of α1,2-fucosylated GSLs disrupts hPC differentiation into mesodermal lineage and reduces differentiation into cardiomyocytes. Conversely, reducing α1,2-fucosylated groups promotes hPC differentiation and mesoderm commitment in response to external signals. We find that bone morphogenetic protein 4 (BMP4), a mesodermal gene inducer, suppresses α1,2-fucosylated GSL expression. Overexpression of α1,2-fucosylated GSLs impairs SMAD activation despite BMP4 presence, suggesting α-fucosyl end groups as BMP pathway regulators. Additionally, the absence of α1,2-fucosylated GSLs in early/late mesoderm and primitive streak stages in mouse embryos aligns with the hPC results. Thus, α1,2-fucosylated GSLs may regulate early cell-fate decisions and embryo development by modulating cell signaling.","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":"142178890","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 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

Activation of an atypical plant NLR with an N-terminal deletion initiates cell death at the vacuole. 激活一种 N 端缺失的非典型植物 NLR 会导致细胞在液泡中死亡。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-06 DOI: 10.1038/s44319-024-00240-4

Sruthi Sunil, Simon Beeh, Eva Stöbbe, Kathrin Fischer, Franziska Wilhelm, Aron Meral, Celia Paris, Luisa Teasdale, Zhihao Jiang, Lisha Zhang, Moritz Urban, Emmanuel Aguilar Parras, Thorsten Nürnberger, Detlef Weigel, Rosa Lozano-Duran, Farid El Kasmi

{"title":"Activation of an atypical plant NLR with an N-terminal deletion initiates cell death at the vacuole.","authors":"Sruthi Sunil, Simon Beeh, Eva Stöbbe, Kathrin Fischer, Franziska Wilhelm, Aron Meral, Celia Paris, Luisa Teasdale, Zhihao Jiang, Lisha Zhang, Moritz Urban, Emmanuel Aguilar Parras, Thorsten Nürnberger, Detlef Weigel, Rosa Lozano-Duran, Farid El Kasmi","doi":"10.1038/s44319-024-00240-4","DOIUrl":"https://doi.org/10.1038/s44319-024-00240-4","url":null,"abstract":"Plants evolve nucleotide-binding leucine-rich repeat receptors (NLRs) to induce immunity. Activated coiled-coil (CC) domain containing NLRs (CNLs) oligomerize and form apparent cation channels promoting calcium influx and cell death, with the alpha-1 helix of the individual CC domains penetrating the plasma membranes. Some CNLs are characterized by putative N-myristoylation and S-acylation sites in their CC domain, potentially mediating permanent membrane association. Whether activated Potentially Membrane Localized NLRs (PMLs) mediate cell death and calcium influx in a similar way is unknown. We uncovered the cell-death function at the vacuole of an atypical but conserved Arabidopsis PML, PML5, which has a significant deletion in its CCG10/GA domain. Active PML5 oligomers localize in Golgi membranes and the tonoplast, alter vacuolar morphology, and induce cell death, with the short N-terminus being sufficient. Mutant analysis supports a potential role of PMLs in plant immunity. PML5-like deletions are found in several Brassicales paralogs, pointing to the evolutionary importance of this innovation. PML5, with its minimal CC domain, represents the first identified CNL utilizing vacuolar-stored calcium for cell death induction.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145317","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

Molecular mechanism of β-arrestin-2 pre-activation by phosphatidylinositol 4,5-bisphosphate. 4,5-二磷酸磷脂酰肌醇预激活 β-阿瑞斯汀-2的分子机制

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-06 DOI: 10.1038/s44319-024-00239-x

Kiae Kim, Ka Young Chung

{"title":"Molecular mechanism of β-arrestin-2 pre-activation by phosphatidylinositol 4,5-bisphosphate.","authors":"Kiae Kim, Ka Young Chung","doi":"10.1038/s44319-024-00239-x","DOIUrl":"https://doi.org/10.1038/s44319-024-00239-x","url":null,"abstract":"Phosphorylated residues of G protein-coupled receptors bind to the N-domain of arrestin, resulting in the release of its C-terminus. This induces further allosteric conformational changes, such as polar core disruption, alteration of interdomain loops, and domain rotation, which transform arrestins into the receptor-activated state. It is widely accepted that arrestin activation occurs by conformational changes propagated from the N- to the C-domain. However, recent studies have revealed that binding of phosphatidylinositol 4,5-bisphosphate (PIP2) to the C-domain transforms arrestins into a pre-active state. Here, we aimed to elucidate the mechanisms underlying PIP2-induced arrestin pre-activation. We compare the conformational changes of β-arrestin-2 upon binding of PIP2 or phosphorylated C-tail peptide of vasopressin receptor type 2 using hydrogen/deuterium exchange mass spectrometry (HDX-MS). Introducing point mutations on the potential routes of the allosteric conformational changes and analyzing these mutant constructs with HDX-MS reveals that PIP2-binding at the C-domain affects the back loop, which destabilizes the gate loop and βXX to transform β-arrestin-2 into the pre-active state.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145319","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

HIV-1 Vpu induces neurotoxicity by promoting Caspase 3-dependent cleavage of TDP-43. HIV-1 Vpu 通过促进 Caspase 3 依赖性裂解 TDP-43 来诱导神经毒性。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-06 DOI: 10.1038/s44319-024-00238-y

Jiaxin Yang, Yan Li, Huili Li, Haichen Zhang, Haoran Guo, Xiangyu Zheng, Xiao-Fang Yu, Wei Wei

引用次数: 0

Ubiquitylation of nucleic acids by DELTEX ubiquitin E3 ligase DTX3L. DELTEX 泛素 E3 连接酶 DTX3L 对核酸的泛素化。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-06 DOI: 10.1038/s44319-024-00235-1

Kang Zhu, Chatrin Chatrin, Marcin J Suskiewicz, Vincent Aucagne, Benjamin Foster, Benedikt M Kessler, Ian Gibbs-Seymour, Dragana Ahel, Ivan Ahel

引用次数: 0

An hepatitis B and D virus infection model using human pluripotent stem cell-derived hepatocytes. 利用人体多能干细胞衍生肝细胞建立乙型和丁型肝炎病毒感染模型。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-04 DOI: 10.1038/s44319-024-00236-0

Huanting Chi, Bingqian Qu, Angga Prawira, Talisa Richardt, Lars Maurer, Jungen Hu, Rebecca M Fu, Florian A Lempp, Zhenfeng Zhang, Dirk Grimm, Xianfang Wu, Stephan Urban, Viet Loan Dao Thi

{"title":"An hepatitis B and D virus infection model using human pluripotent stem cell-derived hepatocytes.","authors":"Huanting Chi, Bingqian Qu, Angga Prawira, Talisa Richardt, Lars Maurer, Jungen Hu, Rebecca M Fu, Florian A Lempp, Zhenfeng Zhang, Dirk Grimm, Xianfang Wu, Stephan Urban, Viet Loan Dao Thi","doi":"10.1038/s44319-024-00236-0","DOIUrl":"https://doi.org/10.1038/s44319-024-00236-0","url":null,"abstract":"Current culture systems available for studying hepatitis D virus (HDV) are suboptimal. In this study, we demonstrate that hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) are fully permissive to HDV infection across various tested genotypes. When co-infected with the helper hepatitis B virus (HBV) or transduced to express the HBV envelope protein HBsAg, HLCs effectively release infectious progeny virions. We also show that HBsAg-expressing HLCs support the extracellular spread of HDV, thus providing a valuable platform for testing available anti-HDV regimens. By challenging the cells along the differentiation with HDV infection, we have identified CD63 as a potential HDV co-entry factor that was rate-limiting for HDV infection in immature hepatocytes. Given their renewable source and the potential to derive hPSCs from individual patients, we propose HLCs as a promising model for investigating HDV biology. Our findings offer new insights into HDV infection and expand the repertoire of research tools available for the development of therapeutic interventions.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":null,"pages":null},"PeriodicalIF":6.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132171","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