EMBO Reports最新文献_第8页

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 : 2024-10-01 Epub 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":"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":" ","pages":"4311-4336"},"PeriodicalIF":6.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466959/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Espressogate. Espressogate.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-01 Epub Date: 2024-09-16 DOI: 10.1038/s44319-024-00247-x

David R Smith

引用次数: 0

Novel mechanisms of MITF regulation identified in a mouse suppressor screen. 在小鼠抑制因子筛选中发现新的 MITF 调节机制。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-01 Epub Date: 2024-08-21 DOI: 10.1038/s44319-024-00225-3

Hong Nhung Vu, Matti Már Valdimarsson, Sara Sigurbjörnsdóttir, Kristín Bergsteinsdóttir, Julien Debbache, Keren Bismuth, Deborah A Swing, Jón H Hallsson, Lionel Larue, Heinz Arnheiter, Neal G Copeland, Nancy A Jenkins, Petur O Heidarsson, Eiríkur Steingrímsson

{"title":"Novel mechanisms of MITF regulation identified in a mouse suppressor screen.","authors":"Hong Nhung Vu, Matti Már Valdimarsson, Sara Sigurbjörnsdóttir, Kristín Bergsteinsdóttir, Julien Debbache, Keren Bismuth, Deborah A Swing, Jón H Hallsson, Lionel Larue, Heinz Arnheiter, Neal G Copeland, Nancy A Jenkins, Petur O Heidarsson, Eiríkur Steingrímsson","doi":"10.1038/s44319-024-00225-3","DOIUrl":"10.1038/s44319-024-00225-3","url":null,"abstract":"MITF, a basic Helix-Loop-Helix Zipper (bHLHZip) transcription factor, plays vital roles in melanocyte development and functions as an oncogene. We perform a genetic screen for suppressors of the Mitf-associated pigmentation phenotype in mice and identify an intragenic Mitf mutation that terminates MITF at the K316 SUMOylation site, leading to loss of the C-end intrinsically disordered region (IDR). The resulting protein is more nuclear but less stable than wild-type MITF and retains DNA-binding ability. As a dimer, it can translocate wild-type and mutant MITF partners into the nucleus, improving its own stability thus ensuring nuclear MITF supply. smFRET analysis shows interactions between K316 SUMOylation and S409 phosphorylation sites across monomers; these interactions largely explain the observed effects. The recurrent melanoma-associated E318K mutation in MITF, which affects K316 SUMOylation, also alters protein regulation in concert with S409. This suggests that residues K316 and S409 of MITF are impacted by SUMOylation and phosphorylation, respectively, mediating effects on nuclear localization and stability through conformational changes. Our work provides a novel mechanism of genetic suppression, and an example of how apparently deleterious mutations lead to normal phenotypes.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4252-4280"},"PeriodicalIF":6.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016722","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

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 : 2024-10-01 Epub 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":"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":" ","pages":"4358-4386"},"PeriodicalIF":6.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467418/pdf/","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":"OA","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 : 2024-10-01 Epub 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":"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":" ","pages":"4190-4205"},"PeriodicalIF":6.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467438/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Goliath, meet David. 歌利亚，见大卫。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-01 Epub Date: 2024-09-16 DOI: 10.1038/s44319-024-00257-9

K Heran Darwin

引用次数: 0

mTOR signalling controls the formation of smooth muscle cell-derived luminal myofibroblasts during vasculitis. mTOR 信号在脉管炎期间控制平滑肌细胞衍生的管腔肌成纤维细胞的形成。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-01 Epub Date: 2024-09-13 DOI: 10.1038/s44319-024-00251-1

Angus T Stock, Sarah Parsons, Jacinta A Hansen, Damian B D'Silva, Graham Starkey, Aly Fayed, Xin Yi Lim, Rohit D'Costa, Claire L Gordon, Ian P Wicks

{"title":"mTOR signalling controls the formation of smooth muscle cell-derived luminal myofibroblasts during vasculitis.","authors":"Angus T Stock, Sarah Parsons, Jacinta A Hansen, Damian B D'Silva, Graham Starkey, Aly Fayed, Xin Yi Lim, Rohit D'Costa, Claire L Gordon, Ian P Wicks","doi":"10.1038/s44319-024-00251-1","DOIUrl":"10.1038/s44319-024-00251-1","url":null,"abstract":"The accumulation of myofibroblasts within the intimal layer of inflamed blood vessels is a potentially catastrophic complication of vasculitis, which can lead to arterial stenosis and ischaemia. In this study, we have investigated how these luminal myofibroblasts develop during Kawasaki disease (KD), a paediatric vasculitis typically involving the coronary arteries. By performing lineage tracing studies in a murine model of KD, we reveal that luminal myofibroblasts develop independently of adventitial fibroblasts and endothelial cells, and instead derive from smooth muscle cells (SMCs). Notably, the emergence of SMC-derived luminal myofibroblasts-in both mice and patients with KD, Takayasu's arteritis and Giant Cell arteritis-coincided with activation of the mechanistic target of rapamycin (mTOR) signalling pathway. Moreover, SMC-specific deletion of mTOR signalling, or pharmacological inhibition, abrogated the emergence of luminal myofibroblasts. Thus, mTOR is an intrinsic and essential regulator of luminal myofibroblast formation that is activated in vasculitis patients and therapeutically tractable. These findings provide molecular insight into the pathogenesis of coronary artery stenosis and identify mTOR as a therapeutic target in vasculitis.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4570-4593"},"PeriodicalIF":6.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282182","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

Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression. Drp1 剪接变体调控卵巢癌线粒体动力学和肿瘤进展。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-10-01 Epub Date: 2024-08-27 DOI: 10.1038/s44319-024-00232-4

Zaineb Javed, Dong Hui Shin, Weihua Pan, Sierra R White, Amal Taher Elhaw, Yeon Soo Kim, Shriya Kamlapurkar, Ya-Yun Cheng, J Cory Benson, Ahmed Emam Abdelnaby, Rébécca Phaëton, Hong-Gang Wang, Shengyu Yang, Mara L G Sullivan, Claudette M St Croix, Simon C Watkins, Steven J Mullett, Stacy L Gelhaus, Nam Lee, Lan G Coffman, Katherine M Aird, Mohamed Trebak, Karthikeyan Mythreye, Vonn Walter, Nadine Hempel

{"title":"Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.","authors":"Zaineb Javed, Dong Hui Shin, Weihua Pan, Sierra R White, Amal Taher Elhaw, Yeon Soo Kim, Shriya Kamlapurkar, Ya-Yun Cheng, J Cory Benson, Ahmed Emam Abdelnaby, Rébécca Phaëton, Hong-Gang Wang, Shengyu Yang, Mara L G Sullivan, Claudette M St Croix, Simon C Watkins, Steven J Mullett, Stacy L Gelhaus, Nam Lee, Lan G Coffman, Katherine M Aird, Mohamed Trebak, Karthikeyan Mythreye, Vonn Walter, Nadine Hempel","doi":"10.1038/s44319-024-00232-4","DOIUrl":"10.1038/s44319-024-00232-4","url":null,"abstract":"Aberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4281-4310"},"PeriodicalIF":6.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079668","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

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 : 2024-10-01 Epub 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

{"title":"HIV-1 Vpu induces neurotoxicity by promoting Caspase 3-dependent cleavage of TDP-43.","authors":"Jiaxin Yang, Yan Li, Huili Li, Haichen Zhang, Haoran Guo, Xiangyu Zheng, Xiao-Fang Yu, Wei Wei","doi":"10.1038/s44319-024-00238-y","DOIUrl":"10.1038/s44319-024-00238-y","url":null,"abstract":"Despite the efficacy of highly active antiretroviral therapy in controlling the incidence and mortality of AIDS, effective interventions for HIV-1-induced neurological damage and cognitive impairment remain elusive. In this study, we found that HIV-1 infection can induce proteolytic cleavage and aberrant aggregation of TAR DNA-binding protein 43 (TDP-43), a pathological protein associated with various severe neurological disorders. The HIV-1 accessory protein Vpu was found to be responsible for the cleavage of TDP-43, as ectopic expression of Vpu alone was sufficient to induce TDP-43 cleavage, whereas HIV-1 lacking Vpu failed to cleave TDP-43. Mechanistically, the cleavage of TDP-43 at Asp89 by HIV-1 relies on Vpu-mediated activation of Caspase 3, and pharmacological inhibition of Caspase 3 activity effectively suppressed the HIV-1-induced aggregation and neurotoxicity of TDP-43. Overall, these results suggest that TDP-43 is a conserved host target of HIV-1 Vpu and provide evidence for the involvement of TDP-43 dysregulation in the neural pathogenesis of HIV-1.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"4337-4357"},"PeriodicalIF":6.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145318","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

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 : 2024-10-01 Epub 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