EMBO Reports最新文献_第10页

Embryonic stem cells maintain high origin activity and slow forks to coordinate replication with cell cycle progression. 胚胎干细胞保持高起源活性和慢叉，以协调复制和细胞周期进展。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-07-25 DOI: 10.1038/s44319-024-00207-5

Kiminori Kurashima, Yasunao Kamikawa, Tomomi Tsubouchi

{"title":"Embryonic stem cells maintain high origin activity and slow forks to coordinate replication with cell cycle progression.","authors":"Kiminori Kurashima, Yasunao Kamikawa, Tomomi Tsubouchi","doi":"10.1038/s44319-024-00207-5","DOIUrl":"10.1038/s44319-024-00207-5","url":null,"abstract":"Embryonic stem (ES) cells are pluripotent stem cells that can produce all cell types of an organism. ES cells proliferate rapidly and are thought to experience high levels of intrinsic replication stress. Here, by investigating replication fork dynamics in substages of S phase, we show that mammalian pluripotent stem cells maintain a slow fork speed and high active origin density throughout the S phase, with little sign of fork pausing. In contrast, the fork speed of non-pluripotent cells is slow at the beginning of S phase, accompanied by increased fork pausing, but thereafter fork pausing rates decline and fork speed rates accelerate in an ATR-dependent manner. Thus, replication fork dynamics within the S phase are distinct between ES and non-ES cells. Nucleoside addition can accelerate fork speed and reduce origin density. However, this causes miscoordination between the completion of DNA replication and cell cycle progression, leading to genome instability. Our study indicates that fork slowing in the pluripotent stem cells is an integral aspect of DNA replication.","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/PMC11387781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757804","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

Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice. 基于粘膜 IFNλ1 mRNA 的免疫调节可有效降低 SARS-CoV-2 诱导的小鼠死亡率。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-07-26 DOI: 10.1038/s44319-024-00216-4

Anna Macht, Yiqi Huang, Line S Reinert, Vincent Grass, Kristin Lohmer, Elke Tatjana Aristizabal Prada, Eveline Babel, Alexandra Semmler, Wen Zhang, Andrea Wegner, Eva Lichtenegger-Hartl, Sonja Haas, Günther Hasenpusch, Steffen Meyer, Søren R Paludan, Andreas Pichlmair, Carsten Rudolph, Thomas Langenickel

{"title":"Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice.","authors":"Anna Macht, Yiqi Huang, Line S Reinert, Vincent Grass, Kristin Lohmer, Elke Tatjana Aristizabal Prada, Eveline Babel, Alexandra Semmler, Wen Zhang, Andrea Wegner, Eva Lichtenegger-Hartl, Sonja Haas, Günther Hasenpusch, Steffen Meyer, Søren R Paludan, Andreas Pichlmair, Carsten Rudolph, Thomas Langenickel","doi":"10.1038/s44319-024-00216-4","DOIUrl":"10.1038/s44319-024-00216-4","url":null,"abstract":"RNA vaccines elicit protective immunity against SARS-CoV-2, but the use of mRNA as an antiviral immunotherapeutic is unexplored. Here, we investigate the activity of lipidoid nanoparticle (LNP)-formulated mRNA encoding human IFNλ1 (ETH47), which is a critical driver of innate immunity at mucosal surfaces protecting from viral infections. IFNλ1 mRNA administration promotes dose-dependent protein translation, induction of interferon-stimulated genes without relevant signs of unspecific immune stimulation, and dose-dependent inhibition of SARS-CoV-2 replication in vitro. Pulmonary administration of IFNλ1 mRNA in mice results in a potent reduction of virus load, virus-induced body weight loss and significantly increased survival. These data support the development of inhaled administration of IFNλ1 mRNA as a potential prophylactic option for individuals exposed to SARS-CoV-2 or at risk suffering from COVID-19. Based on the broad antiviral activity of IFNλ1 regardless of virus or variant, this approach might also be utilized for other respiratory viral infections or pandemic preparedness.","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/PMC11387833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765737","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

BCL-2 and BOK regulate apoptosis by interaction of their C-terminal transmembrane domains. BCL-2 和 BOK 通过其 C 端跨膜结构域的相互作用调节细胞凋亡。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-07-24 DOI: 10.1038/s44319-024-00206-6

Tobias B Beigl, Alexander Paul, Thomas P Fellmeth, Dang Nguyen, Lynn Barber, Sandra Weller, Benjamin Schäfer, Bernhard F Gillissen, Walter E Aulitzky, Hans-Georg Kopp, Markus Rehm, David W Andrews, Kristyna Pluhackova, Frank Essmann

{"title":"BCL-2 and BOK regulate apoptosis by interaction of their C-terminal transmembrane domains.","authors":"Tobias B Beigl, Alexander Paul, Thomas P Fellmeth, Dang Nguyen, Lynn Barber, Sandra Weller, Benjamin Schäfer, Bernhard F Gillissen, Walter E Aulitzky, Hans-Georg Kopp, Markus Rehm, David W Andrews, Kristyna Pluhackova, Frank Essmann","doi":"10.1038/s44319-024-00206-6","DOIUrl":"10.1038/s44319-024-00206-6","url":null,"abstract":"The Bcl-2 family controls apoptosis by direct interactions of pro- and anti-apoptotic proteins. The principle mechanism is binding of the BH3 domain of pro-apoptotic proteins to the hydrophobic groove of anti-apoptotic siblings, which is therapeutically exploited by approved BH3-mimetic anti-cancer drugs. Evidence suggests that also the transmembrane domain (TMD) of Bcl-2 proteins can mediate Bcl-2 interactions. We developed a highly-specific split luciferase assay enabling the analysis of TMD interactions of pore-forming apoptosis effectors BAX, BAK, and BOK with anti-apoptotic Bcl-2 proteins in living cells. We confirm homotypic interaction of the BAX-TMD, but also newly identify interaction of the TMD of anti-apoptotic BCL-2 with the TMD of BOK, a peculiar pro-apoptotic Bcl-2 protein. BOK-TMD and BCL-2-TMD interact at the endoplasmic reticulum. Molecular dynamics simulations confirm dynamic BOK-TMD and BCL-2-TMD dimers and stable heterotetramers. Mutation of BCL-2-TMD at predicted key residues abolishes interaction with BOK-TMD. Also, inhibition of BOK-induced apoptosis by BCL-2 depends specifically on their TMDs. Thus, TMDs of Bcl-2 proteins are a relevant interaction interface for apoptosis regulation and provide a novel potential drug target.","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/PMC11387410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757803","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

Ubiquitination of VE-cadherin regulates inflammation-induced vascular permeability in vivo. VE-cadherin的泛素化调节炎症诱导的体内血管通透性。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-07 DOI: 10.1038/s44319-024-00221-7

Markus Wilkens, Leonie Holtermann, Ann-Kathrin Stahl, Rebekka I Stegmeyer, Astrid F Nottebaum, Dietmar Vestweber

{"title":"Ubiquitination of VE-cadherin regulates inflammation-induced vascular permeability in vivo.","authors":"Markus Wilkens, Leonie Holtermann, Ann-Kathrin Stahl, Rebekka I Stegmeyer, Astrid F Nottebaum, Dietmar Vestweber","doi":"10.1038/s44319-024-00221-7","DOIUrl":"10.1038/s44319-024-00221-7","url":null,"abstract":"VE-cadherin is a major component of the cell adhesion machinery which provides integrity and plasticity of the barrier function of endothelial junctions. Here, we analyze whether ubiquitination of VE-cadherin is involved in the regulation of the endothelial barrier in inflammation in vivo. We show that histamine and thrombin stimulate ubiquitination of VE-cadherin in HUVEC, which is completely blocked if the two lysine residues K626 and K633 are replaced by arginine. Similarly, these mutations block histamine-induced endocytosis of VE-cadherin. We describe two knock-in mouse lines with endogenous VE-cadherin being replaced by either a VE-cadherin K626/633R or a VE-cadherin KallR mutant, where all seven lysine residues are mutated. Mutant mice are viable, healthy and fertile with normal expression levels of junctional VE-cadherin. Histamine- or LPS-induced vascular permeability in the skin or lung of both of these mutant mice are clearly and similarly reduced in comparison to WT mice. Additionally, we detect a role of K626/633 for lysosomal targeting. Collectively, our findings identify ubiquitination of VE-cadherin as important for the induction of vascular permeability in the inflamed skin and lung.","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/PMC11387630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901322","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

Satellite cell-derived TRIM28 is pivotal for mechanical load- and injury-induced myogenesis. 卫星细胞衍生的TRIM28对机械负荷和损伤诱导的肌肉生成至关重要。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-14 DOI: 10.1038/s44319-024-00227-1

Kuan-Hung Lin, Jamie E Hibbert, Corey Gk Flynn, Jake L Lemens, Melissa M Torbey, Nathaniel D Steinert, Philip M Flejsierowicz, Kiley M Melka, Garrison T Lindley, Marcos Lares, Vijayasaradhi Setaluri, Amy J Wagers, Troy A Hornberger

{"title":"Satellite cell-derived TRIM28 is pivotal for mechanical load- and injury-induced myogenesis.","authors":"Kuan-Hung Lin, Jamie E Hibbert, Corey Gk Flynn, Jake L Lemens, Melissa M Torbey, Nathaniel D Steinert, Philip M Flejsierowicz, Kiley M Melka, Garrison T Lindley, Marcos Lares, Vijayasaradhi Setaluri, Amy J Wagers, Troy A Hornberger","doi":"10.1038/s44319-024-00227-1","DOIUrl":"10.1038/s44319-024-00227-1","url":null,"abstract":"Satellite cells are skeletal muscle stem cells that contribute to postnatal muscle growth, and they endow skeletal muscle with the ability to regenerate after a severe injury. Here we discover that this myogenic potential of satellite cells requires a protein called tripartite motif-containing 28 (TRIM28). Interestingly, different from the role reported in a previous study based on C2C12 myoblasts, multiple lines of both in vitro and in vivo evidence reveal that the myogenic function of TRIM28 is not dependent on changes in the phosphorylation of its serine 473 residue. Moreover, the functions of TRIM28 are not mediated through the regulation of satellite cell proliferation or differentiation. Instead, our findings indicate that TRIM28 regulates the ability of satellite cells to progress through the process of fusion. Specifically, we discover that TRIM28 controls the expression of a fusogenic protein called myomixer and concomitant fusion pore formation. Collectively, the outcomes of this study expose the framework of a novel regulatory pathway that is essential for myogenesis.","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/PMC11387408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981909","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

Ambassadors of peace : The anthropology of war and how to overcome the human killing instinct. 和平大使：战争人类学以及如何克服人类的杀戮本能。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-19 DOI: 10.1038/s44319-024-00231-5

Gian Paolo Dotto

引用次数: 0

Retinoic acid-induced protein 14 links mechanical forces to Hippo signaling. 视黄酸诱导蛋白 14 将机械力与 Hippo 信号传递联系起来。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-19 DOI: 10.1038/s44319-024-00228-0

Wonyoung Jeong, Hyeryun Kwon, Sang Ki Park, In-Seob Lee, Eek-Hoon Jho

{"title":"Retinoic acid-induced protein 14 links mechanical forces to Hippo signaling.","authors":"Wonyoung Jeong, Hyeryun Kwon, Sang Ki Park, In-Seob Lee, Eek-Hoon Jho","doi":"10.1038/s44319-024-00228-0","DOIUrl":"10.1038/s44319-024-00228-0","url":null,"abstract":"Cells sense and respond to various mechanical forces from the extracellular matrix primarily by modulating the actin cytoskeleton. Mechanical forces can be translated into biochemical signals in a process called mechanotransduction. Yes-associated protein (YAP) is an effector of Hippo signaling and a mediator of mechanotransduction, but how mechanical forces regulate Hippo signaling is still an open question. We propose that retinoic acid-induced protein 14 (RAI14) responds to mechanical forces and regulates Hippo signaling. RAI14 positively regulates the activity of YAP. RAI14 interacts with NF2, a key component of the Hippo pathway, and the interaction occurs on filamentous actin. When mechanical forces are kept low in cells, NF2 dissociates from RAI14 and filamentous actin, resulting in increased interactions with LATS1 and activation of the Hippo pathway. Clinical data show that tissue stiffness and expression of RAI14 and YAP are upregulated in tumor tissues and that RAI14 is strongly associated with adverse outcome in patients with gastric cancer. Our data suggest that RAI14 links mechanotransduction with Hippo signaling and mediates Hippo-related biological functions such as cancer progression.","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/PMC11387738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003905","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

Reversible acetylation of HDAC8 regulates cell cycle. HDAC8 的可逆乙酰化调节细胞周期。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-07-23 DOI: 10.1038/s44319-024-00210-w

Chaowei Sang, Xuedong Li, Jingxuan Liu, Ziyin Chen, Minhui Xia, Miao Yu, Wei Yu

引用次数: 0

WIPI2b recruitment to phagophores and ATG16L1 binding are regulated by ULK1 phosphorylation. WIPI2b 招募到吞噬细胞和 ATG16L1 的结合受 ULK1 磷酸化的调控。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-08-16 DOI: 10.1038/s44319-024-00215-5

Andrea Gubas, Eleanor Attridge, Harold Bj Jefferies, Taki Nishimura, Minoo Razi, Simone Kunzelmann, Yuval Gilad, Thomas J Mercer, Michael M Wilson, Adi Kimchi, Sharon A Tooze

{"title":"WIPI2b recruitment to phagophores and ATG16L1 binding are regulated by ULK1 phosphorylation.","authors":"Andrea Gubas, Eleanor Attridge, Harold Bj Jefferies, Taki Nishimura, Minoo Razi, Simone Kunzelmann, Yuval Gilad, Thomas J Mercer, Michael M Wilson, Adi Kimchi, Sharon A Tooze","doi":"10.1038/s44319-024-00215-5","DOIUrl":"10.1038/s44319-024-00215-5","url":null,"abstract":"One of the key events in autophagy is the formation of a double-membrane phagophore, and many regulatory mechanisms underpinning this remain under investigation. WIPI2b is among the first proteins to be recruited to the phagophore and is essential for stimulating autophagy flux by recruiting the ATG12-ATG5-ATG16L1 complex, driving LC3 and GABARAP lipidation. Here, we set out to investigate how WIPI2b function is regulated by phosphorylation. We studied two phosphorylation sites on WIPI2b, S68 and S284. Phosphorylation at these sites plays distinct roles, regulating WIPI2b's association with ATG16L1 and the phagophore, respectively. We confirm WIPI2b is a novel ULK1 substrate, validated by the detection of endogenous phosphorylation at S284. Notably, S284 is situated within an 18-amino acid stretch, which, when in contact with liposomes, forms an amphipathic helix. Phosphorylation at S284 disrupts the formation of the amphipathic helix, hindering the association of WIPI2b with membranes and autophagosome formation. Understanding these intricacies in the regulatory mechanisms governing WIPI2b's association with its interacting partners and membranes, holds the potential to shed light on these complex processes, integral to phagophore biogenesis.","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/PMC11387628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995543","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

Mandatory national language requirements in higher education. 高等教育中的强制性国家语言要求。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2024-09-01 Epub Date: 2024-07-18 DOI: 10.1038/s44319-024-00211-9

Shina Caroline Lynn Kamerlin

引用次数: 0