EMBO Reports最新文献

Praja2 controls P-body assembly and translation in glioblastoma by non-proteolytic ubiquitylation of DDX6.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-27 DOI: 10.1038/s44319-025-00425-5

Emanuela Senatore, Rosario Avolio, Laura Rinaldi, Francesco Chiuso, Maria A Oliva, Chiara D'Ambrosio, Antonio Giuseppe Bianco, Emiliano Dalla, Stefano Maria Pagnotta, Raffaella Flammia, Concetta Ambrosino, Domenico Memoli, Gabriele Turacchio, Sonia Ines Mimoune, Yves Toiron, Stephane Audebert, Luc Camoin, Luca Lignitto, Andrea Scaloni, Antonietta Arcella, Antonio Feliciello

{"title":"Praja2 controls P-body assembly and translation in glioblastoma by non-proteolytic ubiquitylation of DDX6.","authors":"Emanuela Senatore, Rosario Avolio, Laura Rinaldi, Francesco Chiuso, Maria A Oliva, Chiara D'Ambrosio, Antonio Giuseppe Bianco, Emiliano Dalla, Stefano Maria Pagnotta, Raffaella Flammia, Concetta Ambrosino, Domenico Memoli, Gabriele Turacchio, Sonia Ines Mimoune, Yves Toiron, Stephane Audebert, Luc Camoin, Luca Lignitto, Andrea Scaloni, Antonietta Arcella, Antonio Feliciello","doi":"10.1038/s44319-025-00425-5","DOIUrl":"https://doi.org/10.1038/s44319-025-00425-5","url":null,"abstract":"Glioblastoma multiforme (GBM) is the most lethal form of malignant brain tumor in adults. Dysregulation of protein synthesis contributes to cancer cell plasticity, driving GBM cell heterogeneity, metastatic behavior, and drug resistance. Understanding the complex network and signaling pathways governing protein translation, is therefore an important goal for GBM treatment. Here we identify a novel signaling network centered on the E3 ubiquitin ligase praja2 that controls protein translation in GBM. Praja2 forms a multimeric complex with the RNA helicase DDX6, which inhibits translation of target RNAs within processing bodies (P-bodies). Stimulation of cAMP signaling through activation of G-protein-coupled receptors induces P-body assembly through praja2-mediated non-proteolytic polyubiquitylation of DDX6. Genetic inactivation of praja2 reshapes DDX6/mRNA complexes and translating polysomes and promotes cellular senescence and GBM growth arrest. Expression of an ubiquitylation-defective DDX6 mutant suppresses the assembly of P-bodies and sustains GBM growth. Taken together, our findings identify a cAMP-driven network that controls translation in P-bodies and GBM growth.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729243","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

Gen AI and research integrity: Where to now? : The integration of Generative AI in the research process challenges well-established definitions of research integrity.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-24 DOI: 10.1038/s44319-025-00424-6

Sonia Vasconcelos, Ana Marušić

引用次数: 0

Molecular architecture of glideosome and nuclear F-actin in Plasmodium falciparum.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-24 DOI: 10.1038/s44319-025-00415-7

Vojtěch Pražák, Daven Vasishtan, Kay Grünewald, Ross G Douglas, Josie L Ferreira

{"title":"Molecular architecture of glideosome and nuclear F-actin in Plasmodium falciparum.","authors":"Vojtěch Pražák, Daven Vasishtan, Kay Grünewald, Ross G Douglas, Josie L Ferreira","doi":"10.1038/s44319-025-00415-7","DOIUrl":"https://doi.org/10.1038/s44319-025-00415-7","url":null,"abstract":"Actin-based motility is required for the transmission of malaria sporozoites. While this has been shown biochemically, filamentous actin has remained elusive and has not been directly visualised inside the parasite. Using focused ion beam milling and electron cryo-tomography, we studied dynamic actin filaments in unperturbed Plasmodium falciparum cells for the first time. This allowed us to dissect the assembly, path and fate of actin filaments during parasite gliding and determine a complete 3D model of F-actin within sporozoites. We observe micrometre long actin filaments, much longer than expected from in vitro studies. After their assembly at the parasite's apical end, actin filaments continue to grow as they are transported down the cell as part of the glideosome machinery, and are disassembled at the basal end in a rate-limiting step. Large pores in the IMC, constrained to the basal end, may facilitate actin exchange between the pellicular space and cytosol for recycling and maintenance of directional flow. The data also reveal striking actin bundles in the nucleus. Implications for motility and transmission are discussed.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699923","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

Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-24 DOI: 10.1038/s44319-025-00423-7

Johannes Lang, Tim Bergner, Julia Zinngrebe, Alice Lepelley, Katharina Vill, Steffen Leiz, Meinhard Wlaschek, Matias Wagner, Karin Scharffetter-Kochanek, Pamela Fischer-Posovszky, Clarissa Read, Yanick J Crow, Maximilian Hirschenberger, Konstantin M J Sparrer

{"title":"Distinct pathogenic mutations in ARF1 allow dissection of its dual role in cGAS-STING signalling.","authors":"Johannes Lang, Tim Bergner, Julia Zinngrebe, Alice Lepelley, Katharina Vill, Steffen Leiz, Meinhard Wlaschek, Matias Wagner, Karin Scharffetter-Kochanek, Pamela Fischer-Posovszky, Clarissa Read, Yanick J Crow, Maximilian Hirschenberger, Konstantin M J Sparrer","doi":"10.1038/s44319-025-00423-7","DOIUrl":"10.1038/s44319-025-00423-7","url":null,"abstract":"Tight control of cGAS-STING-mediated DNA sensing is crucial to avoid auto-inflammation. The GTPase ADP-ribosylation factor 1 (ARF1) is crucial to maintain cGAS-STING homeostasis and various pathogenic ARF1 variants are associated with type I interferonopathies. Functional ARF1 inhibits STING activity by maintaining mitochondrial integrity and facilitating COPI-mediated retrograde STING trafficking and deactivation. Yet the factors governing the two distinct functions of ARF1 remained unexplored. Here, we dissect ARF1's dual role by a comparative analysis of disease-associated ARF1 variants and their impact on STING signalling. We identify a de novo heterozygous s.55 C > T/p.R19C ARF1 variant in a patient with type I interferonopathy symptoms. The GTPase-deficient variant ARF1 R19C selectively disrupts COPI binding and retrograde transport of STING, thereby prolonging innate immune activation without affecting mitochondrial integrity. Treatment of patient fibroblasts in vitro with the STING signalling inhibitors H-151 and amlexanox reduces chronic interferon signalling. Summarizing, our data reveal the molecular basis of a ARF1-associated type I interferonopathy allowing dissection of the two roles of ARF1, and suggest that pharmacological targeting of STING may alleviate ARF1-associated auto-inflammation.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699919","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

Induction of a transcriptional adaptation response by RNA destabilization events.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-24 DOI: 10.1038/s44319-025-00427-3

Lihan Xie, Gabrielius Jakutis, Christopher M Dooley, Stefan Guenther, Zacharias Kontarakis, Sarah P Howard, Thomas Juan, Didier Y R Stainier

{"title":"Induction of a transcriptional adaptation response by RNA destabilization events.","authors":"Lihan Xie, Gabrielius Jakutis, Christopher M Dooley, Stefan Guenther, Zacharias Kontarakis, Sarah P Howard, Thomas Juan, Didier Y R Stainier","doi":"10.1038/s44319-025-00427-3","DOIUrl":"10.1038/s44319-025-00427-3","url":null,"abstract":"Transcriptional adaptation (TA) is a cellular process whereby mRNA-destabilizing mutations are associated with the transcriptional upregulation of so-called adapting genes. The nature of the TA-triggering factor(s) remains unclear, namely whether an mRNA-borne premature termination codon or the subsequent mRNA decay process, and/or its products, elicits TA. Here, working with mouse Actg1, we first establish two types of perturbations that lead to mRNA destabilization: Cas9-induced mutations predicted to lead to mutant mRNA decay, and Cas13d-mediated mRNA cleavage. We find that both types of perturbations are effective in degrading Actg1 mRNA, and that they both upregulate Actg2. Notably, increased chromatin accessibility at the Actg2 locus was observed only in the Cas9-induced mutant cells but not in the Cas13d-targeted cells, suggesting that chromatin remodeling is not required for Actg2 upregulation. We further show that ribozyme-mediated Actg1 pre-mRNA cleavage also leads to a robust upregulation of Actg2, and that this upregulation is again independent of chromatin remodeling. Together, these data highlight the critical role of RNA destabilization events as a trigger for TA, or at least a TA-like response.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699922","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

Epicardial VEGFC/D signaling is essential for coronary lymphangiogenesis.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-24 DOI: 10.1038/s44319-025-00431-7

Ester de la Cruz, Vanessa Cadenas, Susana Temiño, Guillermo Oliver, Miguel Torres

引用次数: 0

Structural insights into the selective recognition of RF-amide peptides by neuropeptide FF receptor 2.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-24 DOI: 10.1038/s44319-025-00428-2

Jeesoo Kim, Sooyoung Hong, Hajin Lee, Hyun Sik Lee, Chaehee Park, Jinuk Kim, Wonpil Im, Hee-Jung Choi

{"title":"Structural insights into the selective recognition of RF-amide peptides by neuropeptide FF receptor 2.","authors":"Jeesoo Kim, Sooyoung Hong, Hajin Lee, Hyun Sik Lee, Chaehee Park, Jinuk Kim, Wonpil Im, Hee-Jung Choi","doi":"10.1038/s44319-025-00428-2","DOIUrl":"10.1038/s44319-025-00428-2","url":null,"abstract":"Neuropeptide FF Receptor 2 (NPFFR2), a G-protein-coupled receptor, plays a role in pain modulation and diet-induced thermogenesis. While NPFFR2 is strongly activated by neuropeptides FF (NPFFs), it shows low activity in response to RF-amide-related peptides (RFRPs), despite the peptides belonging to a shared family. In contrast, NPFFR1, which shares high sequence similarity with NPFFR2, is activated by RFRPs and regulates reproductive hormone balance. The molecular basis for these receptor-specific interactions with their RF-amide peptides remains unclear. Here, we present cryo-electron microscopy structures of NPFFR2 in its active state bound to the agonist RF-amide peptide hNPSF, and in its ligand-free state. Structural analysis reveals that the C-terminal RF-amide moiety engages conserved residues in the transmembrane domain, while the N-terminal segment interacts in a receptor subtype-specific manner. Key selectivity-determining residues in NPFFR2 are also identified. A homology model of NPFFR1 bound to RFRP, supported by mutagenesis studies, further validates this selectivity mechanism. Additionally, structural comparison between the inactive and active states of NPFFR2 suggests a TM3-mediated activation mechanism. These findings provide insights into RF-amide peptide recognition by NPFF receptors.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699924","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

Lack of AtMC1 catalytic activity triggers autoimmunity dependent on NLR stability. 缺乏 AtMC1 催化活性会引发依赖于 NLR 稳定性的自身免疫。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-20 DOI: 10.1038/s44319-025-00426-4

Jose Salguero-Linares, Laia Armengot, Joel Ayet, Nerea Ruiz-Solaní, Svenja C Saile, Marta Salas-Gómez, Esperanza Fernandez, Lode Denolf, Fernando Navarrete, Jenna Krumbach, Markus Kaiser, Simon Stael, Frank Van Breusegem, Kris Gevaert, Farnusch Kaschani, Morten Petersen, Farid El Kasmi, Marc Valls, Núria S Coll

{"title":"Lack of AtMC1 catalytic activity triggers autoimmunity dependent on NLR stability.","authors":"Jose Salguero-Linares, Laia Armengot, Joel Ayet, Nerea Ruiz-Solaní, Svenja C Saile, Marta Salas-Gómez, Esperanza Fernandez, Lode Denolf, Fernando Navarrete, Jenna Krumbach, Markus Kaiser, Simon Stael, Frank Van Breusegem, Kris Gevaert, Farnusch Kaschani, Morten Petersen, Farid El Kasmi, Marc Valls, Núria S Coll","doi":"10.1038/s44319-025-00426-4","DOIUrl":"https://doi.org/10.1038/s44319-025-00426-4","url":null,"abstract":"Plants utilize cell surface-localized pattern recognition receptors (PRRs) and intracellular nucleotide-binding leucine-rich repeat (NLR) receptors to detect non-self and elicit robust immune responses. Fine-tuning the homeostasis of these receptors is critical to prevent their hyperactivation. Here, we show that Arabidopsis plants lacking metacaspase 1 (AtMC1) display autoimmunity dependent on immune signalling components downstream of NLR and PRR activation. Overexpression of a catalytically inactive AtMC1 in an atmc1 background triggers severe autoimmunity partially dependent on the same immune signalling components. Overexpression of the E3 ligase SNIPER1, a master regulator of NLR homeostasis, fully reverts the AtMC1-dependent autoimmunity phenotype, inferring that a broad defect in NLR turnover may underlie the severe phenotype observed. Catalytically inactive AtMC1 localizes to punctate structures that are degraded through autophagy. Considering also previous evidence on the proteostatic functions of AtMC1, we speculate that Wt AtMC1 may either directly or indirectly control NLR protein levels, thereby preventing autoimmunity.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669185","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

Liquid-liquid phase separation of LARP7 restrains HIV-1 replication. LARP7 的液-液相分离抑制了 HIV-1 的复制。

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-20 DOI: 10.1038/s44319-025-00421-9

Zhuoxin Li, Xiya Fang, Bing Zhao, Ran Liu, Yezhuang Shen, Tingting Li, Yining Wang, Zenglin Guo, Wen Wang, Biyu Zhang, Qiuying Han, Xin Xu, Kai Wang, Libing Yin, Weili Gong, Ailing Li, Tao Zhou, Teng Li, Weihua Li

引用次数: 0

tRNA lysidinylation is essential for the minimal translation system in the Plasmodium falciparum apicoplast.

IF 6.5 1区生物学

EMBO Reports Pub Date : 2025-03-20 DOI: 10.1038/s44319-025-00420-w

Rubayet Elahi, Sean T Prigge

{"title":"tRNA lysidinylation is essential for the minimal translation system in the Plasmodium falciparum apicoplast.","authors":"Rubayet Elahi, Sean T Prigge","doi":"10.1038/s44319-025-00420-w","DOIUrl":"10.1038/s44319-025-00420-w","url":null,"abstract":"For decades, researchers have sought to define minimal translation systems to uncover fundamental principles of life and advance biotechnology. tRNAs, essential components of this machinery, decode mRNA codons into amino acids. The apicoplast of malaria parasites contains 25 tRNA isotypes in its organellar genome-the lowest number found in known translation systems. Efficient translation in such minimal systems depends heavily on post-transcriptional tRNA modifications. One such modification, lysidine at the wobble position (C34) of tRNACAU, distinguishes between methionine (AUG) and isoleucine (AUA) codons. tRNA isoleucine lysidine synthetase (TilS) produces lysidine, which is nearly ubiquitous in bacteria and essential for cellular viability. Here, we report a TilS ortholog (PfTilS) targeted to the apicoplast of Plasmodium falciparum. We demonstrate that PfTilS activity is essential for parasite survival and apicoplast function, likely due to its role in protein translation. This study is the first to characterize TilS in an endosymbiotic organelle, contributing to research on eukaryotic organelles and minimal translational systems. Moreover, the absence of lysidine in humans highlights a potential target for antimalarial strategies.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669293","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