EMBO ReportsPub Date : 2025-05-14DOI: 10.1038/s44319-025-00463-z
Ryan J Conrad, James A Mondo, Mike Lingjue Wang, Peter S Liu, Zijuan Lai, Feroza K Choudhury, Qingling Li, Weng Ruh Wong, James Lee, Frances Shanahan, Eva Lin, Scott Martin, Joachim Rudolph, John G Moffat, Dewakar Sangaraju, Wendy Sandoval, Timothy Sterne-Weiler, Scott A Foster
{"title":"NRF2 supports non-small cell lung cancer growth independently of CBP/p300-enhanced glutathione synthesis.","authors":"Ryan J Conrad, James A Mondo, Mike Lingjue Wang, Peter S Liu, Zijuan Lai, Feroza K Choudhury, Qingling Li, Weng Ruh Wong, James Lee, Frances Shanahan, Eva Lin, Scott Martin, Joachim Rudolph, John G Moffat, Dewakar Sangaraju, Wendy Sandoval, Timothy Sterne-Weiler, Scott A Foster","doi":"10.1038/s44319-025-00463-z","DOIUrl":"https://doi.org/10.1038/s44319-025-00463-z","url":null,"abstract":"<p><p>Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress responsive transcription factor that is mutationally activated in a subset (~25%) of clinically-aggressive non-small cell lung cancers (NSCLC). Mechanistic insight into drivers of the NRF2 dependency remains poorly understood. Here, we defined a novel NRF2 target gene set linked to NRF2-dependency in cancer cell lines, and observed that a significant portion of these genes is devoid of promoter-proximal NRF2 occupancy. Using integrated genomic analyses, we characterized extensive NRF2-dependent enhancer RNA (eRNA) synthesis and NRF2-mediated H3K27ac deposition at proximal and distal enhancer regions regulating these genes. While CBP/p300 is a well-validated direct interaction partner of NRF2 with prominent functions at enhancers, we report that this interaction is not required for NRF2-dependent NSCLC cell growth, indicating that NRF2 can sustain sufficient transcriptional activity in the absence of CBP/p300 coactivation. Broad metabolic profiling established a primary role for CBP/p300 in NRF2-dependent accumulation of glutathione and glutathione-related metabolites. While redox homeostasis via enhanced glutathione production is commonly associated with the normal physiological role of NRF2, collectively our results suggest that NRF2-dependent cancer cell growth does not require this enhanced glutathione production.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076741","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}
EMBO ReportsPub Date : 2025-05-12DOI: 10.1038/s44319-025-00472-y
Ioanna Panagi, Janina H Muench, Alexi Ronneau, Ines Diaz-Del-Olmo, Agnel Aliyath, Xiu-Jun Yu, Hazel Mak, Enkai Jin, Jingkun Zeng, Diego Esposito, Elliott Jennings, Timesh D Pillay, Regina A Günster, Sarah L Maslen, Katrin Rittinger, Teresa L M Thurston
{"title":"Bacterial effectors mediate kinase reprogramming through mimicry of conserved eukaryotic motifs.","authors":"Ioanna Panagi, Janina H Muench, Alexi Ronneau, Ines Diaz-Del-Olmo, Agnel Aliyath, Xiu-Jun Yu, Hazel Mak, Enkai Jin, Jingkun Zeng, Diego Esposito, Elliott Jennings, Timesh D Pillay, Regina A Günster, Sarah L Maslen, Katrin Rittinger, Teresa L M Thurston","doi":"10.1038/s44319-025-00472-y","DOIUrl":"https://doi.org/10.1038/s44319-025-00472-y","url":null,"abstract":"<p><p>Bacteria have evolved numerous biochemical processes that underpin their biology and pathogenesis. The small, non-enzymatic bacterial (Salmonella) effector SteE mediates kinase reprogramming, whereby the canonical serine/threonine host kinase GSK3 gains tyrosine-directed activity towards neosubstrates, promoting Salmonella virulence. Yet, both the mechanism behind the switch in GSK3's activity and the diversity of this phenomenon remain to be determined. Here we show that kinase reprogramming of GSK3 is mediated by putative homologues from diverse Gram-negative pathogens. Next, we identify both the molecular basis of how SteE targets GSK3 and uncover that the SteE-induced tyrosine activity conferred on GSK3 requires an L/xGxP motif. This motif, found in several CMGC kinases that undergo auto-tyrosine phosphorylation, was previously shown to mediate GSK3 autophosphorylation on a tyrosine. Together, we suggest that the SteE family of intrinsically disordered proteins mediates kinase reprogramming via several short linear motifs that each appear to mimic eukaryotic signalling motifs. With this insight comes the potential for the rationale design of synthetic reprogramming proteins.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978611","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}
EMBO ReportsPub Date : 2025-05-12DOI: 10.1038/s44319-025-00467-9
Noriko Osumi
{"title":"Catalysts of change: Japan's universities for international research excellence.","authors":"Noriko Osumi","doi":"10.1038/s44319-025-00467-9","DOIUrl":"https://doi.org/10.1038/s44319-025-00467-9","url":null,"abstract":"","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997738","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}
EMBO ReportsPub Date : 2025-05-01DOI: 10.1038/s44319-025-00455-z
Kim J Lapacz, Konstantin Weiss, Franziska Mueller, Yuxing Xue, Simon Poepsel, Matthias Weith, Tanja Bange, Jan Riemer
{"title":"DPP8/9 processing of human AK2 unmasks an IAP binding motif.","authors":"Kim J Lapacz, Konstantin Weiss, Franziska Mueller, Yuxing Xue, Simon Poepsel, Matthias Weith, Tanja Bange, Jan Riemer","doi":"10.1038/s44319-025-00455-z","DOIUrl":"https://doi.org/10.1038/s44319-025-00455-z","url":null,"abstract":"<p><p>Adenylate kinase 2 (AK2) is localized in the intermembrane space of mitochondria, where it ensures efficient adenine nucleotide exchange between cytosol and mitochondria. For mitochondrial import, AK2 relies on the MIA40 disulphide relay system. Its cytosolic stability is subject to regulation through N-terminal processing by the dipeptidyl peptidases DPP8 and DPP9, which sensitize AK2 for proteasomal degradation. Here, we find that cytosolic AK2 degradation is mediated by Inhibitors of Apoptosis (IAPs), a class of E3 ligases that interacts with target proteins by binding to IAP-binding motifs (IBM). We have identified an IBM at the very end of AK2's novel N-terminus, which becomes exposed due to processing by DPP8/9. N-terminal acetylation mediated by the N-acetyltransferase NatA prevents this AK2-IAP interaction, therefore stabilizing AK2 in the cytosol. Performing a genome-wide in silico screen, we could identify 129 potential substrates in which an IBM becomes potentially unmasked by DPP8/9 processing. For one of these potential substrates, EIF2A, we demonstrate its targeting to IAPs after IBM exposure by DPP8/9 indicating that DPP8/9-mediated unmasking of IBMs is a general phenomenon.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957225","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}
EMBO ReportsPub Date : 2025-05-01DOI: 10.1038/s44319-025-00461-1
Patrick J Dickinson, Sebastian Triesch, Urte Schlüter, Andreas P M Weber, Julian M Hibberd
{"title":"A transcription factor module mediating C<sub>2</sub> photosynthesis in the Brassicaceae.","authors":"Patrick J Dickinson, Sebastian Triesch, Urte Schlüter, Andreas P M Weber, Julian M Hibberd","doi":"10.1038/s44319-025-00461-1","DOIUrl":"https://doi.org/10.1038/s44319-025-00461-1","url":null,"abstract":"<p><p>C<sub>4</sub> photosynthesis has arisen from the ancestral C<sub>3</sub> state in over sixty lineages of angiosperms. It is widely accepted that an early step in C<sub>4</sub> evolution is associated with the appearance of so-called C<sub>2</sub> photosynthesis caused by loss of glycine decarboxylase activity from mesophyll cells followed by activation in the bundle sheath. Although changes in cis to a distal enhancer upstream of the P-subunit of GLYCINE DECARBOXYLASE (GLDP) from C<sub>2</sub> Moricandia enable loss of expression from mesophyll cells, the mechanism then allowing GLDP expression in the bundle sheath is not known. Here we identify a MYC-MYB transcription factor module previously associated with the control of glucosinolate biosynthesis as the basis of this foundational event in the evolution of C<sub>2</sub> photosynthesis. Specifically, we find that in the C<sub>3</sub> state this MYC-MYB module already patterns GLDP expression to bundle sheath cells. As a consequence, when GLDP expression is lost from the mesophyll, the MYC-MYB dependent expression in the bundle sheath is revealed. Evolution of C<sub>2</sub> photosynthesis is thus associated with a MYC-MYB based transcriptional network already present in the C<sub>3</sub> state. This work identifies a molecular genetic mechanism underlying the bundle sheath accumulation of glycine decarboxylase required for C<sub>2</sub> photosynthesis and thus a fundamental step in the evolution of C<sub>4</sub> photosynthesis.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964483","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}
{"title":"CD47-amyloid-β-CD74 signaling triggers adaptive immunosuppression in sepsis.","authors":"Zhongxue Feng, Lijun Wang, Yang Li, Yonggang Wei, Yueyue Zhou, Siying Wang, Xiaoqi Zhang, Chunling Jiang, Xuelian Liao, Yan Kang, Fei Xiao, Wei Zhang","doi":"10.1038/s44319-025-00442-4","DOIUrl":"10.1038/s44319-025-00442-4","url":null,"abstract":"<p><p>Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. However, how this dysregulation occurs remains to be elucidated. In this study, we use single-cell RNA sequencing (scRNA-seq) and conventional RNA-seq to analyze the immune landscape of sepsis and observe that adaptive immunity is acutely and strongly suppressed. This systemic immunosuppression occurs not only in the peripheral blood but also in all other immune compartments, including the spleen, lymph nodes, and bone marrow. Clinical data show that these adaptive immunity-related genes may have the potential to be used to distinguish patients with sepsis from those with common infections. CD47 is found to play a pivotal role in this immunosuppression by inducing the production of amyloid-β (Aβ), which interacts with CD74 on B cells, leading to B-cell suppression and subsequent adaptive immunosuppression. Blocking CD47-Aβ signaling significantly reduces organ injury and improves the survival rate of septic mice by restoring phagocytic cell functions and alleviating B-cell suppression and adaptive immunosuppression.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"2683-2714"},"PeriodicalIF":6.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12116991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788015","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}
EMBO ReportsPub Date : 2025-05-01Epub Date: 2025-04-30DOI: 10.1038/s44319-025-00441-5
Jelle Huysentruyt, Wolf Steels, Mario Ruiz Pérez, Bruno Verstraeten, Tatyana Divert, Kayleigh Flies, Kelly Lemeire, Nozomi Takahashi, Elke De Bruyn, Marie Joossens, Andrew S Brown, Bart N Lambrecht, Wim Declercq, Tom Vanden Berghe, Jonathan Maelfait, Peter Vandenabeele, Peter Tougaard
{"title":"RIPK1 ablation in T cells results in spontaneous enteropathy and TNF-driven villus atrophy.","authors":"Jelle Huysentruyt, Wolf Steels, Mario Ruiz Pérez, Bruno Verstraeten, Tatyana Divert, Kayleigh Flies, Kelly Lemeire, Nozomi Takahashi, Elke De Bruyn, Marie Joossens, Andrew S Brown, Bart N Lambrecht, Wim Declercq, Tom Vanden Berghe, Jonathan Maelfait, Peter Vandenabeele, Peter Tougaard","doi":"10.1038/s44319-025-00441-5","DOIUrl":"10.1038/s44319-025-00441-5","url":null,"abstract":"<p><p>RIPK1 is a crucial regulator of cell survival, inflammation and cell death. Human RIPK1 deficiency leads to early-onset intestinal inflammation and peripheral T cell imbalance, though its role in αβT cell-mediated intestinal homeostasis remains unclear. In this study, we demonstrate that mice with RIPK1 ablation in conventional αβT cells (Ripk1<sup>ΔCD4</sup>) developed a severe small intestinal pathology characterized by small intestinal elongation, crypt hyperplasia, and duodenum-specific villus atrophy. Using mixed bone marrow chimeras reveals a survival disadvantage of αβT cells compared to γδT cells in the small intestine. Broad-spectrum antibiotic treatment ameliorates crypt hyperplasia and prevents intestinal elongation, though villus atrophy persists. Conversely, crossing Ripk1<sup>ΔCD4</sup> with TNF receptor 1 Tnfr1<sup>-/-</sup> knockout mice rescues villus atrophy but not intestinal elongation. Finally, combined ablation of Ripk1<sup>∆CD4</sup> and Casp8<sup>∆CD4</sup> fully rescues intestinal pathology, revealing that αβT cell apoptosis in Ripk1<sup>∆CD4</sup> drives the enteropathy. These findings demonstrate that RIPK1-mediated survival of αβT cells is essential for proximal small intestinal homeostasis. In Ripk1<sup>∆CD4</sup> mice, the imbalanced T cell compartment drives microbiome-mediated intestinal elongation and TNF-driven villus atrophy.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"2654-2682"},"PeriodicalIF":6.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973323","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}
EMBO ReportsPub Date : 2025-05-01Epub Date: 2025-03-27DOI: 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":"10.1038/s44319-025-00425-5","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"2347-2377"},"PeriodicalIF":6.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12069581/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-05-01Epub Date: 2025-04-04DOI: 10.1038/s44319-025-00435-3
Aline Fréville, Flavia Moreira-Leite, Camille Roussel, Matthew R G Russell, Aurelie Fricot, Valentine Carret, Abdoulaye Sissoko, Matthew J Hayes, Aissatou Bailo Diallo, Nicole Cristine Kerkhoven, Margarida Ressurreição, Safi Dokmak, Michael J Blackman, Lucy M Collinson, Pierre A Buffet, Sue Vaughan, Papa Alioune Ndour, Christiaan van Ooij
{"title":"Malaria parasites undergo a rapid and extensive metamorphosis after invasion of the host erythrocyte.","authors":"Aline Fréville, Flavia Moreira-Leite, Camille Roussel, Matthew R G Russell, Aurelie Fricot, Valentine Carret, Abdoulaye Sissoko, Matthew J Hayes, Aissatou Bailo Diallo, Nicole Cristine Kerkhoven, Margarida Ressurreição, Safi Dokmak, Michael J Blackman, Lucy M Collinson, Pierre A Buffet, Sue Vaughan, Papa Alioune Ndour, Christiaan van Ooij","doi":"10.1038/s44319-025-00435-3","DOIUrl":"10.1038/s44319-025-00435-3","url":null,"abstract":"<p><p>Within the human host, the symptoms of malaria are caused by the replication of malaria parasites within erythrocytes. Growth inside the erythrocyte exposes the parasites to the normal surveillance of erythrocytes by the host organism, in particular the clearance of erythrocytes in the spleen. Here we show that the malaria parasite Plasmodium falciparum undergoes a rapid, multi-step metamorphosis that transforms the invasive merozoite into an amoeboid-shaped cell within minutes after invading erythrocytes. This transformation involves an increase in the parasite surface area and is mediated by factors already present in the merozoite, including the parasite phospholipid transfer protein PV6. Parasites lacking PV6 do not assume an amoeboid form and instead are spherical and have a smaller surface area than amoeboid forms. Furthermore, erythrocytes infected with P. falciparum parasites lacking PV6 undergo a higher loss of surface area upon infection, which affects the traversal of infected erythrocytes through the spleen. This is the first evidence that after invasion, the parasite undergoes a rapid, complex metamorphosis within the host erythrocyte that promotes survival in the host.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"2545-2573"},"PeriodicalIF":6.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12116788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788035","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}
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