EMBO ReportsPub Date : 2025-07-01Epub Date: 2025-05-22DOI: 10.1038/s44319-025-00480-y
Michelle C C Lim, Gunter Maubach, Michael Naumann
{"title":"CYLD-TRAF6 interaction promotes ADP-heptose-induced NF-κB signaling in H. pylori infection.","authors":"Michelle C C Lim, Gunter Maubach, Michael Naumann","doi":"10.1038/s44319-025-00480-y","DOIUrl":"10.1038/s44319-025-00480-y","url":null,"abstract":"<p><p>The inflammatory response associated with Helicobacter pylori (H. pylori) infection causes a multitude of alterations in the gastric microenvironment, leading to the slow and steady disruption of the gastric epithelial barrier. Activation of NF-κB during H. pylori infection is crucial to this inflammatory response. Here, we show that CYLD, which interacts constitutively with TRAF6, enhances H. pylori's ADP-heptose-induced activation of the classical NF-κB pathway in gastric epithelial cells. This activating effect of CYLD contrasts with the inhibitory effect of CYLD on receptor-mediated NF-κB activity. Mechanistically, CYLD counteracts the hydrolysis of ubiquitin chains from TRAF6 by deubiquitinylase A20 in a catalytically independent manner, thus supporting the auto-ubiquitinylation of TRAF6 upon activation of NF-κB in early H. pylori infection. In addition, the subsequent classical NF-κB-dependent de novo synthesis of A20 provides a negative feedback loop leading to shutdown not only of the classical but also of the alternative NF-κB pathway. Our findings highlight the regulatory relationship between CYLD and A20 in controlling classical as well as alternative NF-κB signaling in H. pylori infection.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3241-3263"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127016","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 : 2025-07-01Epub Date: 2025-06-06DOI: 10.1038/s44319-025-00492-8
Matthew J McNulty, Andrew J Stout, David L Kaplan
{"title":"Meating the moment : Challenges and opportunities for cellular agriculture to produce the foods of the future.","authors":"Matthew J McNulty, Andrew J Stout, David L Kaplan","doi":"10.1038/s44319-025-00492-8","DOIUrl":"10.1038/s44319-025-00492-8","url":null,"abstract":"","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3229-3235"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247006","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 : 2025-07-01Epub Date: 2025-06-09DOI: 10.1038/s44319-025-00430-8
Orane Lerouley, Isabelle Larrieu, Tom Louis Ducrocq, Benoît Pinson, Marie-France Giraud, Arnaud Mourier
{"title":"An alternative mechanism by which If1 prevents ATP hydrolysis by the ATP synthase subcomplex in S. cerevisiae.","authors":"Orane Lerouley, Isabelle Larrieu, Tom Louis Ducrocq, Benoît Pinson, Marie-France Giraud, Arnaud Mourier","doi":"10.1038/s44319-025-00430-8","DOIUrl":"10.1038/s44319-025-00430-8","url":null,"abstract":"<p><p>The mitochondrial F<sub>1</sub>F<sub>0</sub>-ATP synthase is crucial for maintaining the ATP/ADP balance which is critical for cell metabolism, ion homeostasis and cell proliferation. This enzyme, conserved across evolution, is found in the mitochondria or chloroplasts of eukaryotic cells and the plasma membrane of bacteria. In vitro studies have shown that the mitochondrial F<sub>1</sub>F<sub>0</sub>-ATP synthase is reversible, capable of hydrolyzing instead of synthesizing ATP. In vivo, its reversibility is inhibited by the endogenous peptide If1 (Inhibitory Factor 1), which specifically prevents ATP hydrolysis in a pH-dependent manner. Despite its presumed importance, the loss of If1 in various model organisms does not cause severe phenotypes, suggesting its role may be confined to specific stress or metabolic conditions yet to be discovered. Our analyses indicate that inhibitory peptides are crucial in mitigating mitochondrial depolarizing stress under glyco-oxidative metabolic conditions. Additionally, we found that the absence of If1 destabilizes the nuclear-encoded free F<sub>1</sub> subcomplex. This mechanism highlights the role of If1 in preventing harmful ATP wastage, offering new insights into its function under physiological and pathological conditions.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3305-3326"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257582","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 : 2025-07-01Epub Date: 2025-06-11DOI: 10.1038/s44319-025-00489-3
Emma Cavazzoni, Sabina Leonelli, Daniele Giannetti, Niccolò Patelli, Giacomo Vaccari, Lara Maistrello, Maria Cristina Pinotti
{"title":"Monitoring technology for pest-plant interactions : The need for transdisciplinary research design.","authors":"Emma Cavazzoni, Sabina Leonelli, Daniele Giannetti, Niccolò Patelli, Giacomo Vaccari, Lara Maistrello, Maria Cristina Pinotti","doi":"10.1038/s44319-025-00489-3","DOIUrl":"10.1038/s44319-025-00489-3","url":null,"abstract":"","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3236-3240"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274454","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 : 2025-07-01Epub 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":"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":"3529-3553"},"PeriodicalIF":6.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287357/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EMBO ReportsPub Date : 2025-07-01Epub Date: 2025-06-18DOI: 10.1038/s44319-025-00495-5
Guiomar Martín, Ana Confraria, Irene Zapata, Alvaro Santiago Larran, Julia Irene Qüesta, Paula Duque
{"title":"Cotyledon opening during seedling deetiolation is determined by ABA-mediated splicing regulation.","authors":"Guiomar Martín, Ana Confraria, Irene Zapata, Alvaro Santiago Larran, Julia Irene Qüesta, Paula Duque","doi":"10.1038/s44319-025-00495-5","DOIUrl":"10.1038/s44319-025-00495-5","url":null,"abstract":"<p><p>During seedling deetiolation, plants adjust their development to expose photosynthetic tissues to sunlight, enabling the transition from heterotrophic to autotrophic growth. While various plant hormones are known to influence this process, the role of abscisic acid (ABA) remains unclear. Here, we reveal that ABA plays a major role in controlling the dynamics of cotyledon aperture during seedling deetiolation. In the dark, ABA accumulates in the cotyledons to effectively repress their opening. However, light exposure reverses this effect, allowing the cotyledons to open. Our findings indicate that ABA-mediated regulation of cotyledon dynamics is accompanied by genome-wide rearrangements in both transcriptional and splicing patterns. We demonstrate that ABA-dependent adjustments of cotyledon and splicing dynamics in response to light depend on the positive role of two splicing factors, RS40 and RS41. Moreover, we identify transcriptional and posttranscriptional mechanisms that control the activity of these proteins. Altogether, this work sheds light on the interplay between light and ABA, highlighting cotyledon opening as a new developmental outcome, and identifying alternative splicing as the underlying layer of gene regulation.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3663-3678"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324792","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 : 2025-07-01Epub Date: 2025-06-18DOI: 10.1038/s44319-025-00500-x
Maximilian Pfisterer, Jan Dreute, M Lienhard Schmitz
{"title":"Insights from human NF-κB knockouts.","authors":"Maximilian Pfisterer, Jan Dreute, M Lienhard Schmitz","doi":"10.1038/s44319-025-00500-x","DOIUrl":"10.1038/s44319-025-00500-x","url":null,"abstract":"<p><p>The well-studied NF-κB signaling system is a key mediator of the inflammatory response. Large-scale sequencing studies in humans now allow initial insights into non-essential human genes in which both alleles carry mutations that prevent protein expression or function. Here, we compiled the non-essential genes identified in various sequencing studies and analyzed the occurrence of knockouts in the human NF-κB signaling system. This revealed a lower knockout frequency in the NF-κB system compared to the entire genome. Since drugs inhibiting NF-κB pathway components were unsuccessful in clinical trials so far, the naturally occurring knockouts of NF-κB and its upstream regulators could provide new candidates for therapeutic intervention. To investigate the potential functional importance of posttranslational modifications (PTMs) occurring on NF-κB components, we analyzed not only their evolutionary conservation but also, as a second criterion, their genetic constraint in the sequenced individuals. This approach revealed the absence of missense mutations at key modification sites involved in NF-κB activation and identified additional candidate sites for future studies.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3491-3505"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324796","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}
{"title":"KEAP1 retention in phase-separated p62 bodies drives liver damage under autophagy-deficient conditions.","authors":"Shuhei Takada, Nozomi Shinomiya, Gaoxin Mao, Hikaru Tsuchiya, Tomoaki Koga, Satoko Komatsu-Hirota, Yu-Shin Sou, Manabu Abe, Elena Ryzhii, Michitaka Suzuki, Mitsuyoshi Nakao, Satoshi Waguri, Hideaki Morishita, Masaaki Komatsu","doi":"10.1038/s44319-025-00483-9","DOIUrl":"10.1038/s44319-025-00483-9","url":null,"abstract":"<p><p>Phase-separated p62 bodies activate NRF2, a key transcription factor for antioxidant response, by sequestering KEAP1, which targets NRF2 for degradation. Although p62 bodies containing KEAP1 are degraded by autophagy, they accumulate in various liver disorders. Their precise disease role remains unclear. We show that excessive KEAP1 retention in p62 bodies and NRF2 activation are major causes of liver damage when autophagy is impaired. In mice with weakened or blocked p62-KEAP1 interactions, KEAP1 retention and NRF2 activation under autophagy-deficient conditions were suppressed. Transcriptome and proteome analyses reveal that p62 mutants unable to bind KEAP1 normalize the expression of NRF2 targets induced by defective autophagy. Autophagy deficiency causes organelle accumulation, especially of the ER, regardless of p62 mutation. Liver damage and hepatomegaly resulting from autophagy suppression markedly improved in mice carrying p62 mutants, particularly those with blocked KEAP1 binding. These findings highlight excessive KEAP1 retention in p62 bodies and defective organelle turnover as key drivers of liver pathology, underscoring the significance of phase separation in vivo.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3384-3410"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173357","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 : 2025-07-01Epub Date: 2025-06-11DOI: 10.1038/s44319-025-00466-w
Khansa Saadallah, Benoît Vianay, Louise Bonnemay, Hélène Pasquer, Lois Kelly, Stéphanie Mathis, Cécile Culeux, Raphael Marie, Paul Arthur Meslin, Sofiane Fodil, Paul Chaintreuil, Emeline Kerreneur, Arnaud Jacquel, Emmanuel Raffoux, Rémy Nizard, Camille Lobry, Laurent Blanchoin, Lina Benajiba, Manuel Théry
{"title":"AML patient blasts exhibit polarization defects upon interaction with bone marrow stromal cells.","authors":"Khansa Saadallah, Benoît Vianay, Louise Bonnemay, Hélène Pasquer, Lois Kelly, Stéphanie Mathis, Cécile Culeux, Raphael Marie, Paul Arthur Meslin, Sofiane Fodil, Paul Chaintreuil, Emeline Kerreneur, Arnaud Jacquel, Emmanuel Raffoux, Rémy Nizard, Camille Lobry, Laurent Blanchoin, Lina Benajiba, Manuel Théry","doi":"10.1038/s44319-025-00466-w","DOIUrl":"10.1038/s44319-025-00466-w","url":null,"abstract":"<p><p>Hematopoietic stem and progenitor cells (HSPCs) polarize in contact with the bone marrow stromal cells constituting their niche. Given the role of cell polarity in protection against tumorigenesis and the importance of the niche in the progression of acute myeloid leukemias (AMLs), we investigated the polarization capacities of leukemic blasts. Using engineered micro-niches and centrosome position with respect to the contact site with stromal cells as a proxy for cell polarization, we show that AML cell lines and primary cells from AML patient blasts are unable to polarize in contact with healthy stromal cells. Exposure to AML patient-derived stromal cells compromises the polarization of healthy adult HSPCs and AML blasts from patients. When cultured in \"bone-marrow-on-a-chip\", stromal cells from a leukemic niche stimulate the migration of healthy HSPCs and AML blast. These results reveal the detrimental influences of both intrinsic transformation and extrinsic contact with transformed stromal cells on the polarization of AML blasts.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":"3264-3279"},"PeriodicalIF":6.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274433","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}