The FEBS journal最新文献

{"title":"Extreme multivalency and a composite short linear motif facilitate PCNA-binding, localisation and abundance of p21 (CDKN1A).","authors":"Signe Simonsen, Fia B Larsen, Caroline K Søgaard, Nicolas Jonsson, Kresten Lindorff-Larsen, Per Bruheim, Marit Otterlei, Rasmus Hartmann-Petersen, Birthe B Kragelund","doi":"10.1111/febs.70133","DOIUrl":"https://doi.org/10.1111/febs.70133","url":null,"abstract":"<p><p>Cyclin-dependent kinase inhibitor 1 (CDKN1A; also known as p21) promotes cell cycle arrest and regulates DNA replication and DNA repair by high-affinity binding to proliferating cell nuclear antigen (PCNA) using a C-terminal short linear motif (SLiM). High-affinity binding to PCNA is driven by positively charged flanking regions of the SLiM, but the molecular details of their interaction as well as their roles for other p21 functions are not known. Using biophysics to study the interaction between PCNA and p21 variants with different Lys/Arg compositions in the flanking regions, as well as using D-amino acids, we find that the flanking regions of p21 bind to PCNA likely through an interaction driven by complementary charges without specific contacts. Although the exact Lys/Arg composition of the p21 flanking regions is unimportant for high-affinity PCNA binding, these positions are conserved in p21 orthologs, implying a conserved biological function. Accordingly, in cell-based experiments, we find that, while the flanking regions affect p21 abundance, both the context and the Lys/Arg composition of the N-terminal flanking region are crucial for p21 nuclear localisation. Such integration of SLiMs into a composite SLiM may be a widespread phenomenon and complicates the separation of function and drug development.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Bimodal substrate binding in the active site of the glycosidase BcX”","authors":"","doi":"10.1111/febs.70141","DOIUrl":"10.1111/febs.70141","url":null,"abstract":"<p>Saberi M, Chikunova A, Bdira FB, Cramer-Blok A, Timmer M, Voskamp P, and Ubbink M (2024) Bimodal substrate binding in the active site of the glycosidase BcX. <i>FEBS J</i>, 291: 4222–4239. https://doi.org/10.1111/febs.17251</p><p>During the finalization of this article, the authors inadvertently omitted part of the Acknowledgements. This correction replaces the incomplete Acknowledgements section. The authors have checked the entire document and assert that they found no further errors.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"292 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70141","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic context analysis enables the discovery of an unusual NAD-dependent racemase in phosphonate catabolism.","authors":"Francesca Ruffolo, Silvia Conciatori, Giovanni Merici, Tamara Dinhof, Jason P Chin, Claudio Rivetti, Andrea Secchi, Katharina Pallitsch, Alessio Peracchi","doi":"10.1111/febs.70130","DOIUrl":"https://doi.org/10.1111/febs.70130","url":null,"abstract":"<p><p>Phosphonates are organic molecules containing a direct carbon-phosphorus (C-P) bond. They are chemically sturdy compounds that can, however, be degraded by environmental microorganisms. In the frame of bacterial phosphonate catabolism, we recently reported the discovery of (R)-1-hydroxy-2-aminoethylphosphonate ammonia-lyase (PbfA), a lyase acting on the natural compound (R)-2-amino-1-hydroxyethylphosphonate (R-HAEP). PbfA converts R-HAEP into phosphonoacetaldehyde (PAA), which can be subsequently processed and cleaved by further enzymes. However, PbfA is not active toward S-HAEP (the enantiomer of R-HAEP), whose metabolic fate remained unknown. We now describe the identification of a racemase, discovered through genomic context analysis, which converts S-HAEP into R-HAEP, thereby enabling degradation of S-HAEP. We propose for this enzyme the official name 2-amino-1-hydroxyethylphosphonate racemase (shorthand PbfF). To our knowledge, PbfF is the first NAD-dependent racemase ever described and is structurally unrelated to other known NAD-dependent isomerases. The enzyme uses NAD⁺ as a cofactor, is inhibited by NADH, and shows catalytic parameters comparable to those of other racemases acting on similar substrates. The presence of a pathway for the breakdown of S-HAEP in numerous bacteria suggests that this compound may be more common in the environment than currently appreciated. Notably, the route for S-HAEP degradation appears to have developed through a mechanism of retrograde metabolic evolution.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144096620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased chromatin accessibility underpins senescence.","authors":"Stéphane Lopes-Paciencia, Gerardo Ferbeyre","doi":"10.1111/febs.70136","DOIUrl":"https://doi.org/10.1111/febs.70136","url":null,"abstract":"<p><p>Senescence is a cellular state induced by various stressors or extracellular signals, but a universal pathway that triggers this process irrespective of the initial stressor has yet to be identified. Recent data indicate that chromatin opening, particularly in the noncoding genome, is a hallmark of cellular senescence. We propose a model in which this increased chromatin accessibility mediated by transcription factors downstream of the senescence-inducing stressors acts as a decisive factor to commit cells toward the senescence fate. Engagement toward senescence is then determined by the balance between mechanisms that increase or decrease chromatin accessibility and can be influenced by modulating the activity of specific histone-modifying complexes. Traits of senescent cells, such as increased nuclear and nucleolar size, the secretion of pro-inflammatory cytokines, reduced rRNA biogenesis, telomere dysfunction, expression of retrotransposons and endogenous retroviruses, as well as DNA damage, can all be attributed to increased chromatin accessibility. This concept suggests potential targets to tilt the balance toward the senescence response in the context of future therapies against cancer and age-related diseases.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144096621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Building up and breaking down: co-ordination of cell wall production and proteasome assembly.","authors":"Thomas D Williams","doi":"10.1111/febs.70135","DOIUrl":"https://doi.org/10.1111/febs.70135","url":null,"abstract":"<p><p>Cell wall maintenance and proteome remodelling are fundamental requirements for fungal cells subjected to stress. Previous work has shown that the cell wall integrity pathway is activated upon diverse stresses to both increase the production of cell wall constituents and proteasome assembly factors through activation of Mpk1 kinase. In a recent study, Šupljika and colleagues identified a further link between the two processes. The E3 ligase adaptor Mub1 is a negative regulator of both proteasome subunit production and cell wall maintenance factors. These multifactoral links may have emerged from interspecies competition, providing a benefit to linking these diverse stress adaptation mechanisms.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144096619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linear free energy relationship between reduction potential and photoreduction rate: studies on Drosophila cryptochrome.","authors":"Moustafa Okasha, Jing Chen, Audrey Ayekoi, Eike Jacob, Valentin Radtke, Anton Schmidt, Adelbert Bacher, Stefan Weber, Erik Schleicher","doi":"10.1111/febs.70129","DOIUrl":"https://doi.org/10.1111/febs.70129","url":null,"abstract":"<p><p>Cryptochromes are flavin adenine dinucleotide (FAD)-containing blue-light photoreceptors involved in the regulation of the circadian clock and may play a role in magnetic field sensing. The photochemistry of cryptochromes is based on the isoalloxazine moiety, which can be photoreduced and subsequently reoxidized by an electron acceptor such as oxygen, corresponding to a photo-switch between the dark and signaling state. We replaced the FAD cofactor of Drosophila cryptochrome with a series of FAD cofactors modified at the 7α or 8α positions, in order to modulate the chemical properties of the electron acceptor. These modifications were shown to alter the kinetics of the light-dependent reactions. Notably, 7-halogenated FADs form the signaling state more than six times faster compared to the natural FAD cofactor. The more positive reduction potentials as well as the increased intersystem crossing rates due to heavy halogen atoms were identified as reasons for the altered photochemistry. Both parameters show a linear dependence on the reaction kinetics, according to the Hammett relationship. With this knowledge, the photochemistry of cryptochromes may be modified in a defined way without changing its amino acid sequence.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144083065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gal-1 promotes lung cancer cell survival by enhancing PARP1/H1.2 interaction to promote DNA repair upon DNA damage response.","authors":"Yihao Chen, Xiaomei Liu, Buju Li, Xinru Xie, Jin Xia, Hui Sun","doi":"10.1111/febs.70134","DOIUrl":"https://doi.org/10.1111/febs.70134","url":null,"abstract":"<p><p>Galectin-1 (Gal-1), a member of the galectin family, has emerged as a regulator of tumor progression. Several studies have reported the upregulation of Gal-1 expression in multiple cancer cells and its promotion on tumor proliferation. However, the mechanism by which Gal-1 promotes tumor growth remains to be thoroughly understood. In this study, it was discovered that high expression of Gal-1 in various cancers was inversely correlated with the overall survival of patients. Through constructing Gal-1-overexpressing cell lines, it was uncovered that cell proliferation and colony formation were significantly improved. The results of transcriptomic and proximity-labeling-based proteomic analyses indicated that Gal-1 interacted with poly [ADP-ribose] polymerase 1 (PARP1) and histone H1.2 in lung cancer cells. In the case of etoposide treatment leading to DNA double-strand break, Gal-1 accelerated the degradation of H1.2 by enhancing its interaction with PARP1 and promoting its PARylation. It caused the activation of downstream DNA repair pathways such as the serine-protein kinase ATM and nibrin (NBS1) signaling pathways, thus reducing apoptosis, and the Gal-1 inhibitor thiodigalactoside (TDG) could restore cell sensitivity to etoposide. Upon knockdown of Gal-1, DNA damage led to impaired activation of ATM and NBS1 phosphorylation, thereby increasing the sensitivity of the A549 cell line to etoposide. Finally, using a tumor-bearing mouse model, we observed that, in tumors with high Gal-1 expression, the combination treatment of TDG and etoposide significantly inhibited tumor growth. This study provides new clues for the role of Gal-1 in the development of tumors and renders suggestions for the medication of patients with high Gal-1 expression in the clinic.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin protects the heart against chronic intermittent hypoxia through AMPK-dependent phosphorylation of HIF-1α.","authors":"Sophie Moulin, Britanny Blachot-Minassian, Anita Kneppers, Amandine Thomas, Stéphanie Paradis, Laurent Bultot, Claire Arnaud, Jean-Louis Pépin, Luc Bertrand, Rémi Mounier, Elise Belaidi","doi":"10.1111/febs.70110","DOIUrl":"https://doi.org/10.1111/febs.70110","url":null,"abstract":"<p><p>Chronic intermittent hypoxia (IH), a major feature of obstructive sleep apnea syndrome (OSA), is associated with greater severity of myocardial infarction. In this study, we performed RNA sequencing of cardiac samples from mice exposed to IH, which reveals a specific transcriptomic signature of the disease, relative to mitochondrial remodeling and cell death. Corresponding to its activation under chronic IH, we stabilized the Hypoxia Inducible Factor-1α (HIF-1α) in cardiac cells in vitro and observed its association with an increased autophagic flux. In accordance, IH induced autophagy and mitophagy, which are decreased in HIF-1α^+/- mice compared to wild-type animals, suggesting that HIF-1 plays a significant role in IH-induced mitochondrial remodeling. Next, we showed that the AMPK metabolic sensor, typically activated by mitochondrial stress, is inhibited after 3 weeks of IH in hearts. Therefore, we assessed the effect of metformin, an anti-diabetic drug and potent activator of AMPK, on myocardial response to ischemia-reperfusion (I/R) injury. Daily administration of metformin significantly decreases infarct size without any systemic beneficial effect on insulin resistance under IH conditions. The cardioprotective effect of metformin was lost in AMPKα2 knock-out mice, demonstrating that AMPKα2 isoform promotes metformin-induced cardioprotection in mice exposed to IH. Mechanistically, we found that metformin inhibits IH-induced mitophagy in myocardium and decreases HIF-1α nuclear expression in mice subjected to IH. In vitro experiments demonstrated that metformin induced HIF-1α phosphorylation, decreased its nuclear localization, and HIF-1 transcriptional activity. Collectively, these results identify the AMPKα2 metabolic sensor as a novel modulator of HIF-1 activity. Our data suggest that metformin could be considered as a cardioprotective drug in OSA patients independently of their metabolic status.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and mechanistic characterization of a probiotic-origin 3β-OH-Δ^5-6-cholesterol-5β-reductase directly converting cholesterol to coprostanol.","authors":"Urmila Netter, Vishakha Bisht, Amit Gaurav, Rekha Sharma, Avik Ghosh, Vinod Singh Bisht, Kiran Ambatipudi, Hanuman Prasad Sharma, Sujata Mohanty, Shubham Loat, Mihir Sarkar, Kapil Tahlan, Naveen K Navani","doi":"10.1111/febs.70131","DOIUrl":"https://doi.org/10.1111/febs.70131","url":null,"abstract":"<p><p>Cholesterol serves as a fundamental molecule in various structural and biochemical pathways; however, high cholesterol levels are linked to cardiovascular diseases. Some selected strains of Lactobacilli are known for modulating cholesterol levels. However, the molecular mechanism underlying cholesterol transformation by lactobacilli has remained elusive. This study describes the discovery and function of a microbial 3β-OH-Δ^5-6-cholesterol-5β-reductase (5βChR) from Limosilactobacillus fermentum NKN51, which directly converts cholesterol to coprostanol, thereby unraveling this longstanding mystery. Protein engineering of the reductase enzyme identified the cholesterol and NADPH interacting amino acid residues, detailing the catalytic mechanism of 5βChR. Phylogenetic analyses highlight the prevalence of 5βChRs in gut commensal lactobacilli, which share a common evolutionary origin with plant 5β reductases. Meta-analysis of microbiomes from healthy individuals underscores the importance of 5βChR homologs, while a cohort study demonstrates an inverse association between 5βChR abundance and diabetes. The discovery of the 5βChR enzyme and its molecular mechanism in cholesterol metabolism paves the way for a better understanding of the gut-associated microbiome and the design of practical applications to ameliorate dyslipidemia.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the outcomes of pluripotent stem-cell-derived photoreceptor transplantation in retinal repair.","authors":"Darin Zerti, Birthe Dorgau, Evelyne Sernagor, Lyle Armstrong, Majlinda Lako, Gerrit Hilgen","doi":"10.1111/febs.70127","DOIUrl":"https://doi.org/10.1111/febs.70127","url":null,"abstract":"<p><p>In recent decades, numerous research groups have focused on restoring visual function through the transplantation of stem cells into animal models of retinal neurodegeneration. Significant advancements in surgical techniques, the maturation of donor cells, and the production of cell suspensions, along with ensuring proper synaptic connectivity with the host environment, are key considerations for the potential implementation of this strategy in clinical practice. In this review, we summarize the latest progress in the transplantation of stem cell-derived photoreceptors, emphasizing the outcomes related to visual function observed in the used animal models. Additionally, we analyze the various methods of stem cell differentiation and the surgical techniques selected for transplanting these photoreceptor precursors. Finally, we report on functional assessments from recent studies to highlight the considerable potential of stem cell-derived photoreceptor transplants as a therapeutic approach for retinal degenerative diseases.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}