The FEBS journal最新文献

{"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}

{"title":"Msp1 and Pex19-Pex3 cooperate to achieve correct localization of Pex15 to peroxisomes.","authors":"Shunsuke Matsumoto, Yoshiki Kogure, Suzuka Ono, Tomoyuki Numata, Toshiya Endo","doi":"10.1111/febs.70132","DOIUrl":"https://doi.org/10.1111/febs.70132","url":null,"abstract":"<p><p>Yeast Msp1 is a dual-localized AAA-ATPase on the mitochondrial outer membrane (OM) and peroxisomal membrane. We previously showed that Msp1 transfers mistargeted tail-anchored (TA) proteins from mitochondria to the endoplasmic reticulum (ER) for degradation or delivery to their original destinations. However, the mechanism by which Msp1 in mitochondria and peroxisomes handles authentic peroxisomal TA proteins remains unclear. We show that newly synthesized Pex15 is targeted to peroxisomes primarily via the Pex19- and Pex3-dependent pathway. Mistargeted Pex15 on the mitochondrial OM is extracted by mitochondrial Msp1 and transferred to the ER via the guided-entry of TA proteins pathway for degradation or to peroxisomes via the Pex19-Pex3 pathway. Intriguingly, endogenous Pex15 localized in peroxisomes is also extracted from the membranes by peroxisomal Msp1 but returns to peroxisomes via the Pex19-Pex3 pathway. These results suggest that correct Pex15 localization to peroxisomes relies on not only the initial targeting by Pex19-Pex3 but also the constant re-routing by Msp1 and Pex19-Pex3.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000986","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":"STIM2β is a Ca²⁺ signaling modulator for the regulation of mitotic clonal expansion and PPARG2 transcription in adipogenesis.","authors":"Su Ji Jeong, Bo-Woong Sim, Sun-Uk Kim, Chan Young Park","doi":"10.1111/febs.70118","DOIUrl":"https://doi.org/10.1111/febs.70118","url":null,"abstract":"<p><p>Intracellular Ca²⁺ is crucial in the regulation of adipocyte lipid metabolism and adipogenesis. In this study, we aimed to investigate the regulation mechanism of intracellular Ca²⁺ levels ([Ca²⁺]_i) during adipocyte differentiation. We found that the expression of stromal interaction molecule 2 beta (STIM2β), which is the inhibitor of store-operated Ca²⁺ entry (SOCE), is upregulated throughout the differentiation process. Evaluation of [Ca²⁺]_i in 3 T3-L1 and primary stromal vascular fraction (SVF) cells revealed that the basal Ca²⁺ level is downregulated after differentiation. Knockout (KO) of STIM2β in 3T3-L1 and primary SVF cells showed increased [Ca²⁺]_i, indicating the involvement of STIM2β in the regulation of [Ca²⁺]_i during adipogenesis. We further evaluated the function of STIM2β-mediated [Ca²⁺]_i in early and terminal differentiation of adipogenesis. Analysis of cell proliferation rate during mitotic clonal expansion (MCE) in wild-type and STIM2β KO 3T3-L1 cell lines revealed that a larger population of KO cells underwent G1 arrest, suggesting that reduced [Ca²⁺]_i by STIM2β induces MCE. Additionally, ablation of STIM2β increased differentiation efficiency, with more lipid accumulation and rapid transcriptional activation of adipogenic genes, especially proliferator-activator receptor γ2 (PPARG2). We found that PPARG2 transcription is regulated by store-operated calcium entry (SOCE) downstream transcription factors, confirming that increased [Ca²⁺]_i by STIM2β ablation promotes PPARG2 transcription during adipogenesis. Additionally, STIM2β KO mice showed hypertrophic adipose tissue development. Our data suggest that STIM2β-mediated [Ca²⁺]_i plays a pivotal role in the regulation of mitotic clonal expansion and PPARG2 gene activation and provides evidence that MCE is not a prerequisite process for terminal differentiation during adipogenesis.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001013","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":"The disease-linked R336C mutation in cystathionine β-synthase disrupts communication with the PLP cofactor, yet maintains the enzyme's overall structural integrity.","authors":"Carolina Conter, Reyes Núñez-Franco, Duaa Walid Al-Sadeq, Carmen Fernández-Rodríguez, Naroa Goikoetxea-Usandizaga, Gheyath K Nasrallah, Michail Nomikos, Maria Luz Martinez-Chantar, Alessandra Astegno, Gonzalo Jiménez-Osés, Luis Alfonso Martínez-Cruz","doi":"10.1111/febs.70116","DOIUrl":"https://doi.org/10.1111/febs.70116","url":null,"abstract":"<p><p>Cystathionine β-synthase (CBS) is a pyridoxal-phosphate (PLP)-dependent enzyme essential for the reverse transsulfuration pathway, where homocysteine and serine combine to form cystathionine, the immediate precursor of cysteine. Mutations in the CBS gene cause homocystinuria, a disorder associated with intellectual disability, multisystem complications, and reduced life expectancy. The CBS p.R336C mutation, linked to severe pyridoxine non-responsiveness, results in reduced enzyme activity, previously attributed to protein instability and weakened substrate and PLP binding. To clarify the effects of the pathological R336C mutation, we performed biochemical, biophysical, and crystallographic analyses, as well as molecular dynamics simulations. Our findings show that the R336C mutation minimally impacts the structural environment around residue 336, does not cause enzyme misfolding, and does not impair the binding of PLP or the allosteric activator S-adenosylmethionine (AdoMet) binding. Instead, the mutation induces subtle reorientations in nearby hydrophobic residues, including F185 and Y381, altering intramolecular contacts that perturb the interaction between asparagine 149 and the O3 oxygen of PLP. This alteration is known to potentially shift the tautomeric equilibrium of the PLP Schiff base from its catalytically active ketoenamine form to the inactive enolimine form, which aligns with the reduced activity of the R336C variant. Additionally, the R336C mutation disrupts intermolecular contacts between the catalytic core and Bateman module, altering the Bateman module's intrinsic mobility in the enzyme's basal state and potentially affecting the cavity opening required for catalysis. Importantly, the R336C variant retains the native enzyme's ability to assemble into polymeric chains in crystals, preserving its filament formation capacity.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046855","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}