The FEBS journal最新文献

{"title":"Tks5 interactome reveals endoplasmic-reticulum-associated translation machinery in invadosomes.","authors":"Léa Normand, Benjamin Bonnard, Margaux Sala, Sylvaine Di Tommaso, Cyril Dourthe, Anne-Aurélie Raymond, Jean-William Dupuy, Luc Mercier, Jacky G Goetz, Violaine Moreau, Elodie Henriet, Frédéric Saltel","doi":"10.1111/febs.70196","DOIUrl":"https://doi.org/10.1111/febs.70196","url":null,"abstract":"<p><p>The ability to progress and invade through the extracellular matrix is a characteristic shared by both normal and cancer cells through the formation of structures called invadosomes, which include invadopodia and podosomes. These invadosomes are plastic and dynamic structures that can adopt different organizations-such as rosettes, dots, or linear invadosomes-depending on the cell types and the environment. In this study, we used the specific invadosome marker SH3 and PX domain-containing protein 2A (SH3PXD2A; also known as Tks5) to identify common features in these different organizations. Tks5 immunoprecipitation coupled with mass spectrometry analysis allowed us to identify common proteins in these different models. We identified elements of the translation machinery, in particular the eukaryotic translation initiation factor 4B (EIF4B) protein, but also endoplasmic reticulum (ER) proteins as part of the invadosome structure. Providing new data on invadosome molecular composition through the Tks5 interactome, we identified that ER-associated translation machinery is recruited to invadosomes and involved in their formation, persistence, and function in all types of invadosomes.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710430","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":"A CRISPR/Cas9 knockout model for AADC deficiency reveals structural loop3 instability as a key driver of catalytic failure.","authors":"Sema Kalkan Uçar, Cem Yıldırım, Thomas Opladen","doi":"10.1111/febs.70204","DOIUrl":"https://doi.org/10.1111/febs.70204","url":null,"abstract":"<p><p>The CRISPR-Cas9 dopa decarboxylase (DDC) gene knockout SH-SY5Y model for aromatic L-amino acid decarboxylase (AADC) deficiency provides a valuable neuronal platform for functional and structural investigation of pathogenic variants. In their study, Bertoldi et al. successfully recapitulate the biochemical and metabolic hallmarks of AADC deficiency using the AADC catalytic variants R347Q and L353P. Their combined structural and cellular approach identifies loop3 dynamics as a critical determinant of enzymatic dysfunction. This model may pave the way for the development of precision therapies.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710426","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":"Altered fatty acid oxidation via CPT1A promotes epithelial-to-mesenchymal transition in ovarian cancer.","authors":"Suman Pakhira, Sib Sankar Roy","doi":"10.1111/febs.70193","DOIUrl":"https://doi.org/10.1111/febs.70193","url":null,"abstract":"<p><p>Metabolic alterations are increasingly recognized as fundamental features of cancer. Recent studies have highlighted the involvement of altered fatty acid oxidation (FAO) at different stages of tumor development. As the rate-limiting enzyme of FAO, CPT1 plays a crucial role in these metabolic adaptations in cancer cells. However, the regulation of CPT1 expression and activity in tumor cells still requires detailed investigation. Our studies reveal that CPT1A, a variant of CPT1, is significantly upregulated in ovarian cancer (OC) and correlates with poor prognosis. Inhibition of CPT1A, either by siRNA-mediated knockdown or by etomoxir, reduces the migratory and invasive properties of the OC cells. CPT1A exerts these effects by modulating the expression of epithelial-to-mesenchymal transition (EMT)-associated genes at transcriptional and protein levels. Growth factors such as transforming growth factor beta (TGFβ) are abundant in the tumor microenvironment and modulate the metabolic profile of tumors, thereby promoting EMT. Our findings demonstrate that TGFβ treatment increases the rate of FAO in ovarian cancer cells. Mechanistically, TGFβ mediates this effect by enhancing CPT1A expression and its enzymatic activity in OC cells through an AMPK-dependent pathway. Additionally, we identified NRF2 as a potential transcriptional regulator of CPT1A within the context of TGFβ-AMPK signaling. Finally, inhibiting CPT1A successfully attenuates TGFβ-induced EMT in ovarian cancer cells. Cumulatively, our study underscores the role of CPT1A-mediated FAO in facilitating ovarian cancer progression through TGFβ-induced EMT.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710427","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":"Phosphoproteomic analysis reveals the diversity of signaling behind ErbB-inhibitor-induced phenotypes.","authors":"Katri Vaparanta, Zejia Song, Iman Farahani, Anne Jokilammi, Johannes Merilahti, Johanna Örling, Noora Virtanen, Pekka Haapaniemi, Cecilia Sahlgren, Klaus Elenius, Ilkka Paatero","doi":"10.1111/febs.70197","DOIUrl":"https://doi.org/10.1111/febs.70197","url":null,"abstract":"<p><p>The impact of kinase inhibitors on the phosphoproteome has been rarely investigated at a whole-organism level. Here, we performed a phosphoproteomic analysis in embryonic zebrafish to identify the signaling pathways perturbed by ErbB receptor tyrosine-protein kinase inhibitors gefitinib, lapatinib, and AG1478 at the organism level. The phosphorylation of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), p38 mitogen-activated protein kinase (MAPK), Notch, Hippo/Yap, and β-catenin signaling pathways was differentially regulated by the ErbB inhibitors. Gene set enrichment analyses indicated differential neurological and myocardial phenotypes of different ErbB inhibitors. To assess the neurological and myocardial effects, motility and ventricle growth assays were performed with inhibitor-treated embryos. The treatment with the inhibitors targeting the PI3K/Akt, p38 MAPK, and Notch signaling pathways, along with the ErbB inhibitors AG1478 and lapatinib, perturbed the overall movement and ventricle wall growth of zebrafish embryos. Taken together, these results indicate that inhibitors with overlapping primary targets can affect different signaling pathways while eliciting similar physiological phenotypes.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710428","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":"Therapeutic outlooks for Gal-1 and genotoxic agents.","authors":"Eric J Sohn, Jaewon Min","doi":"10.1111/febs.70203","DOIUrl":"https://doi.org/10.1111/febs.70203","url":null,"abstract":"<p><p>Gal1 belongs to a family of soluble lectins that have both intracellular and extracellular functions. Elevated Gal1 is implicated in numerous signaling cascades, immune response pathways, and chemotherapy resistance, and may contribute to proliferation or cell death, depending on cancer cell type. Chen et al. describe a new interaction between Gal1 and PARP1 in non-small-cell lung cancer cell lines, which enhances DNA damage response and reduces cell death. Furthermore, the authors show that tumors can be resensitized to etoposide treatment using Gal1 inhibitors. They further explore the role of PARP1 in homologous recombination and that of Gal1 in cell metastasis.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710429","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":"TSC22D1 is a newly identified inhibitor of insulin secretion in pancreatic beta cells.","authors":"Sümbül Yıldırım, Amit Mhamane, Svenja Lösch, Annika Wieder, Ezgi Ermis, Ann-Christine König, Sevgican Yilmaz, Stefanie M Hauck, Fatih Kocabas, Julia Szendroedi, Stephan Herzig, Bilgen Ekim","doi":"10.1111/febs.70194","DOIUrl":"https://doi.org/10.1111/febs.70194","url":null,"abstract":"<p><p>The loss of pancreatic beta cell function leads to chronically high blood glucose levels, contributing to diabetes mellitus, one of the leading causes of morbidity and mortality worldwide. Understanding the molecular mechanisms that regulate beta cell function could pave the way for the development of more effective antidiabetic treatments. In this study, we identify the evolutionarily conserved transforming growth factor β-1 stimulated clone D1 (TSC22D1) protein as a previously unknown regulator of beta cell function. TSC22D1 depletion in INS-1E cells enhances the expression of key beta cell identity genes, including Ins1, Ins2, Pdx1, Slc2a2, and Nkx6.1, and promotes glucose-stimulated insulin secretion without altering intracellular insulin content. Mechanistically, TSC22D1 and Forkhead box protein O1 (FoxO1) interact and regulate each other in a reciprocal manner to control beta cell function. Our follow-up interactome and RNA-Seq analyses reveal that TSC22D1 is crucial for glucose-responsive cellular processes in beta cells, including mRNA processing, ribonucleoprotein complex biogenesis, and Golgi vesicle transport. Overall, our findings indicate that TSC22D1 plays a significant role in regulating beta cell function at multiple levels, with potential implications for metabolic diseases, such as diabetes.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664138","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":"A phosphoserine phosphatase variant present in the brain of Alzheimer's disease patients favors nuclear mistargeting.","authors":"Silvia Sacchi, Valeria Buoli Comani, Ivan Arisi, Francesco Marchesani, Valentina Rabattoni, Omar De Bei, Zoraide Motta, Alessio Peracchi, Stefano Bruno, Loredano Pollegioni, Barbara Campanini","doi":"10.1111/febs.70169","DOIUrl":"https://doi.org/10.1111/febs.70169","url":null,"abstract":"<p><p>Phosphoserine phosphatase (PSP) catalyzes the dephosphorylation of 3-phosphoserine, which is the final step in the de novo biosynthesis of l-serine (l-Ser) via the phosphorylated pathway in human astrocytes. Individuals who are homozygous or compound heterozygous for functionally defective PSP variants exhibit reduced cerebrospinal fluid l-Ser levels and severe neurological symptoms. In the present study, single nucleotide polymorphisms in PSP were identified in hippocampal samples from Alzheimer's disease (AD) patients. Two single nucleotide polymorphisms, likely forming a haplotype (chr7:56088825 T>A and chr7:56088811 T>C, encoding R27S and D32G PSP variants, respectively), were detected exclusively in AD patients (three females and one male). Biochemical characterization of the recombinant R27S/D32G PSP enzyme revealed a slight decrease in thermostability, a 38-fold reduction in catalytic efficiency and a two-fold increase in IC₅₀ for l-Ser, with the D32G substitution being the primary contributor to these effects. Despite its reduced enzyme activity, the R27S/D32G variant did not impair l-Ser biosynthesis either in an in vitro reconstructed pathway or in U251 human glioblastoma cells ectopically expressing the variant under heterozygous conditions. In these cells, PSP colocalized extensively with the other two phosphorylated pathway enzymes, namely phosphoglycerate dehydrogenase and phosphoserine aminotransferase, suggesting that they assemble into a functional complex, known as the serinosome. Notably, the R27S/D32G PSP variant exhibited increased nuclear localization compared to the wild-type enzyme. This mislocalization raises the intriguing possibility that PSP's moonlighting functions, including its putative role as a protein phosphatase, may be affected, potentially implicating it in pathways beyond l-Ser biosynthesis.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664137","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":"In vivo modeling of lethal congenital contracture syndrome 1 suggests pathomechanisms in cellular stress responses.","authors":"Tomáš Zárybnický, Sonja Lindfors, Saana Metso, Julia Koivula, Zoltan Szabo, Rasmus Valtonen, Mikko Tulppo, Johanna Magga, Samu Saarimäki, Sonja Bläuer, Ilkka Miinalainen, Risto Kerkelä, Petteri T Piepponen, Vootele Voikar, Juho Väänänen, Riikka Kivelä, Bhagwan Yadav, Hanna Lindgren, Pirkko Mattila, Fu-Ping Zhang, Petra Sipilä, Reetta Hinttala, Satu Kuure","doi":"10.1111/febs.70195","DOIUrl":"https://doi.org/10.1111/febs.70195","url":null,"abstract":"<p><p>The mRNA export factor GLE1 protein plays critical yet enigmatic functions in RNA processing and has been linked with multiple developmental disorders, including lethal congenital contracture syndrome 1 (LCCS1). Using in vivo genetic engineering to study disturbed GLE1 functions under physiological conditions, we demonstrate that total inactivation of GLE1 results in disorganization of the blastocyst inner cell mass and early embryonic lethality due to defects in lineage specification. In contrast, the knock-in mice genocopying the LCCS1-associated GLE1_FinMajor variant (Gle1^PFQ/PFQ) survive the prenatal period but die suddenly at midadulthood. Gle1^PFQ/PFQ mice present an irregular count and distribution of spinal motor neurons as well as impaired development of neural crest-derived tissues, as demonstrated by defects in the sympathetic innervation of heart ventricles, irregularities in the paravertebral sympathetic ganglia volume, and decreased adrenal chromaffin cell counts. Unlike previously reported for yeast and HeLa cells, analysis of the molecular consequences of the GLE1_FinMajor variant identified normal poly(A) + RNA distribution in Gle1^PFQ/PFQ cells; however, cells were impaired in RNA and protein synthesis and simultaneously showed severely disturbed formation of G3BP stress granule assembly factor 1 (G3BP1)-positive stress granules. Intriguingly, stressed Gle1^PFQ/PFQ cells show microRNA profiles indicative of impaired transcription, protein metabolism, nervous system development, and axon guidance, further corroborating our functional findings. Our results show the necessity of functional GLE1 for life and indicate that LCCS1 etiology is a result of the pathogenic GLE1_FinMajor variant impinging differentiation of neural crest derivatives and leading to complex multiorgan defects.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661492","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":"Hidden protein disorder: Deciphering the structural organisation and dynamics of a non-canonical CP12 from the diatom Thalassiosira pseudonana.","authors":"Alessio Bonucci, Tingting Wang, Hakima Baroudi, Emilien Etienne, Guillaume Gerbaud, Elisabetta Mileo, Goetz Parsiegla, Takahisa Yamato, Brigitte Gontero, Hélène Launay, Valérie Belle, Véronique Receveur-Bréchot","doi":"10.1111/febs.70187","DOIUrl":"https://doi.org/10.1111/febs.70187","url":null,"abstract":"<p><p>The chloroplastic protein CP12 from the diatom Thalassiosira pseudonana exhibits atypical and enigmatic structural properties that have so far hindered our understanding of its functions. Here, we used AlphaFold to generate a three-dimensional (3D) model of the structure of the protein. However, this model did not accurately describe the small-angle X-ray scattering (SAXS) data previously obtained. We have therefore undertaken a study using site-directed spin labelling combined with electron paramagnetic resonance (SDSL-EPR) to characterise the structural dynamics of this atypical CP12 and to investigate its dimeric organisation using double electron-electron resonance (DEER). We then performed molecular dynamics (MD) simulations, constrained by SAXS and DEER data, to refine the AlphaFold model and take into account the flexibility and disordered propensities of this protein. The combination of the experimental techniques together with the in silico AlphaFold and MD simulations reveals that the dimer is organised in an antiparallel arrangement of each monomer and that the C-terminal regions are highly flexible and partly disordered. Additionally, this diatom CP12 contains four structured domains likely to bind phosphoribulokinase regardless of their redox state. Our structural data therefore provide insights into the function of this protein in the regulation of the Calvin cycle and of photosynthesis in diatoms, whereas its structural organisation is completely different from any of its homologous counterparts from Plantae and cyanobacteria.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661491","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":"Enhancing macrophage phagocytosis of cancers by disrupting the SIRPα/CD47 signaling axis and targeting MUC1 antigen.","authors":"Saitong Muneekaew, Pasut Sasithong, Koollawat Chupradit, Kritayaporn Saiprayong, Thunchanok Nuchphongsai, Methichit Wattanapanitch","doi":"10.1111/febs.70192","DOIUrl":"https://doi.org/10.1111/febs.70192","url":null,"abstract":"<p><p>Signal regulatory protein alpha (SIRPα) is an essential immune checkpoint, predominantly expressed on myeloid cells, that binds to CD47. This interaction, termed the 'don't eat me' signal, contributes to immune suppression. Consequently, disruption of the SIRPα/CD47 axis emerges as a promising strategy to intervene in the 'don't eat me' signal, thereby initiating phagocytic activation. Various preclinical and clinical studies employed SIRPα/CD47-targeting molecules to disrupt the SIRPα/CD47 axis to promote cancer phagocytosis. However, concerns regarding their limited efficacy and side effects pose a challenge to applying this approach to cancer therapy. Here, we investigated the role of the SIRPα/CD47 axis in phagocytosis by performing clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated SIRPA gene disruption in the monocytic cell line THP-1. The SIRPα knockout (KO) THP-1 cells were comprehensively characterized for their phenotype and functions, including differentiation into M0 macrophages, polarization into M1 or M2 macrophages, and phagocytosis of bioparticles and cancer cells, and compared to their wild-type (WT) counterparts. The SIRPα KO THP-1 cells retained their monocyte and macrophage characteristics. Remarkably, they exhibited enhanced phagocytosis of bioparticles and leukemic cell lines but not breast cancer cell lines. The introduction of a chimeric antigen receptor (CAR) targeting tumor-associated mucin1 antigen (tMUC1-CAR) further enhanced their phagocytic activity against the breast cancer cell line, MCF-7, which expresses high levels of MUC1. Our findings highlight the therapeutic potential of SIRPα KO macrophages in cancer immunotherapy, particularly for hematologic malignancies. However, a combination with CAR was necessary to enhance the phagocytic activity against solid cancer models.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639172","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}