The FEBS journal最新文献

{"title":"A cellular model of TDP-43 induces phosphorylated TDP-43 aggregation with distinct changes in solubility and autophagy dysregulation.","authors":"Matthew B Dopler, Muhammad I Abeer, Sanaz Arezoumandan, Keyshawn Cox, Tyler L Petersen, Esther H Daniel, Carlton L Cannon, Angelica Bautista, Kennedy D Blancher, Alysia M Bland, Kylie J Bond, Dominque A Davis, Jessica M Francois, Eliana J McCray, Justin M Morgan, Jessica L Pulliam, Zymir A Robinson, Mykia J Taylor, James A Dowell, Nigel J Cairns, Michael A Gitcho","doi":"10.1111/febs.17413","DOIUrl":"10.1111/febs.17413","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that affects neurons in the brain and spinal cord, causing loss of muscle control, and eventually leads to death. Phosphorylated transactive response DNA binding protein-43 (TDP-43) is the major pathological protein in both sporadic and familial ALS, forming cytoplasmic aggregates in over 95% of cases. Of the 10-15% of ALS cases that are familial, mutations in TDP-43 represent about 5% of those with a family history. We have developed an in vitro overexpression model by introducing three familial ALS mutations (A315T, M337V, and S379P) in the TDP-43 (TARDBP) gene which we define as 3X-TDP-43. This overexpression model TDP-43 shows deficits in autophagy flux and colocalization of TDP-43 with stress granules. We also observe a progressive shift of TDP-43 to the cytoplasm in this model. This overexpression model shows a reduction in solubility of phosphorylated TDP-43 from RIPA to urea soluble. Four glycolytic enzymes, phosphoglycerate kinase one (PGK1), aldolase A (ALDOA), enolase 1 (ENO1), and pyruvate dehydrogenase kinase 1 (PDK1) show significant time-dependent decreases in 3X-TDP-43 expressing cells. Shotgun proteomic analysis shows global changes in the importin subunit alpha-1 (KPNA2), heat shock 70 kDa protein 1A (HSPA1A), and protein disulfide-isomerase A3 (PDIA3) expression levels and coimmunoprecipitation reveals that these proteins complex with TDP-43. Overall, these results suggest that the 3X-TDP-43 model may provide new insights into pathophysiology and an avenue for drug screening in vitro for those suffering from ALS and related TDP-43 proteinopathies.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070583","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":"Words of advice for young scientists in developing countries.","authors":"Max Chavarría","doi":"10.1111/febs.17425","DOIUrl":"https://doi.org/10.1111/febs.17425","url":null,"abstract":"<p><p>As scientists, change is the only constant in our journey. We often find ourselves in transition from one laboratory to another, and during our training we are fortunate to experience the excitement of pursuing postgraduate studies abroad in well-funded, high-level research centers. However, after completing doctoral or postdoctoral training, we are frequently drawn to return to our home countries, where funding and support for science are significantly more limited. In this brief commentary, first, I would like to highlight the challenges faced by scientists from developing countries who have had the opportunity to train internationally and then choose to return home, driven both by personal motivations (e.g., family) and by the desire to contribute to the scientific advancement of their regions. Second, I would like to share some advice that has been especially useful to me in establishing my laboratory, defining research topics, and maintaining academic productivity. I hope these insights can be useful to colleagues in similar situations across different regions. Although starting a research group in regions with less investment in Research and Development is challenging, it is achievable with perseverance and the implementation of concrete actions.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069576","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":"Structural insights into substrate transport and drug inhibition of the human vesicular monoamine transporter 2 (VMAT2).","authors":"Di Wu, Yan Zhao, Daohua Jiang","doi":"10.1111/febs.70003","DOIUrl":"https://doi.org/10.1111/febs.70003","url":null,"abstract":"<p><p>Vesicular monoamine transporter 2 (VMAT2) is a proton-monoamine antiporter that is widely expressed in central and peripheral neurons and plays a crucial role in loading monoamine neurotransmitters into secretory vesicles. Dysfunction of VMAT2 causes many neuropsychiatric disorders, such as depression and Parkinson's disease. Consequently, VMAT2 is a valid and important therapeutic target. Reserpine alleviates symptoms of hypertension via potent inhibition of VMAT2. Tetrabenazine selectively inhibits VMAT2 and has been used for the management of chorea, including Huntington's disease. Decades of extensive studies have defined the substrate specificity and transport kinetics of VMAT2. However, the structure and precise mechanisms of monoamine recognition and drug inhibition in VMAT2 remain unknown. Recently, we determined an ensemble of high-resolution cryo-EM structures of human VMAT2 in three distinct states bound to multiple substrates and inhibitors. These results lay a structural foundation for a comprehensive understanding of substrate recognition and transport, drug inhibition, and proton coupling in VMAT2 and shed light on future therapeutic development.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070593","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":"Versatile roles of disordered transcription factor effector domains in transcriptional regulation.","authors":"Rhea R Datta, Dilan Akdogan, Elif B Tezcan, Pinar Onal","doi":"10.1111/febs.17424","DOIUrl":"https://doi.org/10.1111/febs.17424","url":null,"abstract":"<p><p>Transcription, a crucial step in the regulation of gene expression, is tightly controlled and involves several essential processes, such as chromatin organization, recognition of the specific genomic sequences, DNA binding, and ultimately recruiting the transcriptional machinery to facilitate transcript synthesis. At the center of this regulation are transcription factors (TFs), which comprise at least one DNA-binding domain (DBD) and an effector domain (ED). Although the structure and function of DBDs have been well studied, our knowledge of the structure and function of effector domains is limited. EDs are of particular importance in generating distinct transcriptional responses between protein members of the same TF family that have similar DBDs and specificities. The study of transcriptional activity conferred by effector domains has traditionally been conducted through examining protein-protein interactions. However, recent research has uncovered alternative mechanisms by which EDs regulate gene expression, such as the formation of condensates that increase the local concentration of transcription factors, cofactors, and coregulated genes, as well as DNA binding. Here, we provide a comprehensive overview of the known roles of transcription factor EDs, with a specific focus on disordered regions. Additionally, we emphasize the significance of intrinsically disordered regions (IDRs) during transcriptional regulation. We examine the mechanisms underlying the establishment and maintenance of transcriptional specificity through the structural properties of predominantly disordered EDs. We then provide a comprehensive overview of the current understanding of these domains, including their physical and chemical characteristics, as well as their functional roles.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070596","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":"Diel modulation of perireceptor activity influences olfactory sensitivity in diurnal and nocturnal mosquitoes.","authors":"Tanwee Das De, Julien Pelletier, Satyajeet Gupta, Madhavinadha Prasad Kona, Om P Singh, Rajnikant Dixit, Rickard Ignell, Krishanpal Karmodiya","doi":"10.1111/febs.17418","DOIUrl":"https://doi.org/10.1111/febs.17418","url":null,"abstract":"<p><p>Olfaction and diel-circadian rhythm regulate different behaviors, including host-seeking, feeding, and locomotion, in mosquitoes that are important for their capacity to transmit disease. Diel-rhythmic changes of the odorant-binding proteins (OBPs) in olfactory organs are primarily accountable for olfactory rhythmicity. To better understand the molecular rhythm regulating nocturnal and diurnal behaviors in mosquitoes, we performed a comparative RNA-sequencing study of the peripheral olfactory and brain tissues of female Anopheles culicifacies and Aedes aegypti. Data analysis revealed a significant upregulation of genes encoding: OBPs and xenobiotic-metabolizing enzymes including Cytochrome P450 (CYP450) during photophase in Aedes aegypti and the dusk-transition phase in Anopheles culicifacies, hypothesizing their possible function in the regulation of perireceptor events and olfactory sensitivity. RNA interference studies and application of CYP450 inhibitors, coupled with electroantennographic recordings with Anopheles gambiae and Aedes aegypti, established that CYP450 plays a role in odorant detection and antennal sensitivity. Furthermore, brain tissue transcriptome and RNAi-mediated knockdown revealed that daily temporal modulation of neuronal serine proteases may have a crucial function in olfactory signal transmission, thereby affecting olfactory sensitivity. These findings provide a rationale to further explore the species-specific rhythmic expression pattern of the neuro-olfactory encoded molecular factors, which could pave the way to develop and implement successful mosquito control methods.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070586","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":"Characterization of multiple binding sites on microtubule associated protein 2c recognized by dimeric and monomeric 14-3-3ζ.","authors":"Séverine Jansen, Subhash Narasimhan, Paula Cabre Fernandez, Lucia Iľkovičová, Aneta Kozeleková, Kateřina Králová, Jozef Hritz, Lukáš Žídek","doi":"10.1111/febs.17405","DOIUrl":"https://doi.org/10.1111/febs.17405","url":null,"abstract":"<p><p>Microtubule associated protein 2 (MAP2) interacts with the regulatory protein 14-3-3ζ in a cAMP-dependent protein kinase (PKA) phosphorylation dependent manner. Using selective phosphorylation, calorimetry, nuclear magnetic resonance, chemical crosslinking, and X-ray crystallography, we characterized interactions of 14-3-3ζ with various binding regions of MAP2c. Although PKA phosphorylation increases the affinity of MAP2c for 14-3-3ζ in the proline rich region and C-terminal domain, unphosphorylated MAP2c also binds the dimeric 14-3-3ζ via its microtubule binding domain and variable central domain. Monomerization of 14-3-3ζ leads to the loss of affinity for the unphosphorylated residues. In neuroblastoma cell extract, MAP2c is heavily phosphorylated by PKA and the proline kinase ERK2. Although 14-3-3ζ dimer or monomer do not interact with the residues phosphorylated by ERK2, ERK2 phosphorylation of MAP2c in the C-terminal domain reduces the binding of MAP2c to both oligomeric variants of 14-3-3ζ.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061851","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":"Identification and structural characterization of a novel acetyl xylan esterase from Aspergillus oryzae.","authors":"Chihaya Yamada, Tomoe Kato, Yoshihito Shiono, Takuya Koseki, Shinya Fushinobu","doi":"10.1111/febs.17420","DOIUrl":"https://doi.org/10.1111/febs.17420","url":null,"abstract":"<p><p>Acetyl xylan esterase plays a crucial role in the degradation of xylan, the major plant hemicellulose, by liberating acetic acid from the backbone polysaccharides. Acetyl xylan esterase B from Aspergillus oryzae, designated AoAxeB, was biochemically and structurally investigated. The AoAxeB-encoding gene with a native signal peptide was successfully expressed in Pichia pastoris as an active extracellular protein. The purified recombinant protein had pH and temperature optima of 8.0 and 30 °C, respectively, and was stable up to 35 °C. The optimal substrate for hydrolysis by purified recombinant AoAxeB among a panel of α-naphthyl esters was α-naphthyl acetate. Recombinant AoAxeB catalyzed the release of acetic acid from wheat arabinoxylan. The release of acetic acid from wheat arabinoxylan increased synergistically with xylanase addition. No activity was detected for the methyl esters of ferulic, p-coumaric, caffeic, or sinapic acids. The crystal structures of AoAxeB in the apo and succinate complexes were determined at resolutions of 1.75 and 1.90 Å, respectively. Although AoAxeB has been classified in the Esterase_phb family in the ESTerases and alpha/beta-Hydrolase Enzymes and Relatives (ESTHER) database, its structural features partly resemble those of ferulic acid esterase in the FaeC family. Phylogenetic analysis also indicated that AoAxeB is located between the clades of the two families. Docking analysis provided a plausible binding mode for xylotriose substrates acetylated at the 2- or 3-hydroxy position. This study expands the current knowledge of the structures of acetyl xylan esterases and ferulic acid esterases that are required for complete plant biomass degradation.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061908","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":"Cysteine S-conjugate sulfoxide β-lyase activity for human ACCS.","authors":"Jinmin Gao, Yueqi Xu, Christopher Yeh, Yike Zou, Yang Hai","doi":"10.1111/febs.17419","DOIUrl":"https://doi.org/10.1111/febs.17419","url":null,"abstract":"<p><p>1-Aminocyclopropane-1-carboxylate synthase (ACCS) catalyzes the conversion of S-adenosyl-methionine to 1-aminocyclopropane-1-carboxylate (ACC), a rate-limiting step in ethylene biosynthesis. A gene encoding a putative ACCS protein was identified in the human genome two decades ago. It has been shown to not exhibit any canonical ACC synthase activity and its true function remains obscure. In this study, through a biochemical profiling approach, we demonstrate that human ACCS possesses cysteine conjugate sulfoxide β-lyase activity. This function is unexpected but reasonable, as it somewhat parallels the activity of ACCS proteins found in non-seed plants. Structure-function relationship study of human ACCS, guided by an AlphaFold2 model, allowed us to identify key active site residues that are important for its β-lyase activity. Our biochemical study of human ACCS also provided insights into the function of other mammalian ACCS homologs.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061882","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":"Pinocembrin alleviates renal ischemia-reperfusion injury/unilateral ureteral obstruction (UUO)-generated renal fibrosis by targeting the CYP1B1/ROS/MAPK axis.","authors":"Bang-Hua Zhang, Hui Chen, Rui Yang, Zhengyu Jiang, Shiyu Huang, Zhiyuan Chen, Cheng Liu, Lei Wang, Xiu-Heng Liu","doi":"10.1111/febs.17414","DOIUrl":"https://doi.org/10.1111/febs.17414","url":null,"abstract":"<p><p>In our research, we constructed models of renal ischemia-reperfusion (I/R)-exposed acute kidney injury (AKI) and unilateral ureteral obstruction (UUO)-stimulated renal fibrosis (RF) in C57BL/6 mice and HK-2 cells. We firstly authenticated that oral pinocembrin (PIN) administration obviously mitigated tissue damage and renal dysfunction induced by I/R injury, and PIN attenuated UUO-caused RF, as confirmed by the reduced expression of fibrotic markers as well as hematoxylin-eosin (H&E), Sirius red, immunohistochemistry, and Masson staining. Meanwhile, the beneficial role of PIN was again demonstrated in HK-2 cells with hypoxia-reoxygenation (H/R) or transforming growth factor beta-1 (TGF-β1) treatment. Importantly, the \"ingredient-target-pathway-disease\" network was established through bioinformatics analysis and molecular docking, which showed that PIN may target cytochrome P450 1B1 (CYP1B1) and modulate the mitogen-activated protein kinase (MAPK) pathway to exert its impact during injury. Furthermore, experiments confirmed that PIN usage remarkably constrained CYP1B1 expression, reactive oxygen species (ROS) production, MAPK-pathway-associated inflammation, or apoptosis during I/R injury or UUO exposure. PIN also ameliorated the elevated protein phosphorylation of MAPK pathway components [p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase 1 (JNK ERK and JNK)], which validated the PIN-induced inhibition of the MAPK signaling pathway in renal I/R or UUO injury. Moreover, the AAV9 (adeno-associated virus 9)-packed CYP1B1 or pcDNA-CYP1B1 overexpression plasmid was utilized to treat C57BL/6 mice or HK-2 cells to overexpress CYP1B1, respectively. Notably, CYP1B1 overexpression considerably abolished PIN's restriction impact on ROS generation and MAPK pathway activation. In conclusion, via bioinformatics analysis, molecular docking, animal model, and cellular experiments, we proved that PIN alleviates renal I/R injury/UUO-generated renal fibrosis through regulating the CYP1B1/ROS/MAPK axis.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061913","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":"Transcriptomic signatures and network-based methods uncover new senescent cell anti-apoptotic pathways and senolytics.","authors":"Samael Olascoaga, Mina Konigsberg, Jesús Espinal-Enríquez, Hugo Tovar, Félix Matadamas-Martínez, Jaime Pérez-Villanueva, Norma Edith López-Diazguerrero","doi":"10.1111/febs.17402","DOIUrl":"https://doi.org/10.1111/febs.17402","url":null,"abstract":"<p><p>Cellular senescence is an irreversible cell cycle arrest caused by various stressors that damage cells. Over time, senescent cells accumulate and contribute to the progression of multiple age-related degenerative diseases. It is believed that these cells accumulate partly due to their ability to evade programmed cell death through the development and activation of survival and antiapoptotic resistance mechanisms; however, many aspects of how these survival mechanisms develop and activate are still unknown. By analyzing transcriptomic signature profiles generated by the LINCS L1000 project and using network-based methods, we identified various genes that could represent new senescence-related survival mechanisms. Additionally, employing the same methodology, we identified over 600 molecules with potential senolytic activity. Experimental validation of our computational findings confirmed the senolytic activity of Fluorouracil, whose activity would be mediated by a multitarget mechanism, revealing that its targets AURKA, EGFR, IRS1, SMAD4, and KRAS are new senescent cell antiapoptotic pathways (SCAPs). The development of these pathways could depend on the stimulus that induces cellular senescence. The SCAP development and activation mechanisms proposed in this work offer new insights into how senescent cells survive. Identifying new antiapoptotic resistance targets and drugs with potential senolytic activity paves the way for developing new pharmacological therapies to eliminate senescent cells selectively.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143054762","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}