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Plasmodium falciparum acetyltransferase GCN5 acts as a dual regulator of essential glycolytic enzyme phosphoglycerate mutase. 恶性疟原虫乙酰转移酶GCN5作为必需糖酵解酶磷酸甘油酸变异酶的双重调节因子。
The FEBS journal Pub Date : 2025-06-26 DOI: 10.1111/febs.70164
Ankita Tehlan, Poonam Nagar, Reena Prajapati, Krishanu Bhowmick, Amarjeet Kumar, Inderjeet Kaur, Naidu Subbarao, Suman Kumar Dhar
{"title":"Plasmodium falciparum acetyltransferase GCN5 acts as a dual regulator of essential glycolytic enzyme phosphoglycerate mutase.","authors":"Ankita Tehlan, Poonam Nagar, Reena Prajapati, Krishanu Bhowmick, Amarjeet Kumar, Inderjeet Kaur, Naidu Subbarao, Suman Kumar Dhar","doi":"10.1111/febs.70164","DOIUrl":"https://doi.org/10.1111/febs.70164","url":null,"abstract":"<p><p>Lysine acetylation is emerging as a key player in cellular regulation across species by controlling the fate of metabolic proteins as well as modulating gene expression via histone modification. Phosphoglycerate mutase, a conserved enzyme of the sole energy-yielding pathway of glycolysis in the human malaria parasite Plasmodium falciparum, is indispensable for its growth. Here, we demonstrate that P. falciparum phosphoglycerate mutase PfPGM1 (phosphoglycerate mutase) is regulated via lysine acetylation. In mammalian cells, acetylation of phosphoglycerate mutase modulates its catalytic activity, although the acetyl transferase enzyme remains elusive. However, the parasites exhibit a unique way of regulating the fate of PfPGM1 via acetylation that modulates its stability, thus providing an increased protein pool for the rapid growth and proliferation of the parasites. We show that K100, a critical residue for PfPGM1 catalytic activity, is acetylated by the essential histone acetyltransferase PfGCN5. Downregulation of PfGCN5 through a knockdown approach in the parasites along with cycloheximide treatment indeed leads to a reduction of PfPGM1 protein. Additionally, PfGCN5 occupies the promoter of PfPGM1 in a stage-specific manner, and downregulation of PfGCN5 protein leads to a reduced transcript level of PfPGM1. Collectively, our data highlight a dual regulation of PfPGM1 by PfGCN5 through acetylation of the protein as well as regulation of the transcription of the gene. Such dual control is not only rare but showcases the importance of the above two proteins and their potential as excellent targets against malaria.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144499988","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}
引用次数: 0
Studies of the membrane-bound flavocytochrome MsrQ flavin mononucleotide (FMN)-binding site reveal an unexpected ubiquinone cofactor. 膜结合黄细胞色素MsrQ黄素单核苷酸(FMN)结合位点的研究揭示了一个意想不到的泛素辅助因子。
The FEBS journal Pub Date : 2025-06-26 DOI: 10.1111/febs.70162
Philippe Carpentier, Fabien Pierrel, Nicolas Duraffourg, Bruno Guigliarelli, Mahmoud Hajj Chehade, Laura Flandrin, Christian Basset, Christelle Caux, Stéphane Torelli, Vincent Nivière
{"title":"Studies of the membrane-bound flavocytochrome MsrQ flavin mononucleotide (FMN)-binding site reveal an unexpected ubiquinone cofactor.","authors":"Philippe Carpentier, Fabien Pierrel, Nicolas Duraffourg, Bruno Guigliarelli, Mahmoud Hajj Chehade, Laura Flandrin, Christian Basset, Christelle Caux, Stéphane Torelli, Vincent Nivière","doi":"10.1111/febs.70162","DOIUrl":"https://doi.org/10.1111/febs.70162","url":null,"abstract":"<p><p>The methionine sulfoxide reductase PQ system (MsrPQ) is a newly identified type of bacterial methionine sulfoxide reductase (Msr) involved in the repair of periplasmic methionine residues that have been oxidized by hypochlorous acid. MsrP, which carries out the Msr activity, is a molybdoenzyme located in the periplasm, whereas MsrQ, an integral membrane-bound flavohemoprotein, specifically transfers electrons to MsrP to drive catalysis. MsrQ belongs to an important superfamily of heme-containing membrane-bound proteins, which includes the eukaryotic NADPH oxidases (NOX) and six-transmembrane epithelial antigen of the prostate (STEAP) ferric reductases. Like STEAP, and in addition to a b-type heme, MsrQ contains a flavin cofactor [flavin mononucleotide (FMN)], which mediates electron transfer from a cytosolic NADH oxidoreductase to the heme, and subsequently to MsrP. In this study, we characterized the FMN-binding site of MsrQ using an AlphaFold model, identifying R77 and R78 residues as potentially critical for FMN stabilization. The R77A and R78A mutations result in the complete loss of the FMN cofactor, showing that both residues are essential for FMN binding. Surprisingly, electron paramagnetic resonance (EPR) spectroscopy and biochemical analysis of the mutants revealed the presence of a ubiquinone (UQ) cofactor associated with MsrQ, independently of the binding of FMN. The mid-point redox potentials of the MsrQ heme and FMN cofactors, measured through redox titration and cyclic voltammetry experiments, contradict the previous assumption that UQ serves as the electron donor for MsrQ. Instead, our data suggest that UQ may function as an electron acceptor for the reduced form of MsrQ. We propose that UQ bound to MsrQ could act as a protective mechanism when MsrP substrate is limiting.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510176","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}
引用次数: 0
Cryo-EM structural analyses reveal a unique role for elongation factor G2 (EF-G2) in Mycobacteria. 低温电镜结构分析揭示了延伸因子G2 (EF-G2)在分枝杆菌中的独特作用。
The FEBS journal Pub Date : 2025-06-26 DOI: 10.1111/febs.70161
Priya Baid, Jayati Sengupta
{"title":"Cryo-EM structural analyses reveal a unique role for elongation factor G2 (EF-G2) in Mycobacteria.","authors":"Priya Baid, Jayati Sengupta","doi":"10.1111/febs.70161","DOIUrl":"https://doi.org/10.1111/febs.70161","url":null,"abstract":"<p><p>The gene-encoding translation elongation factor G (EF-G) has undergone gene duplication across various bacterial species including Mycobacteria, and in mammalian mitochondria, leading to the emergence of the paralogue elongation factor G2 (EF-G2). Our study reveals that mycobacterial EF-G2, unlike EF-G1, neither participates in ribosome-recycling nor significantly contributes to overall translation, suggesting that it plays an alternative role in Mycobacteria. Remarkably, our investigation found a significant overexpression of mycobacterial EF-G2 during the stationary growth phase. Moreover, EF-G2 lacks ribosome-dependent GTPase activity, an observation consistent with previous reports. Cryo-EM analysis of the M. smegmatis 70S ribosome purified from the nutrient-starved (stationary) phase and complexed with EF-G2 unveiled the structural basis for its inability to hydrolyse GTP in a ribosome-dependent manner. Furthermore, we report an unprecedented binding mode of two EF-G2 copies on the 50S ribosomal subunit that impedes subunit association, thereby preventing the formation of active 70S ribosomes. Thus, instead of performing canonical functions, mycobacterial EF-G2 acts as a translation repressor during nutrient starvation. Altogether, our findings shed light on the multifaceted mechanisms by which EF-G2 modulates protein synthesis under nutrient-limited conditions, providing insights into adaptive strategies employed by Mycobacteria to survive in hostile environments.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510174","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}
引用次数: 0
Potential cytotoxicity of truncated slow skeletal muscle troponin T (ssTnT) in a loss of function TNNT1 myopathy mouse model. 截断慢骨骼肌肌钙蛋白T (ssTnT)在功能丧失TNNT1肌病小鼠模型中的潜在细胞毒性
The FEBS journal Pub Date : 2025-06-26 DOI: 10.1111/febs.70165
Han-Zhong Feng, Kevin A Strauss, Jian-Ping Jin
{"title":"Potential cytotoxicity of truncated slow skeletal muscle troponin T (ssTnT) in a loss of function TNNT1 myopathy mouse model.","authors":"Han-Zhong Feng, Kevin A Strauss, Jian-Ping Jin","doi":"10.1111/febs.70165","DOIUrl":"https://doi.org/10.1111/febs.70165","url":null,"abstract":"<p><p>A nonsense mutation in codon Glu<sub>180</sub> of the TNNT1 gene, which encodes the slow skeletal muscle isoform of troponin T (ssTnT), causes a recessively inherited myopathy (the Amish Nemaline Myopathy, ANM). A ssTnT knockout (ssTnT-KO) mouse model produced the loss of ssTnT function phenotypes of ANM with slow fiber atrophy and decreased fatigue resistance of soleus muscle. We further developed a Tnnt1 p.Glu180* knock-in (ANM-KI) mouse model to precisely mimic the human mutation. In addition to reproducing the loss of function phenotypes, ANM-KI mice exhibit more severe myopathy than that of ssTnT-KO mice. Compared with wild-type controls, ANM-KI and ssTnT-KO soleus muscles show different changes in gene expression profiles, of which gene ontology analysis indicated inflammatory activation in ANM-KI soleus muscle. The mutant Tnnt1 mRNA was readily detectable in ANM-KI soleus muscle. However, the truncated ssTnT<sub>1-179</sub> fragment cannot be detected in western blot, indicating its very low level due to the active proteolytic clearance of non-myofilament-incorporated TnT in muscle cells. Nonetheless, the more severe myopathic impacts of the ANM-KI allele with more fiber number loss and muscle activity/injury-caused hypertrophy support a potent cytotoxicity of the ssTnT fragment, as shown in previous cell culture studies, which is further supported by activity-dependent and age-progressing myopathy with more active regeneration. The notion that non-myofilament-incorporated ssTnT fragments may potentially contribute to the pathogenesis and progression of myopathy merits further investigation.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510175","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}
引用次数: 0
HAX1 mediates SARS-CoV-2 spike-triggered unfolded protein response in host cells. HAX1介导宿主细胞中SARS-CoV-2刺突触发的未折叠蛋白反应
The FEBS journal Pub Date : 2025-06-26 DOI: 10.1111/febs.70163
Fang Zhu, Xiangpeng Sheng, Fan Yang, Xuechen Wang, Cong Yang, Jin Ren, Chengcheng Wang, Ronggui Hu
{"title":"HAX1 mediates SARS-CoV-2 spike-triggered unfolded protein response in host cells.","authors":"Fang Zhu, Xiangpeng Sheng, Fan Yang, Xuechen Wang, Cong Yang, Jin Ren, Chengcheng Wang, Ronggui Hu","doi":"10.1111/febs.70163","DOIUrl":"https://doi.org/10.1111/febs.70163","url":null,"abstract":"<p><p>SARS-CoV-2 continues to evolve with enhanced transmissibility, a feature primarily mediated by its spike (S) protein. While expression of the S protein in human cells can induce the accumulation of reactive oxygen species (ROS), the regulatory mechanisms governing this process remain poorly understood. Here, we identify the human protein HCLS1-associated protein X-1 (HAX1) as a key regulator that mitigates SARS-CoV-2S-induced ROS accumulation. A genome-wide screen revealed HAX1 as a binding partner of the SARS-CoV-2S protein in mammalian cells. HAX1 specifically interacts with the S1 subunit of S, and its deficiency effectively abolishes S-induced activation of endoplasmic reticulum (ER) stress responses, including the unfolded protein response (UPR). Notably, HAX1-dependent UPR activation is unique to SARS-CoV-2S and certain variants and is not triggered by other UPR inducers. Loss of HAX1 markedly exacerbates SARS-CoV-2S-induced ROS accumulation and mitochondrial dysfunction. Collectively, our findings uncover a previously unrecognized mechanism by which S modulates host stress responses and establish HAX1 as a host factor involved in SARS-CoV-2-related processes.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144499987","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}
引用次数: 0
Neocortical neurogenesis: a proneural gene perspective. 新皮质神经发生:前神经基因的观点。
The FEBS journal Pub Date : 2025-06-22 DOI: 10.1111/febs.70158
Lakshmy Vasan, Alexandra Moffat, Pierre Mattar, Carol Schuurmans
{"title":"Neocortical neurogenesis: a proneural gene perspective.","authors":"Lakshmy Vasan, Alexandra Moffat, Pierre Mattar, Carol Schuurmans","doi":"10.1111/febs.70158","DOIUrl":"10.1111/febs.70158","url":null,"abstract":"<p><p>The neocortex, which is the site of higher-order cognitive functioning, is comprised of two main neuronal types: excitatory (E) and inhibitory (I). Neurodevelopmental disorders that disrupt the balance of E:I neurotransmission predispose individuals to atypical brain function, highlighting the importance of generating the correct numbers of each neuronal type. During development, neurons with E and I neurotransmission profiles are primarily generated from neural stem and progenitor cells (NPCs), located in the dorsal and ventral telencephalon, respectively. To ensure that correct numbers of each neuronal type are generated, NPC differentiation dynamics vary depending on positional and temporal information and host species. Despite variations in NPC differentiation kinetics and outcomes, proneural genes encoding basic helix-loop-helix (bHLH) transcription factors (TFs) have remained constant as the core drivers of neurogenesis and neuronal subtype specification from fly to human. This high degree of functional conservation raises the question of how proneural TF activity is regulated to control precise neurogenic patterns. In the neocortex, the proneural genes neurogenin 1 (Neurog1) and Neurog2 specify an excitatory neuronal identity in dorsal telencephalic NPCs, whereas achaete-scute family bHLH transcription factor 1 (Ascl1) specifies an inhibitory neurotransmission fate in ventral NPCs, generating interneurons that then migrate tangentially to enter the neocortex. Here, we review our current knowledge of how Neurog1/Neurog2 and Ascl1 functions are regulated to ensure that E:I balance is ultimately achieved in the lissencephalic murine cortex and in gyrencephalic species. Together, these studies point to emergent and conserved features of proneural gene regulation and function across evolutionary time.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370023","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}
引用次数: 0
Short coiled-coil proteins from plants and metazoans - the 'jacks of all trades'. 来自植物和后生动物的短螺旋状蛋白质——“万事通”。
The FEBS journal Pub Date : 2025-06-22 DOI: 10.1111/febs.70159
Agnieszka Sirko, Jarosław Poznański, Marzena Sieńko
{"title":"Short coiled-coil proteins from plants and metazoans - the 'jacks of all trades'.","authors":"Agnieszka Sirko, Jarosław Poznański, Marzena Sieńko","doi":"10.1111/febs.70159","DOIUrl":"10.1111/febs.70159","url":null,"abstract":"<p><p>The molecular functions of short coiled-coil proteins remain poorly characterized. These proteins typically act as facilitators rather than essential components of metabolic processes, contributing to cellular homeostasis, and are aptly described as 'jacks of all trades but masters of none'. They are found across diverse groups of organisms, including both plants and animals. LSU (RESPONSE TO LOW SULFUR) are plant proteins induced under sulfur deficiency and other environmental stresses. They participate in metabolic pathways, including sulfate assimilation, and manage oxidative stress by stabilizing and protecting antioxidative enzymes. In metazoans, SCOC (SHORT COILED-COIL) proteins regulate autophagy initiation by recruiting proteins essential for forming autophagosomes-key vesicles involved in cellular degradation. SCOC proteins also interact with factors critical for maintaining membrane dynamics and intracellular transport. Despite some functional similarities, the roles of these proteins have diverged significantly between plants and animals, reflecting organism-specific adaptations shaped by evolutionary pressures. This divergence underscores their adaptive versatility and highlights their potential as promising targets for future biological research.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370024","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}
引用次数: 0
Research highlights 研究突出了
The FEBS journal Pub Date : 2025-06-18 DOI: 10.1111/febs.70152
Julija Hmeljak
{"title":"Research highlights","authors":"Julija Hmeljak","doi":"10.1111/febs.70152","DOIUrl":"https://doi.org/10.1111/febs.70152","url":null,"abstract":"<p>In this issue, we highlight four new research papers that span the breadth of <i>The FEBS Journal</i>'s scope and demonstrate that the molecular life sciences field remains as vibrant as ever. Within their diversity, all four papers carry a metabolism component: Giannoni <i>et al</i>. provide a translationally relevant link between cancer cell metabolism and sex-determined immune responses in melanoma. Logan and team solve the structure of a bacterial transcriptional repressor that functions as a flexible nucleotide sensor. Kappel and colleagues probe signalling pathways in soil fungi, providing important insights into the dynamics of soil communities. Finally, Bortoluci's group describes a glycolysis-linked caspase-11-dependent mechanism that suppresses Zika virus replication in astrocytes.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":"292 12","pages":"3034-3036"},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/febs.70152","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315004","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}
引用次数: 0
Alternative substrate-assisted hydrolysis pathways of posttransfer editing by prokaryotic leucyl-tRNA synthetase. 原核亮氨酸- trna合成酶转移后编辑的替代底物辅助水解途径。
The FEBS journal Pub Date : 2025-06-15 DOI: 10.1111/febs.70153
Mykola M Ilchenko, Alexey Rayevsky, Oksana P Kovalenko, Evgeny Demianenko, Oleksandra I Skydanovych, Igor Ya Dubey, Michael A Tukalo
{"title":"Alternative substrate-assisted hydrolysis pathways of posttransfer editing by prokaryotic leucyl-tRNA synthetase.","authors":"Mykola M Ilchenko, Alexey Rayevsky, Oksana P Kovalenko, Evgeny Demianenko, Oleksandra I Skydanovych, Igor Ya Dubey, Michael A Tukalo","doi":"10.1111/febs.70153","DOIUrl":"https://doi.org/10.1111/febs.70153","url":null,"abstract":"<p><p>Leucyl-tRNA synthetase (LeuRS) activates cognate leucine and wrongly activates norvaline (and other proteinogenic and non-proteinogenic amino acids), but then mischarges tRNA. Here, we studied the editing mechanisms of Thermus thermophilus LeuRS (TthLeuRS) by combination of biochemical and computational investigations with the appropriate substrate, norvalyl-tRNA, as previously reported for E. coli LeuRS (EcLeuRS). Based on DFT (density functional theory) calculations, we have proposed three alternative hydrolysis mechanisms. These mechanisms differ according to which group of water molecules present in the editing site of the enzyme-substrate complex participates in the chemical reaction of ester bond cleavage. The main feature of the proposed deacylation pathways is direct assistance by the substrate in the hydrolysis process. In all three cases, the 3'-OH group of the substrate directly participates in the reaction. To confirm the proposed models, the experimental substitution of the 76 3'-OH group of the tRNA<sup>Leu</sup> was constructed yielding a tRNA that is devoid of editing activity. QM and metadynamics have shown that hydrolysis occurs via a common underlying catalysis mechanism involving more than one water molecule. An important element of hydrolysis is the involvement of several amino acid residues of the active centre of enzymatic editing (Asp-347/Asp-344 and Thr-247) in the process of catalytic deacylation. In conclusion, it was noted that the possibility of several alternative hydrolysis pathways may indicate that a sufficiently protected and flexible error-editing mechanism has been implemented for prokaryotic leucyl-tRNA synthetase.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304201","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}
引用次数: 0
Epithelial cell shape changes contribute to regulation of ureteric bud branching morphogenesis. 上皮细胞形态改变参与输尿管芽分支形态发生的调控。
The FEBS journal Pub Date : 2025-06-15 DOI: 10.1111/febs.70156
Kristen Kurtzeborn, Vladislav Iaroshenko, Tomáš Zárybnický, Julia Koivula, Heidi Anttonen, Otto J M Mäkelä, Darren Bridgewater, Ramaswamy Krishnan, Ping Chen, Satu Kuure
{"title":"Epithelial cell shape changes contribute to regulation of ureteric bud branching morphogenesis.","authors":"Kristen Kurtzeborn, Vladislav Iaroshenko, Tomáš Zárybnický, Julia Koivula, Heidi Anttonen, Otto J M Mäkelä, Darren Bridgewater, Ramaswamy Krishnan, Ping Chen, Satu Kuure","doi":"10.1111/febs.70156","DOIUrl":"https://doi.org/10.1111/febs.70156","url":null,"abstract":"<p><p>Branching morphogenesis orchestrates organogenesis in many tissues, including the kidney, where ureteric bud (UB) branching determines kidney size and shape and the final nephron number. Molecular regulation of UB branching is rather well studied, whereas the cellular mechanisms and tissue organization during UB arborization are less understood. Here, we characterized epithelial cell morphology in three dimensions (3D), studied mechanisms regulating cell shape changes, and analyzed their contribution to novel branch initiation in normal and branching-incompetent bud tips. Unbiased machine-learning-based segmentation of tip epithelia identified geometrical round-to-elliptical transformation as a key cellular mechanism facilitating growth direction changes to gain optimal branching complexity. Cell shape and molecular analyses in branching-incompetent epithelia demonstrated a distinct failure to condense cell size and modify its conformation. This, together with changes in adhesive forces, defective actin dynamics, and disorganization in myosin-9 (MYH9)-based microtubules, suggests altered biophysical properties in tip cells, where branch point decisions are made and actualized. The data demonstrate that dynamic changes in volume and morphology of individual epithelial cells, together with optimal traction stress, facilitate novel branch formation in the UB tip niche. Based on these results, we propose a model where epithelial cell crowding, in tandem with stretching, transforms individual cells into elliptical and elongated shapes. This creates local curvatures that drive new branch formation during the ampulla-to-asymmetric ampulla transition of the UB.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144304202","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}
引用次数: 0
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