The FEBS journal最新文献

{"title":"The N6-methyladenosine reader IGF2BP3 promotes bladder cancer progression through enhancing HSP90AB1 expression.","authors":"Xiaoqing Chen, Wenli Diao, Xinyue Guo, Wenmin Cao, Yang Yang, Tianlei Xie, Wei Chen, Lin Yang, Qing Zhang, Meng Ding, Hongqian Guo","doi":"10.1111/febs.70068","DOIUrl":"https://doi.org/10.1111/febs.70068","url":null,"abstract":"<p><p>N⁶-methyladenosine (m⁶A) is the most abundant RNA modification in mammalian cells, and has emerged as an important player in tumour development through post-transcriptional gene regulation. In this study, we found that the m⁶A reader protein IGF2BP3 was the most upregulated m⁶A modifier in bladder cancer through the proteomic analysis of 17 pairs of human bladder cancer tissues and adjacent normal bladder tissues, for which the expression was also positively correlated with higher tumour stage and poorer prognosis. In vitro and in vivo assays demonstrated the powerful oncogenic function of IGF2BP3 in bladder cancer. Further combined analyses of RNA-sequencing, m⁶A-sequencing, and RIP (RNA Binding Protein Immunoprecipitation)-sequencing, as well as site-directed mutagenesis assays and RIP-qPCR identified m⁶A-tagged HSP90AB1 mRNA as a direct target of IGF2BP3. Mechanistically, through in vitro and in vivo assays, as well as clinical sample analysis, we demonstrated that IGF2BP3 modulated the expression of HSP90AB1 in an m⁶A modification-dependent manner, thus activating the PI3K/AKT-signaling pathway, and promoting the development of bladder cancer. Collectively, our study highlights the critical role of the IGF2BP3-HSP90AB1-signaling axis in bladder cancer progression, which may serve as a promising therapeutic approach for bladder cancer.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660184","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":"Tudor staphylococcal nuclease (Tudor-SN) regulates activation of quiescent hepatic stellate cells.","authors":"Baoxin Qian, Yan Zhao, Xinxin Zhang, Chunyan Zhao, Xiaoteng Cui, Fengmei Wang, Xiang Jing, Lin Ge, Zhi Yao, Xingjie Gao, Jie Yang","doi":"10.1111/febs.70073","DOIUrl":"https://doi.org/10.1111/febs.70073","url":null,"abstract":"<p><p>Several liver diseases have been associated with the Tudor staphylococcal nuclease (Tudor-SN) protein. Our previous results demonstrated that, in comparison to wild-type (WT) mice, systemic overexpression of Tudor-SN in transgenic (Tg) mice (Tudor-SN-Tg) ameliorates obesity-induced insulin resistance and hepatic steatosis. In this study, we observed an inverse correlation in the expression levels of Tudor-SN and profibrogenic factors, such as alpha-smooth muscle actin (α-SMA) and collagen alpha-1(I) chain (COL1A1), in liver tissue samples between Tudor-SN-Tg and WT mice. The correlation was further validated in hepatic fibrotic tissues from patients with cirrhosis and fibrosis. Utilizing a carbon tetrachloride (CCl₄)-induced hepatic fibrosis model, we observed that Tudor-SN attenuated hepatic fibrosis in mice. Tudor-SN was abundantly expressed in hepatic stellate cells (HSCs). In the Tudor-SN-Tg group, primary HSCs showed stellate-like morphology as well as reduced in vitro proliferation and chemotactic ability compared to the WT group. Pseudotime series analysis of HSCs further showed the role of Tudor-SN during the dynamic evolution of HSC activation. Reduced Tudor-SN expression facilitated the in vitro activation of LX-2 cells. Furthermore, primary HSC cells from WT and Tudor-SN knockout (KO) mice were isolated for RNA-sequencing analysis. The findings suggested that Tudor-SN may regulate the activation of primary HSCs by influencing lipid metabolism, translation initiation, immune response, and the extracellular matrix. In summary, we identified Tudor-SN as a newly identified regulator involved in the transition of quiescent HSCs to activated states, shedding light on the antifibrotic impact of Tudor-SN expression in the development of hepatic fibrosis.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652840","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 therapeutic efficacy through degradation of endogenous extracellular matrix in primary breast tumor spheroids.","authors":"Alessandra Lo Cicero, Simona Campora, Gabriele Lo Buglio, Paolo Cinà, Margot Lo Pinto, Simone Dario Scilabra, Giulio Ghersi","doi":"10.1111/febs.70069","DOIUrl":"https://doi.org/10.1111/febs.70069","url":null,"abstract":"<p><p>Solid tumors have a complex extracellular matrix (ECM) that significantly affects tumor behavior and response to therapy. Understanding the ECM's role is crucial for advancing cancer research and treatment. This study established an in vitro model using primary cells isolated from a rat breast tumor to generate three-dimensional spheroids. Monolayer cells and spheroid cultures exhibited different protein expression patterns, with primary tumor spheroids presenting an increased level of ECM-related proteins and a more complex extracellular environment. Furthermore, spheroids produce endogenous collagen type I matrix, which is the main component of the tumoral ECM. This matrix is arranged predominantly around the 3D structure, mimicking the conditions of solid tumors. Treatments with recombinant collagenases class II (acting on the linear collagen region) and class I (acting on the 3D-helix region) completely degrade collagen within the spheroid structure. Collagenase pretreatment enhances the accessibility of the anticancer drug doxorubicin to penetrate the core of spheroids and sensitize them to doxorubicin-induced cytotoxicity. Our findings highlight the importance of overcoming drug resistance in breast cancer by targeting the ECM and proposing a novel strategy for improving therapeutic outcomes in solid tumors. By employing a three-dimensional spheroid model, with an endogenous ECM, we can offer more relevant insights into tumor biology and treatment responses.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652812","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":"Potency of agarose gel-supported lipid bilayers for electrophysiologic analysis of channel pores formed by Bacillus thuringiensis insecticidal proteins.","authors":"Tsubasa Okuda, Tomoya Takeuchi, Mami Asakura, Minako Hirano, Toru Ide, Tohru Hayakawa","doi":"10.1111/febs.70070","DOIUrl":"https://doi.org/10.1111/febs.70070","url":null,"abstract":"<p><p>Electrophysiologic analysis using artificial lipid bilayers is useful for studying the formation of pores by insecticidal proteins, especially the ion permeability of toxin pores. However, such studies are time-consuming and require special skills, particularly regarding the construction of lipid bilayers and promoting toxin pore formation. To facilitate the analysis of toxin pore formation in the present study, we evaluated the usefulness of agarose gel-supported lipid bilayers for electrophysiologic measurements using two structurally different mosquito-larvicidal proteins, Mpp46Ab and Cry4Aa. The agarose gel-supported lipid bilayers enabled the measurement of channel currents through pores made by both toxins and, notably, the lipid bilayers could be easily reconstructed even after disruption of the lipid bilayer. Using this system, measurements could be repeated at least five times using the same apparatus and toxins. We also investigated the effect of the lipid bilayer component on toxin pore formation and found that the incorporation of both cholesterol and sphingomyelin into the lipid bilayer facilitates the formation of pores by both Mpp46Ab and Cry4Aa. Both cholesterol and sphingomyelin are major components of lipid raft microdomains, suggesting that, in addition to recruiting toxin receptors, raft microdomains play a key role in membrane insertion and pore formation by insecticidal proteins.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652819","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 metastasis-associated pannexin-1 mutant (Panx1^1-89) forms a minimalist ATP release channel.","authors":"Junjie Wang, Noah J Levi, Maykelis Diaz-Solares, Carsten Mim, Gerhard Dahl, Rene Barro-Soria","doi":"10.1111/febs.70060","DOIUrl":"10.1111/febs.70060","url":null,"abstract":"<p><p>A truncated form of the ATP release channel pannexin 1 (Panx1), Panx1^1-89, is enriched in metastatic breast cancer cells and has been proposed to mediate metastatic cell survival by increasing ATP release through mechanosensitive Panx1 channels. However, whether Panx1^1-89 on its own [without the presence of wild-type Panx1 (wtPanx1)] mediates ATP release has not been tested. Here, we show that Panx1^1-89 by itself can form a constitutively active membrane channel, capable of releasing ATP even in the absence of wtPanx1. Our biophysical characterization reveals that most basic structure-function features of the channel pore are conserved in the truncated Panx1^1-89 polypeptide. Thus, augmenting extracellular potassium ion concentrations enhances Panx1^1-89-mediated conductance. Moreover, despite the severe truncation, Panx1^1-89 retains sensitivity to most wtPanx1 channel inhibitors. Therefore, Panx1 blockers may be of therapeutic value to combat metastatic cell survival. Our study both provides a mechanism for ATP release from cancer cells and suggests that Panx1^1-89 might aid in the structure-function analysis of Panx1 channels.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635043","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":"How to promote co-development between postdocs: a case for peer group meetings.","authors":"Lais Brigliadori Fugio, Tiphaine Douanne, Jane Jardine, Sara Rosińska, Quentin Roux","doi":"10.1111/febs.70067","DOIUrl":"https://doi.org/10.1111/febs.70067","url":null,"abstract":"<p><p>'Who in their right mind would add another meeting to an already overflowing schedule?' This thought crossed our minds when we first discussed the idea of a postdoc peer group meeting. We are five early career researchers working in the same laboratory, each from a different background, shaped as much by our origins, stages in life, and previous research experience. When we started our series of meetings by asking 'What is a postdoc?', we struggled with our own definition of the position, bringing different answers and perspectives. This made us realize that postdoc peer group meetings could be a journey toward open discussion, co-development, and self-discovery.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635045","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":"Critical factors for flow cytometry analysis of the brain.","authors":"Mizuki Sadakata, Ayumu Konno, Akinori Takase, Tetsuhiro Kasamatsu, Takatoshi Iijima, Hirokazu Hirai, Tetsushi Sadakata","doi":"10.1111/febs.70063","DOIUrl":"https://doi.org/10.1111/febs.70063","url":null,"abstract":"<p><p>The brain is difficult to analyze using flow cytometry due to its complex interactions with cells, high lipid content, and high autofluorescence. In this study, we investigated methods to isolate various types of brain cells with high yield and viability. The results showed that protease selection significantly affected the viability of various cell types in the brain. Differences in the developmental stage also affected cell yield and viability. Furthermore, the intensity of autofluorescence differs greatly between various regions of the brain. Additionally, we searched for neuronal indicators capable of identifying a diverse range of neurons. The ratios of various exosomes contained in neurons differ depending on the type of neuronal marker. These results revealed critical factors that must be considered when analyzing various types of brain cells using flow cytometry.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635044","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":"Pharmacological manipulation of liver fibrosis progression using novel HDAC6 inhibitors.","authors":"Maria Teresa Borrello, Dusan Ruzic, Hannah Paish, Eleanor Graham, Amy L Collins, Rebecca Scott, Sam Higginbotham, Branko Radovic, Glyn Nelson, David Bulmer, Lee A Borthwick, Stuart M Robinson, Jeremy French, John Moir, Steve A White, Colin Wilson, Sanjay Pandanaboyana, John Hammond, Rohan Thakkar, Wasfi Alrawashdeh, Rodrigo Figueiredo, Milos Petkovic, Katarina Nikolic, Fiona Oakley, Derek A Mann, Jelena Mann","doi":"10.1111/febs.70062","DOIUrl":"https://doi.org/10.1111/febs.70062","url":null,"abstract":"<p><p>Chronic liver injury characterized by unresolved hepatitis leads to fibrosis, potentially progressing to cirrhosis and hepatocellular carcinoma. Effective treatments for halting or reversing liver fibrosis are currently lacking. This study investigates the potential of HDAC6 as a therapeutic target in liver fibrosis. We synthesized two selective HDAC6 inhibitors, DR-3 and FDR2, and assessed their effects on hepatic stellate cell (HSC) activation and liver fibrosis using human precision cut liver slices (hPCLS). Molecular docking, deacetylation inhibition assays, and various cellular assays were employed to evaluate the specificity and anti-fibrotic efficacy of these inhibitors. DR-3 and FDR2 demonstrated high selectivity for HDAC6 over HDAC1, significantly inhibiting HSC activation markers and fibrogenic gene expression. Both inhibitors increased acetylation of α-tubulin and suppressed TGF-β1-induced SMAD signaling in HSCs. In human precision cut liver slices (hPCLS), DR-3 and FDR2 reduced fibrogenic protein levels and collagen deposition. The selective inhibition of HDAC6 by DR-3 and FDR2 effectively reduces HSC activation and fibrogenesis in liver models, supporting further investigation of HDAC6 inhibitors as potential anti-fibrotic therapies.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627053","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":"Rational design of Chim3, a multifunctional peptide carrying a formyl peptide receptor 2 (FPR2) agonist module released by bacterial signal peptidase I (Spase I).","authors":"Samuel R Costa, Bianca O Lira, Gabriel F G Calixto, João B Nunes, Sabrina A Machado, Andreanne G Vasconcelos, Ana L P Lourenço, Thaís C de Sousa, Sónia Gonçalves, André M Murad, Nuno C Santos, José R de S de Almeida Leite, Kelly G Magalhães, Marcelo S Ramada, Guilherme D Brand","doi":"10.1111/febs.70055","DOIUrl":"https://doi.org/10.1111/febs.70055","url":null,"abstract":"<p><p>Membrane-active peptides are useful tools in the design of multifunctional molecules. For example, peptide chimeras may release, after proteolysis of membrane-adsorbed molecules, pharmacologically active fragments. In previous work, Chim2, an antimicrobial peptide composed of a membrane-active module, an enzymatic hydrolysis site, and an agonist moiety for type 2 formyl peptide receptors (FPR2), was conceptualized. Based on Chim2, a peptide named Chim3 was designed, adding a consensus sequence for the bacterial signal peptidase I (Spase I). Spase I is a protease located in an extracytoplasmic face of Gram-positive and Gram-negative bacterial membranes and is essential for protein export. Chim3 was synthesized and its activity as an antimicrobial agent was determined. In addition, Chim3 was incubated with Escherichia coli and Staphylococcus aureus, and peptide hydrolysis products were evaluated by LC-MS/MS. Data demonstrate that Chim3 has potent antimicrobial activity. After incubation with bacteria, Chim3 underwent intense hydrolysis. Proteolysis was detected in the Chim3 Spase I consensus sequence after incubation with both bacteria, and the release of the FPR2 agonist segment was observed. The synthesis of an improved structure of Chim3 with N-methyl tyrosine in the FPR2 agonist segment was performed, resulting in CHIM3Y-NMe. This modification caused significantly higher concentrations of the FPR2 agonist portion arising from the modified peptide after incubation assays with E. coli. The modified FPR2 agonist WK(Y-NMe)M-NH₂ interacted with the mouth region of FPR2 and induced the release of TNF-α and IL-6 in mouse macrophages, making CHIM3Y-NMe an interesting antimicrobial and immunomodulatory molecule for further development aimed at in vivo application.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607183","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 steric gate prevents mutagenic dATP incorporation opposite 8-oxo-deoxyguanosine in mitochondrial DNA polymerases.","authors":"Noe Baruch-Torres, Carlos H Trasviña-Arenas, Alexandru Ionut Gilea, Upeksha C Dissanayake, Missael Molina-Jiménez, Paola L García-Medel, Corina Díaz-Quezada, Tiziana Lodi, G Andrés Cisneros, Enrico Baruffini, Luis G Brieba","doi":"10.1111/febs.70064","DOIUrl":"https://doi.org/10.1111/febs.70064","url":null,"abstract":"<p><p>Reactive oxygen species (ROS) generate DNA lesions that alter genome integrity. Among those DNA lesions, 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) is particularly mutagenic. 8-oxodG efficiently incorporates deoxycytidine monophosphate (dCMP) and deoxyadenosine monophosphate (dAMP) via base pairing mediated by its anti and syn conformations, respectively. In family-A DNA polymerases (DNAPs), the amino acids responsible for modulating dCMP or dAMP incorporation across 8-oxodG are located in a determined structural position. Those residues are a conserved tyrosine located at the N terminus of the α-helix O and a nonconserved residue located six amino acids after this conserved tyrosine. In yeast mitochondrial DNAP (DNA-directed DNA polymerase gamma MIP1 [Mip1]), those residues correspond to amino acids Y757 and F763. We hypothesized that the phenyl group of the F763 residue impinges on the syn conformation of 8-oxodG, therefore reducing dAMP misincorporation. Here, we measured dCMP and dAMP incorporation across 8-oxodG using wild-type and F763 Mip1 mutants. Our data suggest that both residue F763 and the universally conserved Y757 assemble a steric gate that obtrudes the 8-oxodG(syn) conformation. As the human orthologue of Mip1, DNA polymerase gamma (HsPolγ) or DNAP γ, also harbors phenylalanine at the corresponding position to Mip1-F763, the steric gate mechanism might similarly be responsible for controlling HsPolγ's fidelity when tolerating 8-oxodG lesions.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607219","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}