{"title":"Cis-unsaturated sphingolipids support growth of sphingoid base-deficient yeast but impair plasma membrane integrity.","authors":"Takashi Higuchi, Saki Sugihara, Yohei Ishibashi, Kono Yushi, Hazuki Yamauchi, Motohiro Tani","doi":"10.1002/2211-5463.70100","DOIUrl":"https://doi.org/10.1002/2211-5463.70100","url":null,"abstract":"<p><p>Sphingoid long-chain bases (LCBs) form the backbone of sphingolipids, and their structures vary among eukaryotes. For example, in budding yeast, phytosphingosine is the major LCB, while animals primarily use sphingosine. Animals and plants also produce structurally diverse LCBs, including species with additional cis or trans double bonds, which are absent in yeast. Here, we show that yeast can grow even when its endogenous LCBs are replaced with plant-type unsaturated forms, such as (8Z)-4-hydroxy-8-sphingenine or (4E,8E)-sphinga-4,8-dienine. These cells synthesized ceramides and complex sphingolipids, indicating efficient incorporation of the exogenous LCBs into sphingolipid metabolism. However, cells harboring these unsaturated LCBs exhibited abnormalities in plasma membrane permeability, lipid order, and distribution of some plasma membrane-localized proteins. In contrast, these cells reinforce their cell walls, presumably to compensate for the impaired plasma membrane integrity. Notably, to our knowledge, this is the first report of eukaryotic cells whose sphingolipids are composed almost exclusively of LCBs with a cis double bond, providing a unique model platform to investigate how LCB structural features influence membrane function.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS Open BioPub Date : 2025-08-04DOI: 10.1002/2211-5463.70086
Femke J. Vermeir, Lotte W. Nijman, Robert S. Jansen, Laura van Niftrik, Wouter Versantvoort
{"title":"Nitric oxide-forming nitrite reductases in the anaerobic ammonium oxidizer Kuenenia stuttgartiensis","authors":"Femke J. Vermeir, Lotte W. Nijman, Robert S. Jansen, Laura van Niftrik, Wouter Versantvoort","doi":"10.1002/2211-5463.70086","DOIUrl":"10.1002/2211-5463.70086","url":null,"abstract":"<p>Anaerobic ammonium-oxidizing (anammox) bacteria contribute to the global nitrogen cycle by removing fixed nitrogen from the environment. They do so via the anaerobic oxidation of ammonium to dinitrogen gas, with nitrite as terminal electron acceptor. The first step in this so-called anammox reaction is the proposed conversion of nitrite to nitric oxide by a nitrite reductase. There is an unusual diversity and redundancy in anammox nitrite reductases and to gain more insight into the puzzling redundancy and diversity, we investigated the putative reductases in the model anammox species ‘<i>Candidatus</i> Kuenenia stuttgartiensis’. The genome of this model anammox species encodes for three putative nitrite reductases and we investigated which of these is or are active in <i>K. stuttgartiensis</i> strain MBR1. Active nitric oxide-producing nitrite reductases were enriched from <i>K. stuttgartiensis</i> cells via fast protein liquid chromatography. Nitric oxide production by the enriched nitrite reductases was followed with membrane inlet mass spectrometry. Combining the activity assays with proteomics analysis indicated that the soluble nitrite reductases NirS and HAOr most strongly correlated with enzyme activity. This indicates that <i>K. stuttgartiensis</i> strain MBR1 employs two distinct nitrite reductases to keep its nitric oxide pool replenished. Containing two different nitrite reductases could improve the adaptability of <i>K. stuttgartiensis</i> to changes in environmental nitrite concentrations.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":"15 10","pages":"1696-1713"},"PeriodicalIF":2.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://febs.onlinelibrary.wiley.com/doi/epdf/10.1002/2211-5463.70086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Downregulation of sST2, a decoy receptor for interleukin-33, enhances subcutaneous tumor growth in murine pancreatic cancer cells.","authors":"Miho Akimoto, Nobuko Koshikawa, Takao Morinaga, Mimi Tamamori-Adachi, Atsushi Takatori, Keizo Takenaga","doi":"10.1002/2211-5463.70099","DOIUrl":"https://doi.org/10.1002/2211-5463.70099","url":null,"abstract":"<p><p>Despite the recent scientific advancements, pancreatic cancer remains the seventh leading cause of cancer-related mortality. Pancreatic cancer progression is closely associated with inflammation, and we previously showed that short hairpin RNA-mediated knockdown of sST2 expression, a soluble decoy receptor for the proinflammatory molecule interleukin-33 (IL-33), in mouse Panc02 pancreatic cancer cells reduced malignant growth following pancreatic (orthotopic) implantation. Furthermore, this growth suppression was accompanied by decreased tumor angiogenesis, reduced expression of the neutrophil chemoattractant CXCL3, and a lower number of tumor-associated neutrophils (TANs). In contrast to previous results, in this study, we showed that IL-33-dependent tumor growth and pulmonary metastasis occurred following subcutaneous (ectopic) implantation of sST2-knockdown cells. This was associated with a decrease in the levels of the anti-inflammatory molecule adiponectin and the number of GLUT4-positive cancer-associated adipocytes, as well as an increase in IκBα phosphorylation levels, Cxcl3 expression, and the accumulation of infiltrating CD206<sup>+</sup> protumor N2 TANs. Taken together, these results suggest that Panc02 cell-derived sST2 differentially affects malignant growth in the tumor microenvironment depending on the implantation site.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS Open BioPub Date : 2025-07-31DOI: 10.1002/2211-5463.70091
Karl Josef Föhr, Michael Fauler, Thomas Zimmer, Bettina Jungwirth, Hubert Schrezenmeier, David Alexander Christian Messerer
{"title":"Blocking the voltage-gated sodium channel hNa<sub>v</sub>1.5 as a novel pH-dependent mechanism of action for tamoxifen.","authors":"Karl Josef Föhr, Michael Fauler, Thomas Zimmer, Bettina Jungwirth, Hubert Schrezenmeier, David Alexander Christian Messerer","doi":"10.1002/2211-5463.70091","DOIUrl":"https://doi.org/10.1002/2211-5463.70091","url":null,"abstract":"<p><p>Tamoxifen, a selective estrogen receptor modulator, is widely used in breast cancer treatment, but also affects estrogen receptor-negative tumors, suggesting alternative mechanisms. Voltage-gated sodium channels (VGSCs) are implicated in metastasis, making them potential therapeutic targets. However, broad VGSC inhibition is impractical due to their essential physiological roles. Ideally, blockers should selectively target tumor-associated VGSC properties while sparing normal cells. Since tamoxifen exhibits sodium channel-blocking activity, we investigated its effects on tumor-specific VGSC parameters. Electrophysiological experiments using the patch-clamp technique were conducted on heterologously expressed human cardiac sodium channels (hNa<sub>v</sub>1.5). Tamoxifen does not differentiate between the adult and embryonic splice variants of hNa<sub>v</sub>1.5, the latter being predominant in tumors. However, it effectively blocks hNa<sub>v</sub>1.5 in gating states (slow-inactivated and open) assumed to be prevalent in cancer cells. Binding affinity increases significantly under acidic conditions (pH 6.0 vs. 7.4), mimicking the tumor microenvironment. The affinity for the slow-inactivated state was 0.87 ± 0.16 μm at pH 7.4 and 0.16 ± 0.02 μm at pH 6.0. For the open state, half-maximal inhibition occurred at 2.13 ± 0.08 μm and 0.57 ± 0.02 μm, respectively. Tamoxifen preferentially binds VGSCs under conditions characteristic of cancer tissue, particularly at acidic pH, suggesting its potential as a selective tumor-targeting agent.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS Open BioPub Date : 2025-07-31DOI: 10.1002/2211-5463.70096
Ngoc Nguyen Thi Minh, Esther Lee, Soo-A Kim
{"title":"The cochaperone BAG3 promotes the stabilization of p53 under heat stress conditions.","authors":"Ngoc Nguyen Thi Minh, Esther Lee, Soo-A Kim","doi":"10.1002/2211-5463.70096","DOIUrl":"https://doi.org/10.1002/2211-5463.70096","url":null,"abstract":"<p><p>Bcl-2-associated athanogene 3 (BAG3) is the only member of the BAG cochaperone family that is induced by stressful stimuli such as heat shock and heavy metals. In the present study, bag3 knockout (KO) HeLa cells were generated via the CRISPR-Cas9 system, and the role of BAG3 in relation to p53 under heat stress conditions was investigated. Normally, the levels of p53 were low in both wild-type (WT) and KO cells, while heat shock increased the levels of nuclear p53 in both cell lines. However, the increased level of p53 was much greater in WT cells than in KO cells, which suggested that BAG3 played a role in controlling the level of p53 under heat stress conditions. The mRNA level of p53 did not increase in either WT or KO cells during the heat stress period, which suggested that the differences in the levels of p53 were not due to transcriptional regulation. Both treatment with the proteasome inhibitor MG132 and heat shock drastically increased p53 levels to a similar extent in WT cells. Interestingly, both BAG3 and Hsp70 rapidly translocated to the nucleus and formed a complex with p53 upon heat stress. During a 1-h recovery period from heat stress, the transcriptional activity of p53 increased up to 4-fold in WT cells, but only 1.69-fold in KO cells. These results demonstrate that Hsp70 and BAG3 are involved in the quality control of p53 under heat stress conditions and suggest a role for BAG3 as a cochaperone protein.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS Open BioPub Date : 2025-07-30DOI: 10.1002/2211-5463.70095
{"title":"Correction to 'In-depth multiomic characterization of the effects of obesity in high-fat diet-fed mice'.","authors":"","doi":"10.1002/2211-5463.70095","DOIUrl":"https://doi.org/10.1002/2211-5463.70095","url":null,"abstract":"","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS Open BioPub Date : 2025-07-29DOI: 10.1002/2211-5463.70071
{"title":"Posters","authors":"","doi":"10.1002/2211-5463.70071","DOIUrl":"10.1002/2211-5463.70071","url":null,"abstract":"<p>Moved to LB-R-03-01</p><p>Abstract withdrawn</p><p>Abstract withdrawn</p><p>Abstract withdrawn</p><p>Abstract withdrawn</p><p>Abstract withdrawn</p><p>Abstract moved to P-30-134</p><p>Abstract withdrawn.</p><p>Abstract withdrawn.</p><p>Abstract withdrawn.</p><p>Abstract moved to TALKS SpT-05.3-5.</p><p>Abstract withdrawn.</p><p>Transferred to Spt-01.4-2</p><p>This addendum comprises abstracts whose inclusion in the <i>FEBS Open Bio</i> supplement was delayed during the Congress administration.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":"15 S2","pages":"67-527"},"PeriodicalIF":2.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/2211-5463.70071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS Open BioPub Date : 2025-07-23DOI: 10.1002/2211-5463.70092
Pernilla Israelsson, Lisa Lif, Husam Oda, Alexandra Lorenzzi de Melo, David Lindquist, Håkan Hedman
{"title":"High LRIG1 expression predicts lymph node metastasis in patients with uterine cervical cancer.","authors":"Pernilla Israelsson, Lisa Lif, Husam Oda, Alexandra Lorenzzi de Melo, David Lindquist, Håkan Hedman","doi":"10.1002/2211-5463.70092","DOIUrl":"https://doi.org/10.1002/2211-5463.70092","url":null,"abstract":"<p><p>Fifteen percent of patients with preoperative stage IA2-IB1 uterine cervical cancer are diagnosed with lymph node metastasis (LNM) following surgery. They must be treated with both surgery and radiotherapy, a combination associated with severe side effects. Since current diagnostic methods have limitations, biomarkers are urgently needed to improve staging. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a regulator of growth factor signaling and a prognostic factor in cervical cancer. This study investigates whether LRIG1 expression could predict LNM in cervical cancer. Sixty-seven patients were included: 31 without LNM and 36 with LNM. Tumor blocks were retrieved, and clinical data were collected. Immunohistochemical analysis of LRIG1 expression was performed, and LRIG1 immunoreactivity was correlated with lymph node status and clinicopathological prognostic factors, such as human papillomavirus status and smoking status. High LRIG1 expression (> 25% positive cells) was significantly associated with an increased risk of LNM (odds ratio 9.49, 95% CI: 1.80-50.05, P = 0.008, adjusted for age, smoking status, and BMI), suggesting the potential of LRIG1 as a biomarker. Larger, multicenter studies are needed to validate our results.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FEBS Open BioPub Date : 2025-07-21DOI: 10.1002/2211-5463.70089
Shengjun Fu, Yan Tao, Shan Wu, Yuwen Gong, Youli Zhao, Shaomin Niu, Hui Cheng, You Mu, Na Xu, Ying Wang, Jianzhong Lu, Shanhui Liu, Lanlan Li
{"title":"Ro 31-8220 suppresses bladder cancer progression via enhancing autophagy in vitro and in vivo.","authors":"Shengjun Fu, Yan Tao, Shan Wu, Yuwen Gong, Youli Zhao, Shaomin Niu, Hui Cheng, You Mu, Na Xu, Ying Wang, Jianzhong Lu, Shanhui Liu, Lanlan Li","doi":"10.1002/2211-5463.70089","DOIUrl":"https://doi.org/10.1002/2211-5463.70089","url":null,"abstract":"<p><p>Chemotherapy remains the main treatment for muscle-invasive bladder cancer (BLCA) despite drug resistance and lack of target drugs greatly limiting long-term survival of patients. Thus, novel and effective drugs specific to BLCA are required to aid in its treatment and improve patient survival. In the present study, we found that the compound Ro-31-8220, a pan-protein kinase C inhibitor, displays potent anti-bladder cancer efficacy in vitro and in vivo. Ro-31-8220 treatment suppressed bladder cancer cell migration and invasion and also induced cell apoptosis in a dose-dependent manner. Proteomic analysis showed that Ro-31-8220 treatment altered the expression of numerous proteins and KEGG enrichment analysis demonstrated that multiple signal pathways are regulated by Ro-31-8220, including autophagy. To further validate these results, we carried out western blotting, GFP-LC3 fusion protein and transmission electron microscopy analyses, all of which demonstrated that Ro-31-8220 induced bladder cancer cell autophagy. Blockade of autophagy with chloroquine, an autophagy inhibitor, attenuated Ro-31-8220 induced bladder cancer cell death. In a bladder cancer xenograft tumor growth mice model, we showed that intraperitoneal injection of Ro-31-8220 significantly decreased tumor size and tumor weight compared to the control group, suggesting an in vivo tumor suppression ability of Ro-31-8220 through activation of autophagy. These results suggest that Ro-31-8220 may be a novel promising candidate drug for bladder cancer therapy. Further studies, including clinical trials, are required to validate these results.</p>","PeriodicalId":12187,"journal":{"name":"FEBS Open Bio","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}