Cellular and Molecular Life Sciences最新文献

{"title":"Post-translational modifications of integrins: molecular mechanisms and pathological implications.","authors":"Xiao Wu, Hongquan Zhang, Xiaofan Wei","doi":"10.1007/s00018-026-06370-3","DOIUrl":"10.1007/s00018-026-06370-3","url":null,"abstract":"<p><p>Integrins are cell-surface adhesion receptors that mediate bidirectional signaling governing migration, proliferation, and survival. Emerging evidence reveals that integrin function is finely controlled by an interconnected network of post-translational modifications (PTMs), spanning classical modifications such as glycosylation and phosphorylation, as well as novel metabolite-driven alterations including carbamoylation and cysteine carboxyethylation. These PTMs collectively orchestrate integrin stability, conformation, trafficking, and downstream signaling, with profound implications for tumor progression, metastasis, fibrosis, and therapy resistance. We further highlight critical cross‑talk among distinct modification types and demonstrate how environmental cues (e.g., metabolic byproducts, gut microbiota metabolites) directly modify integrins. Finally, we explore emerging therapeutic strategies inspired by these insights, including targeted enzyme inhibitors, proteolysis targeting chimeras (PROTACs), deubiquitinase-targeting chimeras (DUBTACs), and PTM-editing tools such as dCasRx-based m6A editors. Deciphering the integrin PTM code transforms our understanding of cell adhesion biology and opens new frontiers for diagnostic biomarkers and precision therapy.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional differences of Munc18 isoforms reflect their affinities for the exocytosis site.","authors":"Liangwen Liu, Santiago Echeverry, Muhmmad Omar-Hmeadi, Irina Česnokova, Per-Eric Lund, Jan Saras, Sebastian Barg","doi":"10.1007/s00018-026-06381-0","DOIUrl":"10.1007/s00018-026-06381-0","url":null,"abstract":"<p><p>The SM-protein Munc18 and its binding partner syntaxin are crucial for two distinct steps of regulated exocytosis, docking of secretory granules at the release site, and priming reactions that prepare docked granules for Ca²⁺ dependent fusion. Both proteins cluster simultaneously at the docking site seconds after a granule arrives at the plasma membrane. To study the mechanisms of these separate Munc18 functions, we generated a Munc18-1 knockout (1KO) and a double knockout of both Munc18-1 and Munc18-2 (DKO) in insulin-secreting cells, and quantified granule docking, exocytosis, and protein clustering at the docking site by TIRF imaging and capacitance measurements. In the 1KO, priming and exocytosis were lost, but granule docking remained intact. In the DKO, both priming and granule docking were impaired. Expression of either Munc18-1 or -2 rescued these defects, as did expression of mutants with weakened binding to syntaxin (EA and EK mutants). Munc18 clustered at granule docking sites, with apparent affinities decreasing in the order Munc18-1 > Munc18-1EA > Munc18-1EK > Munc18-2. Clustering of syntaxin-1 and - 3 at granules was impaired in both knockout lines. Finally, single molecule and imaging fluorescence recovery after photobleaching (FRAP) revealed that Syntaxin and Munc18 molecules were bound to each other, regardless of whether the proteins were clustered at a granule or not. We conclude that that Munc18-1 and - 2 molecules co-cluster with syntaxin at the release site and support docking and priming, and different affinities of the isoforms for the granule docking site contribute to the observed functional preferences.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13452794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Helicobacter pylori and Porphyromonas gingivalis infections as emerging biomarkers associated with Correa's cascade.","authors":"Jannis Kountouras, Evangelos Kazakos, Vardaka Elisabeth, Maria C Mouratidou, Christos Zavos, Michael Doulberis","doi":"10.1007/s00018-026-06270-6","DOIUrl":"10.1007/s00018-026-06270-6","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13451460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic fatty acid substrates enhance the structural and mechanical performance of human-induced pluripotent stem cell-derived cardiomyocytes.","authors":"Mahmoud Gaballah, Kirsi Penttinen, Chandra Prajapati, Katriina Aalto-Setälä","doi":"10.1007/s00018-026-06375-y","DOIUrl":"10.1007/s00018-026-06375-y","url":null,"abstract":"<p><p>Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer a powerful platform for disease modeling, drug discovery, and regenerative therapies. However, their clinical and research utility remains limited by their immature, fetal-like phenotype. In the human heart, postnatal metabolic maturation involves a critical switch from glycolysis to fatty acid β-oxidation, enabling efficient ATP production via oxidative phosphorylation. In this study, we investigated whether mimicking this metabolic shift in vitro by culturing hiPSC-CMs in a fatty acid-based maturation medium (FAM) could enhance their structural and functional development compared to a conventional glucose-based medium (GLM). hiPSC-CMs cultured in FAM for two weeks exhibited significant improvements in morphological, metabolic, and mechanical maturation markers. Morphologically, FAM-cultured CMs exhibited enhanced sarcomeric organization, increased cellular alignment, and a more elongated and rod-like shape, which are characteristics typically associated with mature CMs. Ultrastructural analysis further confirmed improved maturation, revealing more organized sarcomeres and densely packed mitochondria compared to GLM-cultured CMs. Metabolically, FAM-cultured CMs demonstrated a clear shift from glycolytic to oxidative metabolism, as evidenced by higher mitochondrial membrane potential, increased oxidative phosphorylation capacity, elevated ATP production, and reduced glycolytic activity. These metabolic adaptations indicate a more adult-like energy profile, consistent with enhanced fatty acid β-oxidation. Mechanically, FAM-cultured cardiomyocytes exhibited enhanced functional maturity, as evidenced by faster calcium transients and greater contraction amplitude, indicating improvements in specific electrophysiological properties. In conclusion, fatty acid supplementation effectively promotes the structural, metabolic, and mechanical maturation of hiPSC-CMs, resulting in a more adult-like phenotype. This strategy provides a robust and straightforward approach to enhance the physiological relevance of hiPSC-CMs for preclinical applications in disease modeling, drug testing, and regenerative medicine.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13451179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A conserved miR-7132a/SOCS1/STAT2 regulatory axis enhances type I IFN antiviral responses in teleost fish.","authors":"Jiamei Liu, Huazhi Chen, Wenxing Li, Yinnan Mu, Xinhua Chen","doi":"10.1007/s00018-026-06378-9","DOIUrl":"10.1007/s00018-026-06378-9","url":null,"abstract":"<p><p>Type I interferon (IFN) signaling plays an essential role in restricting viral infection. Accumulating evidence indicates that microRNAs (miRNAs) serve as key regulators of the type I IFN signaling in mammals. However, whether the miRNA-mediated regulation is involved in type I IFN signaling in teleost fish remains unknown. In large yellow croaker (Larimichthys crocea, Lc), we found that miR-7132a induced by poly(I: C) or type I IFN LcIFNi promotes type I IFN responses in vitro and in vivo. Mechanistically, miR-7132a directly targets the 3'UTR of LcSOCS1 and inhibits LcSOCS1 expression by reducing its mRNA stability and repressing its protein translation. LcSOCS1 promotes K48-linked polyubiquitination at K382 residue of LcSTAT2 via its E3 ubiquitin ligase activity, leading to proteasomal degradation of LcSTAT2. By reducing LcSOCS1-mediated degradation of LcSTAT2, miR-7132a promotes LcSTAT2-dependent type I IFN antiviral responses. Notably, miR-7132a-mediated inhibition of SOCS1 is also present in other teleost species. Collectively, these findings reveal a novel positive regulatory axis by which miR-7132a promotes type I IFN antiviral responses by suppressing SOCS1-mediated STAT2 degradation. Thus, this study provides valuable insights into miRNA-mediated regulatory axis of type I IFN responses in teleost fish.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Primary cilia gene defects in BMSCs induce idiopathic scoliosis.","authors":"Li Zhang, Wenhui Yang, Zhi Zhao, Yingsong Wang, Haonan Wang, Ninghui Zhao, Jin Zhou, Zhibo Song, Zhaoquan Zhang, Tao Li, Shangjia Zhe, Genghao Qian, Yingliang Liu, Jingming Xie","doi":"10.1007/s00018-026-06251-9","DOIUrl":"10.1007/s00018-026-06251-9","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13438093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: GAS5 mediates notch signaling to exacerbate calcium oxalate-induced renal injury through the NF-κB/NLRP3 axis by promoting macrophage polarization.","authors":"Longchao Zhang, Shushuai Yang, Yuanjiong Qi, Haiwen Zhou, Shichao Zhang, Chenglong Xu, Quan Liao, Rui Yao, Shiyong Qi","doi":"10.1007/s00018-026-06363-2","DOIUrl":"10.1007/s00018-026-06363-2","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13438493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of EphA2 triggers ferroptosis by disrupting USP38mediated SLC7A11 stabilization in chemoresistant gastric cancer.","authors":"Runsha Xiao, Yan Mo, Jin Zhou, Yi Xu, Kuo Kang, Zhikang Chen, Yuanyuan Jiang, Chengmin Li, Xueping Feng, Zihua Chen, Si Chen, Chen Lai","doi":"10.1007/s00018-026-06345-4","DOIUrl":"10.1007/s00018-026-06345-4","url":null,"abstract":"<p><p>Aberrant expression of EphA2 (Ephrin receptor A2) in gastric cancer (GC) promotes chemoresistance by suppressing ferroptosis, yet the underlying mechanism remains poorly defined. In this study, we show that EphA2 confers resistance to platinum-based chemotherapy by suppressing ferroptosis through redox homeostasis regulation. Mechanistically, EphA2 directly phosphorylates and activates the deubiquitinase USP38, which in turn stabilizes SLC7A11 by preventing its proteasomal degradation. Elevated SLC7A11 sustains intracellular glutathione homeostasis, attenuates lipid peroxidation, and limits reactive oxygen species accumulation, thereby enabling GC cells to evade ferroptotic cell death under chemotherapeutic stress. Importantly, genetic or pharmacological disruption of the EphA2-USP38 interaction leads to SLC7A11 destabilization, excessive ROS accumulation, ferroptosis induction, and restoration of chemosensitivity. Together, these findings identify the EphA2-USP38/ROS axis as a key determinant of oxaliplatin resistance in GC and highlight a promising therapeutic target for overcoming chemotherapy resistance by reactivating ferroptosis.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sirt5 preserves mitochondrial homeostasis to improve cardiac function in ischemia-reperfusion injury by inhibiting ANT2 lysine lactylation modification.","authors":"Simeng Li, Siman Shen, Yongfang Hong, Kun Ding, Suyun Chen, Jianning Chen, Changsen Wang, Yaofeng Wen, Guixi Mo, Lili Yu, De-Li Shi, Liangqing Zhang","doi":"10.1007/s00018-026-06308-9","DOIUrl":"https://doi.org/10.1007/s00018-026-06308-9","url":null,"abstract":"<p><p>Myocardial ischemia-reperfusion (IR) injury, a prevalent heart disease, disrupts mitochondrial homeostasis, affecting heart energy metabolism. The role of mitochondrial protein Sirt5 in protecting the heart from IR injury is explored in mice. Reduced Sirt5 levels in IR-injured hearts correlate with increased protein lactylation and impaired mitochondrial function. Sirt5 overexpression mitigates, while its knockout worsens, mitochondrial and cardiac damage. Sirt5 interacts with ANT2, reducing its lysine lactylation to enhance its association with VDAC1. This interaction improves cardiac function post-injury. Targeting ANT2 lactylation may offer a therapeutic approach for cardiac injury.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meprin β is specifically inhibited by its cognate synthetic propeptide.","authors":"Fred Armbrust, Hannah Bruhn, Kira Bickenbach, Nicolas Steen, Sapir Shcoory, Nikolaos Afratis, Nele Korn, Hagen Körschgen, Catherine Moali, Claus U Pietrzik, Irit Sagi, Christoph Becker-Pauly","doi":"10.1007/s00018-026-06361-4","DOIUrl":"https://doi.org/10.1007/s00018-026-06361-4","url":null,"abstract":"<p><p>Meprin β is a zinc-dependent metalloprotease of the astacin family highly expressed in kidney and intestine. Dysregulation of meprin β expression and activity was observed in several pathological conditions such as Alzheimer's disease, cancer, fibrosis, and inflammatory bowel disease. Therefore, inhibition of meprin β could be a promising therapeutic option to treat pathological conditions influenced by this protease. However, available small-molecule compounds such as the broad-spectrum metalloproteinases inhibitors marimastat or actinonin lack specificity. Hence, more selective meprin β inhibitors needs to be developed. Here, we provide evidence that the synthetically generated cognate meprin β propeptide serves as highly specific inhibitor for the protease (IC₅₀ = 1.35 µM), while other related metalloproteases such as meprin α and a disintegrin and metalloproteinases (ADAMs) are not affected. Employing a targeted approach revealed that removal of the last four C-terminal amino acids of the propeptide significantly improved its inhibitory capacity (IC₅₀ = 0.68 µM). In cell-based experiments, treatment with the propeptide resulted in diminished meprin β activity and decreased cleavage of its substrates, including the interleukin-6 receptor (IL-6R) and the G protein-coupled receptor latrophilin-3 (LPHN3). Suitability was further confirmed in ex vivo cultivated organotypic brain slices, where the administration of the propeptide also resulted in decreased meprin β activity and diminished latrophilin-3 cleavage. Thus, not only the synthetic wildtype propeptide but especially a C-terminally truncated propeptide of meprin β represent highly specific inhibitors with potential for therapeutic application.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}