Cellular and Molecular Life Sciences最新文献_第5页

Proteomic characterization of MET-amplified esophageal adenocarcinomas reveals enrichment of alternative splicing- and androgen signaling-related proteins. met扩增食管腺癌的蛋白质组学特征揭示了选择性剪接和雄激素信号相关蛋白的富集。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-03-13 DOI: 10.1007/s00018-025-05635-7

Bastian Grothey, Su Ir Lyu, Alexander Quaas, Adrian Georg Simon, Jin-On Jung, Wolfgang Schröder, Christiane J Bruns, Lars M Schiffmann, Felix C Popp, Thomas Schmidt, Karl Knipper

{"title":"Proteomic characterization of MET-amplified esophageal adenocarcinomas reveals enrichment of alternative splicing- and androgen signaling-related proteins.","authors":"Bastian Grothey, Su Ir Lyu, Alexander Quaas, Adrian Georg Simon, Jin-On Jung, Wolfgang Schröder, Christiane J Bruns, Lars M Schiffmann, Felix C Popp, Thomas Schmidt, Karl Knipper","doi":"10.1007/s00018-025-05635-7","DOIUrl":"10.1007/s00018-025-05635-7","url":null,"abstract":"Background: Esophageal adenocarcinomas (EACs) represent an evolving tumor entity with high mortality rates. MET amplification is a recurrent driver in EACs and is associated with decreased patient survival. However, the response to MET inhibitors is limited. Recent studies have identified several mechanisms that lead to resistance against MET inhibitors in different tumor entities. Nonetheless, a characterization of additional vulnerable targets beyond MET has not been conducted in MET-amplified EACs.Methods: In this study, we determined the MET amplification status in a cohort of more than 900 EACs using fluorescence in situ hybridization (FISH) and compared the proteomes of MET-amplified (n = 20) versus non-amplified tumors (n = 39) by mass spectrometry.Results: We identified a phenotype, present in almost all MET-amplified tumors, which shows an enrichment of alternative RNA splicing, and androgen receptor signaling proteins, as well as decreased patient survival. Additionally, our analyses revealed a negative correlation between MET expression and patient survival in MET-amplified EACs, indicating biological heterogeneity with clinical relevance despite the presence of MET amplification as the predominant oncogenic driver. Furthermore, quantitative immunohistochemical analysis of the inflammatory tumor microenvironment showed that an increased percentage of M2 macrophages is associated with lower overall survival in MET-amplified EACs.Conclusions: Our results provide valuable insights into possible new therapeutic approaches for MET-amplified EACs for further research.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"112"},"PeriodicalIF":6.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613747","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}

引用次数: 0

Crip2 affects vascular development by fine-tuning endothelial cell aggregation and proliferation. Crip2通过微调内皮细胞聚集和增殖影响血管发育。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-03-13 DOI: 10.1007/s00018-025-05624-w

Shuaiqi Yang, Xiangmin Zhang, Xianpeng Li, Hongyan Li

{"title":"Crip2 affects vascular development by fine-tuning endothelial cell aggregation and proliferation.","authors":"Shuaiqi Yang, Xiangmin Zhang, Xianpeng Li, Hongyan Li","doi":"10.1007/s00018-025-05624-w","DOIUrl":"10.1007/s00018-025-05624-w","url":null,"abstract":"Endothelial cell adhesion and migration are crucial to various biological processes, including vascular development. The identification of factors that modulate vascular development through these cell functions has emerged as a prominent focus in cardiovascular research. Crip2 is known to play a crucial role in cardiac development, yet its involvement in vascular development and the underlying mechanism remains elusive. In this study, we revealed that Crip2 is expressed predominantly in the vascular system, particularly in the posterior cardinal vein and caudal vein plexus intersegmental vein. Upon Crip2 loss, the posterior cardinal vein plexus and caudal vein plexus are hypoplastic, and endothelial cells exhibit aberrant aggregation. In human umbilical vein endothelial cells (HUVECs), CRIP2 interacts with the cytoskeleton proteins KRT8 and VIM. The absence of CRIP2 negatively regulates their expression, thereby fine-tuning cytoskeleton formation, resulting in a hyperadhesive phenotype. Moreover, CRIP2 deficiency perturbs the VEGFA/CDC42 signaling pathway, which in turn diminishes the migrating capacity of HUVECs. Furthermore, the loss of CRIP2 impairs cell proliferation by affecting its interaction with SRF through PDE10A/cAMP and PDGF/JAK/STAT/SRF signaling. Collectively, our findings delineate a crucial role for CRIP2 in controlling the migration, adhesion and proliferation of endothelial cells, thereby contributing to vascular development in zebrafish. These insights may provide a deeper understanding of the etiology of cardiovascular disorders.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"110"},"PeriodicalIF":6.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613738","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}

引用次数: 0

Endometrium-derived organoids from cystic fibrosis patients and mice as new models to study disease-associated endometrial pathobiology. 囊性纤维化患者和小鼠子宫内膜衍生类器官作为研究疾病相关子宫内膜病理生物学的新模型

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-03-13 DOI: 10.1007/s00018-025-05627-7

Ellen De Pauw, Beau Gommers, Marjolein M Ensinck, Stefan Timmerman, Silke De Vriendt, Celine Bueds, Mengjie Wei, Florian Hermans, Kaline Arnauts, Anabela S Ramalho, Francois Vermeulen, Lieven Dupont, Diether Lambrechts, Marianne S Carlon, Hugo Vankelecom

{"title":"Endometrium-derived organoids from cystic fibrosis patients and mice as new models to study disease-associated endometrial pathobiology.","authors":"Ellen De Pauw, Beau Gommers, Marjolein M Ensinck, Stefan Timmerman, Silke De Vriendt, Celine Bueds, Mengjie Wei, Florian Hermans, Kaline Arnauts, Anabela S Ramalho, Francois Vermeulen, Lieven Dupont, Diether Lambrechts, Marianne S Carlon, Hugo Vankelecom","doi":"10.1007/s00018-025-05627-7","DOIUrl":"10.1007/s00018-025-05627-7","url":null,"abstract":"Cystic fibrosis (CF) is a life-shortening genetic disorder, caused by mutations in the CF transmembrane conductance regulator (CFTR) protein that regulates ion and fluid transport in epithelial tissue. Female CF patients face considerable fertility challenges, with higher prevalence of deficient fertility compared to healthy women. Not much is known about the underlying causes. In particular, the pathobiology of the endometrium, the uterus' inner lining essential for pregnancy and expressing fluctuating CFTR levels during the menstrual cycle, is unexplored in CF. To address this gap, we developed organoid models from CF patient endometrium. The organoids recapitulated CF characteristics and revealed molecular and pathway differences in cycle-recapitulating hormone responses compared to healthy endometrial organoids. Furthermore, specific functional aberrations were restored by CFTR modulator treatment. To further complement human organoid models for unraveling endometrial pathobiology in CF, we also developed organoids from a genetic CF mouse model that were also found to recapitulate CF characteristics. Moreover, single-cell RNA-sequencing analysis of the CF mouse uterus revealed molecular traits in the endometrium similar to the human CF endometrium (as evidenced by its organoid model). Our study provides new endometrium models to advance our understanding of CF-associated endometrial pathobiology, particularly regarding menstrual cycle aberrations that impact fertility. This research is timely since improved CF therapeutics result in increased life expectancy, allowing more CF patients to consider starting a family.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"109"},"PeriodicalIF":6.2,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613740","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}

引用次数: 0

Correction: Required minimal protein domain of flower for synaptobrevin2 endocytosis in cytotoxic T cells. 更正：细胞毒性T细胞中synaptobrevin2内吞作用所需的最小蛋白域。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-03-13 DOI: 10.1007/s00018-025-05619-7

Keerthana Ravichandran, Claudia Schirra, Katja Urbansky, Szu-Min Tu, Nadia Alawar, Stefanie Mannebach, Elmar Krause, David Stevens, C Roy D Lancaster, Veit Flockerzi, Jens Rettig, Hsin-Fang Chang, Ute Becherer

引用次数: 0

The DNase TREX1 is a substrate of the intramembrane protease SPP with implications for disease pathogenesis. dna酶TREX1是膜内蛋白酶SPP的底物，与疾病发病机制有关。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-03-12 DOI: 10.1007/s00018-025-05645-5

Onur Kerem Tever, Torben Mentrup, Ivan Kingyue Chinn, Hitoshi Ishikuma, Regina Fluhrer, Marc Schmitz, Rebekka Wehner, Rayk Behrendt, Javier Chinen, Bernd Schröder

{"title":"The DNase TREX1 is a substrate of the intramembrane protease SPP with implications for disease pathogenesis.","authors":"Onur Kerem Tever, Torben Mentrup, Ivan Kingyue Chinn, Hitoshi Ishikuma, Regina Fluhrer, Marc Schmitz, Rebekka Wehner, Rayk Behrendt, Javier Chinen, Bernd Schröder","doi":"10.1007/s00018-025-05645-5","DOIUrl":"10.1007/s00018-025-05645-5","url":null,"abstract":"Signal peptide peptidase (SPP) is an ER-resident aspartyl intramembrane protease cleaving proteins within type II-oriented transmembrane segments. Here, we identified the tail-anchored protein Three prime repair exonuclease 1 (TREX1) as a novel substrate of SPP. Based on its DNase activity, TREX1 removes cytosolic DNA acting as a negative regulator of the DNA-sensing cGAS/STING pathway. TREX1 loss-of-function variants cause Aicardi-Goutières syndrome (AGS), a type I interferonopathy. Cleavage of ER-bound TREX1 by SPP releases a cleavage product into the cytosol. Proteolysis depends on sequence determinants within the transmembrane segment and is modulated by different disease-associated TREX1 variants. The AGS-causing T303P variant greatly enhanced susceptibility of TREX1 to intramembrane cleavage accounting for increased degradation and reduced protein stability in AGS patients homozygous for this variant. Other variants within the TREX1 transmembrane segment, P290L, Y305C and G306A, associated with systemic lupus erythematosus variably modulated TREX1 proteolytic processing. Altogether, intramembrane proteolysis can act as a regulator of TREX1 both by controlling its cytosolic localization and mediating its turnover with implications for disease pathogenesis.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"107"},"PeriodicalIF":6.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613749","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}

引用次数: 0

Unveiling two distinct osteolineage cell populations linked to age-related osteoporosis in adult mice through integrative single-cell analyses. 通过单细胞综合分析，揭示与成年小鼠年龄相关性骨质疏松症有关的两种不同的骨胶质细胞群。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-03-11 DOI: 10.1007/s00018-025-05597-w

Bo Zhou, Hongwen Huang, Zhen Ding, Kaiwen Luo, Yangshan Chen, Yingying Han, Wei Pang, Wanze Tang, Litong Chen, Wenfei Jin, Guixing Ma, Huiling Cao

{"title":"Unveiling two distinct osteolineage cell populations linked to age-related osteoporosis in adult mice through integrative single-cell analyses.","authors":"Bo Zhou, Hongwen Huang, Zhen Ding, Kaiwen Luo, Yangshan Chen, Yingying Han, Wei Pang, Wanze Tang, Litong Chen, Wenfei Jin, Guixing Ma, Huiling Cao","doi":"10.1007/s00018-025-05597-w","DOIUrl":"10.1007/s00018-025-05597-w","url":null,"abstract":"The bone marrow microenvironment contains heterogeneous stromal cells, which are critical for bone remodeling and provide essential supportive roles for hematopoietic functions. Although the diversity of PDGFRα+β+ mesenchymal stromal/stem cells (MSCs) get consensus, the osteo-lineage cells (OLCs) that constitute the developmental trajectory of osteoblasts are largely remain unclear. Here, we construct a comprehensive atlas of stromal cell via performing integrative single cell analyses for 77 samples from 14 datasets. Besides previously defined Lepr+ BM-MSCs derived OLC1, we present a novel OLC2 with unique molecular signatures and differentiation pathway. Both OLC1 and OLC2 show significant polygenic association with bone mineral density (BMD), while extracellular matrix (ECM) proteins specifically expressed by OLC2 are particularly decreased in bone tissue of aged mice. Notably, OLC1 and OLC2 are consistently reduced in aged mice, which might be induced by the decreased expression of several lineage drivers. Collectively, our study presents a thorough prospect of OLCs in the bone marrow microenvironment and highlights their important roles in age-related osteoporosis.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"106"},"PeriodicalIF":6.2,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11896952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604077","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}

引用次数: 0

IGF2BP1-HAX-1 positive feedback loop-mediated HAX-1 overexpression blocks autophagic flux and promotes chemoresistance in nasopharyngeal carcinoma. IGF2BP1-HAX-1正反馈环介导的HAX-1过表达阻断自噬通量，促进鼻咽癌化疗耐药。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-03-07 DOI: 10.1007/s00018-025-05604-0

Siyu Zhang, Miao Gu, Haimeng Yin, Si Pan, Haijing Xie, Wenhui Chen, Sheraz Gul, Yue Zhao, Zhefang Wang, Wenjie Zheng, Yiwen You, Bo You

{"title":"IGF2BP1-HAX-1 positive feedback loop-mediated HAX-1 overexpression blocks autophagic flux and promotes chemoresistance in nasopharyngeal carcinoma.","authors":"Siyu Zhang, Miao Gu, Haimeng Yin, Si Pan, Haijing Xie, Wenhui Chen, Sheraz Gul, Yue Zhao, Zhefang Wang, Wenjie Zheng, Yiwen You, Bo You","doi":"10.1007/s00018-025-05604-0","DOIUrl":"10.1007/s00018-025-05604-0","url":null,"abstract":"Autophagy is associated with chemoresistance, which is the leading cause of failure in chemotherapeutic treatments. Among the various aspects of autophagy, autophagic flux serves as a critical indicator for evaluating the dynamic processes involved.We report herein that the multifunctional protein HAX-1 promotes chemoresistance by effectively blocking the fusion of autophagosomes with lysosomes. Complementary mass spectrometric and functional studies also demonstrated that HAX-1 recruits NEDD4 to promote Rab7a degradation and inhibits binding of Rab7a with SNAREs by competitively binding to it. Furthermore, HAX-1 binds IGF2BP1 mRNA, thereby contributing to its stability and translation. Moreover, IGF2BP1 enhanced HAX-1 m6A methylation, thereby enhancing its stability. By way of in-vivo and in-vitro experiments, we confirmed the positive role of the IGF2BP1-HAX-1 feedback loop in chemoresistance. Taken together, our findings provide evidence that monitoring of HAX-1, IGF2BP1, and SQSTM1 levels can serve as useful predictors of clinical outcome and chemoresistance risk. In addition, our data provide new insights into the clinical applications of therapies related to autophagic flux and its associated molecular network in targeting cisplatin chemoresistance in nasopharyngeal carcinoma.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"105"},"PeriodicalIF":6.2,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584954","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}

引用次数: 0

Melatonin refines ovarian mitochondrial dysfunction in PCOS by regulating the circadian rhythm gene Clock. 褪黑素通过调节昼夜节律基因时钟改善PCOS患者卵巢线粒体功能障碍。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-03-06 DOI: 10.1007/s00018-025-05609-9

Wenxiu Chen, Hongyan Zhang, Bao Guo, Yumei Tao, Junhui Zhang, Jiayi Wang, Guangyi Chen, Mengting Cheng, Qiang Hong, Yunxia Cao, Fenfen Xie

{"title":"Melatonin refines ovarian mitochondrial dysfunction in PCOS by regulating the circadian rhythm gene Clock.","authors":"Wenxiu Chen, Hongyan Zhang, Bao Guo, Yumei Tao, Junhui Zhang, Jiayi Wang, Guangyi Chen, Mengting Cheng, Qiang Hong, Yunxia Cao, Fenfen Xie","doi":"10.1007/s00018-025-05609-9","DOIUrl":"10.1007/s00018-025-05609-9","url":null,"abstract":"Mitochondrial dysfunction is present in the ovaries of patients with polycystic ovary syndrome (PCOS). Melatonin (MT) has shown promise in treating PCOS by improving mitochondrial dysfunction, though the underlying mechanisms remain unclear. In this study, we first assessed the levels of proteins associated with mitochondrial autophagy and dynamics in ovary granulosa cells (GCs) of PCOS patients and in the ovaries of DHEA-induced PCOS mice. We found abnormal expression of these proteins, indicating the presence of mitochondrial dysfunction in PCOS ovaries. Notably, the expression of the circadian gene Clock and melatonin synthetic enzymes were also decreased in the ovaries of PCOS patients. Studies have suggested a potential role of circadian rhythm genes in the pathogenesis and progression of PCOS. We subsequently observed that pretreatment with MT could ameliorate the abnormal levels of mitochondrial-related proteins, reverse the low expression of CLOCK, and reduce pyroptosis in PCOS ovaries. Given the potential interaction between MT and Clock, we focused on whether exogenous MT improves mitochondrial dysfunction in PCOS ovaries by regulating the expression of the circadian gene Clock. Through in vitro culture of the human ovarian granulosa cell line KGN, we further found that when CLOCK levels were inhibited, the beneficial effects of MT on abnormal mitochondrial autophagy, disturbed mitochondrial dynamics, and mitochondrial dysfunction in PCOS ovaries were not significant, and there was no notable improvement in ovary GCs pyroptosis. Our study suggests that MT may improve ovary mitochondrial dysfunction by regulating circadian gene Clock while also reducing GCs pyroptosis in PCOS.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"104"},"PeriodicalIF":6.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11885701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566267","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}

引用次数: 0

Temporal characterisation and electrophysiological implications of TBI-induced serine/threonine kinase activity in mouse cortex. 脑外伤诱导小鼠皮层丝氨酸/苏氨酸激酶活性的时间表征和电生理意义。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-03-05 DOI: 10.1007/s00018-025-05638-4

Gallagher Celine, Mittmann Thomas

{"title":"Temporal characterisation and electrophysiological implications of TBI-induced serine/threonine kinase activity in mouse cortex.","authors":"Gallagher Celine, Mittmann Thomas","doi":"10.1007/s00018-025-05638-4","DOIUrl":"10.1007/s00018-025-05638-4","url":null,"abstract":"Traumatic brain injury (TBI) remains the leading cause of death and disability worldwide with no existing effective treatment. The early phase after TBI induction triggers numerous molecular cascades to regulate adaptive processes and cortical network activity. Kinases play a particularly prominent role in modifying peptide substrates, which include ion channels, receptors, transcription factors and inflammatory mediators. This study aimed to better understand the post-injury serine/threonine kinome; (1) Which kinases conduct phosphorylation-induced alterations of target peptides following unilateral TBI in mouse cortex? (2) How do these kinases effectuate pathological network hyperexcitability, which has detrimental long-term outcomes? We used a serine/threonine kinase assay at 4 h, 24 h and 72 h post-TBI to identify hyper-/hypo-active/phosphorylated kinases and peptides in the ipsilateral and contralateral cortical hemispheres relative to sham-operated controls. We pharmacologically mimicked the changes seen in ERK1/2 and PKC kinase activity, and using microelectrode array recordings we explored their significant electrophysiological implications on spontaneous and evoked cortical activity. We then used these findings to manipulate key kinase activity changes at 24 h post-TBI to rescue the hyperexcitability that is seen in the contralateral cortical network at this timepoint back to sham level. The contribution of specific downstream peptide target channel/receptor subunits was also shown. We conclude that volatile kinase activity has potent implications on cortical network activity after the injury and that these kinases and/or their peptide substrates should be more seriously considered as therapeutic targets for the clinical treatment of TBI.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"102"},"PeriodicalIF":6.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11883073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566279","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}

引用次数: 0

Retinitis pigmentosa-linked mutations impair the snRNA unwinding activity of SNRNP200 and reduce pre-mRNA binding of PRPF8. 视网膜色素变性相关突变损害SNRNP200的snRNA解绕活性，减少PRPF8的mrna前结合。

IF 6.2 2区生物学

Cellular and Molecular Life Sciences Pub Date : 2025-03-05 DOI: 10.1007/s00018-025-05621-z

Felix Zimmann, Francois McNicoll, Prasoon Kumar Thakur, Michaela Blažíková, Jan Kubovčiak, María Clara Hernández Cañás, Zora Nováková, Cyril Bařinka, Michal Kolář, David Staněk, Michaela Müller-McNicoll, Zuzana Cvačková

{"title":"Retinitis pigmentosa-linked mutations impair the snRNA unwinding activity of SNRNP200 and reduce pre-mRNA binding of PRPF8.","authors":"Felix Zimmann, Francois McNicoll, Prasoon Kumar Thakur, Michaela Blažíková, Jan Kubovčiak, María Clara Hernández Cañás, Zora Nováková, Cyril Bařinka, Michal Kolář, David Staněk, Michaela Müller-McNicoll, Zuzana Cvačková","doi":"10.1007/s00018-025-05621-z","DOIUrl":"10.1007/s00018-025-05621-z","url":null,"abstract":"Retinitis pigmentosa (RP) is a hereditary disorder caused by mutations in more than 70 different genes including those that encode proteins important for pre-mRNA splicing. Most RP-associated mutations in splicing factors reduce either their expression, stability or incorporation into functional splicing complexes. However, we have previously shown that two RP mutations in PRPF8 (F2314L and Y2334N) and two in SNRNP200 (S1087L and R1090L) behaved differently, and it was still unclear how these mutations affect the functions of both proteins. To investigate this in the context of functional spliceosomes, we used iCLIP in HeLa and retinal pigment epithelial (RPE) cells. We found that both mutations in the RNA helicase SNRNP200 change its interaction with U4 and U6 snRNAs. The significantly broader binding profile of mutated SNRNP200 within the U4 region upstream of the U4/U6 stem I strongly suggests that its activity to unwind snRNAs is impaired. This was confirmed by FRAP measurements and helicase activity assays comparing mutant and WT protein. The RP variants of PRPF8 did not affect snRNAs, but showed a reduced binding to pre-mRNAs, which resulted in the slower splicing of introns and altered expression of hundreds of genes in RPE cells. This suggests that changes in the expression and splicing of specific genes are the main driver of retinal degeneration in PRPF8-linked RP.","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"103"},"PeriodicalIF":6.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11883072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566273","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}

引用次数: 0