Journal of Molecular Cell Biology最新文献

{"title":"T-cadherin deprivation in endothelial cells promotes vascular injury in Kawasaki disease through SOD2/ROS/NLRP3 pathway-mediated pyroptosis.","authors":"Yueling Lin, Fei Wang, Xilian Luo, Xiangna Yang, Wan Yang, Zhaojin Lu, Zhouping Wang, Huazhong Zhou, Meiying Ruan, Kaining Chen, Lanyan Fu, Lei Pi, Di Che, Hongyan Yu, Xiaoqiong Gu","doi":"10.1093/jmcb/mjaf039","DOIUrl":"10.1093/jmcb/mjaf039","url":null,"abstract":"<p><p>Kawasaki disease (KD) is an acute febrile systemic vasculitis associated with the development of coronary artery lesion and coronary artery aneurysm. This condition is characterized by sustained vascular inflammation and endothelial dysfunction, in which pyroptosis serves as a pivotal driver of inflammatory response. However, the molecular mechanisms linking pyroptosis to endothelium injury and KD pathogenesis remain poorly understood. Analysis of public datasets revealed a marked decrease in T-cadherin (T-cad, CDH13) expression in cardiac tissues from KD patients and KD model mice compared to controls. In vitro and in vivo experiments revealed the reduced T-cad expression in both the treated human umbilical vein endothelial cells (HUVECs) and the abdominal aorta of Lactobacillus casei cell wall extract-induced KD mice. RNA sequencing analysis of HUVECs with siRNA-mediated T-cad knockdown showed significant enrichment of genes involved in pro-inflammatory cascades and pyroptosis-associated pathways. Western blot analysis further validated the upregulation of pyroptosis-associated proteins, including NLRP3, caspase-1, GSDMD, IL-1β, and IL-18, in the T-cad knockdown group compared to controls. These findings were supported by functional assays demonstrating the increased lactate dehydrogenase release, higher TUNEL-positive cells, and elevated reactive oxygen species (ROS) levels in the T-cad knockdown group. Collectively, our results indicate that inflammatory stimuli downregulate T-cad expression in endothelial cells, subsequently reducing superoxide dismutase 2 (SOD2) expression and its enzymatic activity. This leads to ROS accumulation, which activates the NLRP3 inflammasome and initiates pyroptosis. Thus, T-cad deficiency induces pyroptosis in HUVECs via the activation of the SOD2/ROS/NLRP3 pathway. These findings highlight the pivotal role of T-cad deprivation-mediated endothelial cell pyroptosis in the initiation and progression of KD, providing novel insights into its pathophysiology and potential therapeutic targets.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145489077","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":"BAR-PH tandem of ACAP4 remodels membranes to drive migration via Ezrin-dependent activation.","authors":"Shan Huang, Jiasheng Chen, Xinyu Wang, Xiaoyu Song, Xiaojie Zhu, Chuanhai Fu, Xuan Zhang, Xing Liu, Chao Wang","doi":"10.1093/jmcb/mjaf038","DOIUrl":"10.1093/jmcb/mjaf038","url":null,"abstract":"<p><p>ADP-ribosylation factor (Arf)-specific GTPase-activating proteins (ArfGAPs) regulate cell migration through interactions with small G proteins, including Arfs. In ArfGAPs, the Bin/Amphiphysin/Rvs (BAR) domain plays a key role in membrane binding and curvature induction, yet the molecular mechanisms underlying these processes remain unclear. Here, we investigate the function of the BAR domain and its adjacent pleckstrin homology (PH) domain of ACAP4 in cell migration. We demonstrate that the BAR-PH tandem of ACAP4 induces membrane curvature, promotes cell migration, forms condensates in vitro, and exhibits membrane-associated distribution in cells. The crystal structure of the ACAP4 BAR domain, determined at 2.8 Å resolution, reveals multiple positively charged surface patches. Structural modeling further identifies conserved positively charged residue pairs in the PH domain, which collectively mediate electrostatic interactions essential for both membrane remodeling and membrane localization. Mutagenesis experiments confirm that these regions are required for ACAP4's subcellular localization and pro-migratory activity. Furthermore, we identify that the actin-binding protein Ezrin interacts with a specific C-terminal region of ACAP4 to regulate its function. Ezrin binding enhances condensate formation and enables full-length ACAP4 to associate with membranes and promote cell migration, particularly when co-expressed with the activated Ezrin (T567D). Together, our findings uncover the molecular basis by which ACAP4 coordinates membrane remodeling and cytoskeletal dynamics, offering new insights into the mechanisms that drive cell migration.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13000378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145444984","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":"The tumor-associated fibroblasts regulate urothelial carcinoma progression.","authors":"Yu Xiao, Junfeng Yang, Mengjie Sun, Yongfu Li, Qinyin Liu, Jinjun Leng, Maolin Yang, Jinrui Wang, Hongju Li, Caifeng Yang, Changfen Luo, Jiahong Li, Longli Kang, Fen Huang, Yanhong Yu, Chuanmao Zhang","doi":"10.1093/jmcb/mjaf032","DOIUrl":"10.1093/jmcb/mjaf032","url":null,"abstract":"<p><p>Tumor-associated fibroblasts (CAFs) regulate tumorigenesis, tumor cell proliferation, and metastasis via secreting related regulatory factors; however, the role of CAFs in regulating the development of upper tract urothelial carcinoma (UTUC) remains unclear. Here, by utilizing single-cell RNA sequencing, single-nucleus RNA sequencing, SpaTial enhanced resolution omics-sequencing, and UTUC immunofluorescence chip cohort to construct the first comprehensive microenvironmental atlas of CAFs, we investigated the roles of CAFs in UTUC progression. Through hierarchical clustering and the copy number variation scores of UTUC epithelial cells, we classified tumor epithelial cells into high-malignant, medium-malignant, and low-malignant potential categories. We found pronounced interaction signals between different CAF subclusters and all three types of epithelial cells, among which high-malignant epithelial cells exhibited the most significant communication signals with the myofibroblastic CAFs1 (myCAFs1) and myCAFs2 subclusters, and FN1 and COL1A1 generated by CAFs played critical roles in this process, suggesting that the progression of UTUC may be attributed to the activation of tumor cells by CAFs. Additionally, both myCAFs1 and myCAFs2 simultaneously affect bladder urothelial carcinoma (BUC) prognosis, with the risk model showing good consistency across cohorts. Therefore, this study constructs a multi-omics landscape of UTUC and identifies common prognostic markers shared with BUC.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13032880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091953","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":"Preserving the UFMylation-cilium axis mitigates blue light-induced retinal degeneration.","authors":"Guizhi Guo, Runa Wang, Sai Zhang, Yufei Zhang, Lin Li, Miaoyuan Liu, Long Yin, Changfeng Wei, Yingxin Gong, Li Jiao, Dengwen Li, Jun Zhou, Min Liu, Jie Ran","doi":"10.1093/jmcb/mjag007","DOIUrl":"https://doi.org/10.1093/jmcb/mjag007","url":null,"abstract":"<p><p>Blue light damage (BLD) is a complex process implicated in a variety of ocular diseases, including age-related macular degeneration and dry eye diseases. However, the molecular mechanisms underlying the BLD process remain largely unknown. In this study, using a mouse model, we identify photoreceptor cilium disruption as a key event in BLD and show that the UFMylation of kinesin family member 11 (KIF11) is decreased under BLD conditions. We further reveal that ubiquitin-fold modifier 1-specific ligase 1 (UFL1), the sole ligase for UFMylation, localizes to the basal body and is required for maintaining photoreceptor cilia. Strikingly, exposure to blue light disrupts the basal body localization of UFL1, leading to ciliary defects and subsequent photoreceptor dysfunction. Ufl1 knockout mice exhibit similar ciliary donlefects and retinal impairments. Importantly, intravitreal injection of agents that enhance UFMylation or ciliogenesis can mitigate the pathological changes induced by blue light exposure. These findings establish that UFL1-mediated ciliary integrity contributes to retinal deficits associated with BLD and demonstrate that targeting the UFMylation-cilium axis represents a promising therapeutic strategy for BLD-associated retinal diseases.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444078","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}

{"title":"Methylation of MATCAP by PRMT5 regulates microtubule detyrosination to ensure mitotic fidelity.","authors":"Tongtong Yang, Wenping Hu, Yaqian Zhang, Fangyuan Xiong, Zhikai Wang, Xing Liu, Kai Jiang, Xuebiao Yao, Liangyu Zhang","doi":"10.1093/jmcb/mjag008","DOIUrl":"https://doi.org/10.1093/jmcb/mjag008","url":null,"abstract":"<p><p>During mitosis, motor protein-driven chromosome motility is essential for faithful chromosome segregation. The tubulin code, comprising tubulin isotypes and post-translational modifications, guides motor proteins along microtubules. Recent studies show that MATCAP-mediated α-tubulin detyrosination guides proper chromosome congression and segregation during mitosis. However, the mechanisms of action underlying MATCAP activity regulation remain poorly understood. Here, we identify PRMT5 as a novel MATCAP methyl-transferase and that the methylation guides MATCAP activity for chromosome alignment. PRMT5 depletion or inhibition impairs chromosome alignment and segregation. Biochemical analyses reveal that MATCAP interacts with PRMT5 and is a bona fide substrate of PRMT5. Our mass spectrometry analyses show that PRMT5 symmetrically dimethylates the N-terminus of MATCAP at Arg74, Arg99, and Arg104. Importantly, the PRMT5-elicited methylation attenuates MATCAP's microtubule-binding and detyrosination activities. Loss of PRMT5 or expression of non-methylatable MATCAP mutants causes excessive tubulin detyrosination and disrupts chromosome congression. These findings suggest that PRMT5-mediated dynamic methylation of MATCAP is a novel regulatory mechanism that guides accurate tyrosination and ensures mitotic fidelity.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147433796","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}

{"title":"Energetic metabolic reprogramming in idiopathic pulmonary fibrosis: mechanisms and therapeutics.","authors":"Yanlin Zhou, Yuqing Zhang, Shuang Huang, Xiaoyue Pan, Man Zhao, Yingchun Guo, Yuqi Wang, Xia Cong, Bin Li, Huibing Liu, Zhongzheng Li, Xinghua Pan, Juntang Yang, Qiwen Wang, Lan Wang, Guoying Yu","doi":"10.1093/jmcb/mjag006","DOIUrl":"https://doi.org/10.1093/jmcb/mjag006","url":null,"abstract":"","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147355552","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}

{"title":"Dynamic crotonylation of Bub3 regulates mitotic checkpoint silencing and chromosome segregation.","authors":"Xufan Shi, Xingchen Yu, Wenwen Wang, Fangyuan Xiong, Xiao Yuan, Qing Hu, Xiaoyu Song, Zhen Dou, Xuebiao Yao, Liangyu Zhang","doi":"10.1093/jmcb/mjaf040","DOIUrl":"10.1093/jmcb/mjaf040","url":null,"abstract":"","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513072","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":"TUBA8 promotes neuronal dendrite development through its 40th alanine.","authors":"Fengxia Shao, Huaqing Xue, Boran Chang, Yanling Liu, Suhao Cao, Jinsong Li, Xu Zhang, Lei Diao, Lan Bao","doi":"10.1093/jmcb/mjaf036","DOIUrl":"10.1093/jmcb/mjaf036","url":null,"abstract":"<p><p>The functional specificity of tubulin isotypes has been demonstrated by various neurological diseases caused by an increasing number of mutations in tubulin isotypes. TUBA8 is specifically localized in cerebellar Purkinje cells, which exhibit the most elaborate dendritic trees in the central nervous system. However, the role and related molecular mechanism of TUBA8 in regulating neuronal dendritic morphology remain poorly understood. Here, we report that TUBA8 is required for neuronal dendrite development. As the most divergent member in α-tubulin isotypes, the expression of TUBA8 in Purkinje cells starts at P0, plateaus at P10, and persists into adulthood. Loss of TUBA8 in Purkinje cells induces global dendritic height defects in multiple lobules during development and aging. Meanwhile, TUBA8 deficiency causes age-dependent decreased locomotor activity and anxiety-like behavior. In contrast to TUBA8, TUBA4A, another tubulin isotype highly expressed in Purkinje cells, is not required for dendrite development. Furthermore, the 40th alanine, which differs with any other α-tubulin isotype and cannot be modified by acetylation, methylation, or lactylation, mediates the promoting effect of TUBA8 in neuronal dendrite development. This study reveals a specific role of TUBA8 in regulating neuronal dendritic morphology and highlights the importance of the 40th amino acid in implementing functions of α-tubulin isotypes.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12977328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308254","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":"MEK1/2 inhibition prevents DENV and ZIKV infection via disrupting the cytoskeletal vimentin cage required for viral replication.","authors":"Yuhan Huang, Jiageng Lu, Shuzhi Cui, Shuangshuang Zhao, Shengming Sun, Yaming Jiu","doi":"10.1093/jmcb/mjaf037","DOIUrl":"10.1093/jmcb/mjaf037","url":null,"abstract":"<p><p>Flaviviridae Dengue virus (DENV) and Zika virus (ZIKV) have posed significant threats to global public health in the past decades. Despite extensive study on therapeutic strategies against these viruses, effective treatment options are still lacking. Within host cells, the cytoskeletal vimentin intermediate filament network facilitates viral replication during DENV and ZIKV infection by shrinking and forming a cage-like structure. Our previous work indicated that MEK1/2 inhibitors can induce the dispersion of vimentin, but their potential impact on flavivirus infection remains unclear. Here, we observed that the MEK1/2 signaling pathway is activated in host cells infected with DENV and ZIKV. Treatment with MEK1/2 inhibitors significantly impaired the replication of both viruses. Further mechanistic studies revealed that MEK1/2 inhibitors prevent viral infection by promoting the dispersion of intracellular vimentin network, thereby disrupting the cytoskeletal structure required for viral replication. Our findings not only expand the understanding of vimentin regulatory mechanisms from a cellular biology perspective but also provide a new perspective on MEK1/2 inhibition as a potential anti-DENV and anti-ZIKV strategy.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12968617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145368100","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":"APP ubiquitination by VHL protein is essential for MVB sorting and lysosomal degradation.","authors":"Chunyan Shan, Rixu Cong, Xiangyu Xu, Yuanjun Li, Yonglu Tian, Wenyuan Cao, Wei Zhao, Linqing Miao, Junlin Teng, Ning Huang, Jianguo Chen","doi":"10.1093/jmcb/mjaf033","DOIUrl":"10.1093/jmcb/mjaf033","url":null,"abstract":"<p><p>Amyloid precursor protein (APP), a type I transmembrane protein, is closely related to the pathogenesis of Alzheimer's disease (AD). Amyloid beta (Aβ) is generated by sequential processing of APP in the Golgi apparatus and endosomes, and its toxicity leads to neuron dysfunction and neurodegeneration. APP is selectively shuttled between intracellular membrane compartments and ultimately transported into lysosomes. However, the mechanisms underlying APP sorting signals and lysosomal degradation are largely unclear. In this study, we show that the von Hippel‒Lindau (VHL) protein, a subunit of an E3 ligase, recognizes the cytoplasmic domain of APP and mediates its ubiquitination. VHL-mediated ubiquitination facilitates the sorting of membrane APP into intraluminal vesicles of multivesicular bodies (MVBs) and subsequent degradation in lysosomes. Therefore, the loss of VHL accelerates Aβ plaque deposition and memory deficits in AD model mice. Our findings reveal the role of VHL in restricting AD pathogenesis through ubiquitination-dependent MVB sorting and lysosomal degradation of APP.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12951519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238843","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}