首页 > 最新文献

Journal of Molecular Cell Biology最新文献

英文 中文
Highly efficient conversion of mouse fibroblasts into functional hepatic cells under chemical induction. 化学诱导下小鼠成纤维细胞高效转化为功能性肝细胞。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-04-10 DOI: 10.1093/jmcb/mjad071
Zhi Zhong, Jiangchuan Du, Xiangjie Zhu, Lingting Guan, Yanyu Hu, Peilin Zhang, Hongyang Wang

Previous studies have shown that hepatocyte-like cells can be generated from fibroblasts using either lineage-specific transcription factors or chemical induction methods. However, these methods have their own deficiencies that restrict the therapeutic applications of such induced hepatocytes. In this study, we present a transgene-free, highly efficient chemical-induced direct reprogramming approach to generate hepatocyte-like cells from mouse embryonic fibroblasts (MEFs). Using a small molecule cocktail (SMC) as an inducer, MEFs can be directly reprogrammed into hepatocyte-like cells, bypassing the intermediate stages of pluripotent and immature hepatoblasts. These chemical-induced hepatocyte-like cells (ciHeps) closely resemble mature primary hepatocytes in terms of morphology, biological behavior, gene expression patterns, marker expression levels, and hepatic functions. Furthermore, transplanted ciHeps can integrate into the liver, promote liver regeneration, and improve survival rates in mice with acute liver damage. ciHeps can also ameliorate liver fibrosis caused by chronic injuries and enhance liver function. Notably, ciHeps exhibit no tumorigenic potential either in vitro or in vivo. Mechanistically, SMC-induced mesenchymal-to-epithelial transition and suppression of SNAI1 contribute to the fate conversion of fibroblasts into ciHeps. These results indicate that this transgene-free, chemical-induced direct reprogramming technique has the potential to serve as a valuable means of producing alternative hepatocytes for both research and therapeutic purposes. Additionally, this method also sheds light on the direct reprogramming of other cell types under chemical induction.

先前的研究表明,使用谱系特异性转录因子或化学诱导方法,可以从成纤维细胞生成肝细胞样细胞。然而,这些方法有其自身的不足,限制了这种诱导肝细胞的治疗应用。在这项研究中,我们提出了一种无转基因的、高效的化学诱导的直接重编程方法,从小鼠胚胎成纤维细胞(mef)中产生肝细胞样细胞。使用小分子鸡尾酒(SMC)作为诱导剂,mef可以直接重编程为肝细胞样细胞,绕过多能性和未成熟的肝母细胞中间阶段。这些化学诱导的肝细胞样细胞(ciHeps)在形态、生物学行为、基因表达模式、标志物表达水平和肝功能方面与成熟的原代肝细胞非常相似。此外,移植的ciHeps可以融入肝脏,促进肝脏再生,提高急性肝损伤小鼠的存活率。ciHeps还能改善慢性损伤引起的肝纤维化,增强肝功能。值得注意的是,无论是体外还是体内,ciHeps都没有表现出致瘤性。从机制上讲,smc诱导的间质向上皮的转化和SNAI1的抑制有助于成纤维细胞向ciHeps的命运转化。这些结果表明,这种无转基因的、化学诱导的直接重编程技术有潜力作为一种有价值的方法来生产用于研究和治疗目的的替代肝细胞。此外,该方法还揭示了化学诱导下其他细胞类型的直接重编程。
{"title":"Highly efficient conversion of mouse fibroblasts into functional hepatic cells under chemical induction.","authors":"Zhi Zhong, Jiangchuan Du, Xiangjie Zhu, Lingting Guan, Yanyu Hu, Peilin Zhang, Hongyang Wang","doi":"10.1093/jmcb/mjad071","DOIUrl":"10.1093/jmcb/mjad071","url":null,"abstract":"<p><p>Previous studies have shown that hepatocyte-like cells can be generated from fibroblasts using either lineage-specific transcription factors or chemical induction methods. However, these methods have their own deficiencies that restrict the therapeutic applications of such induced hepatocytes. In this study, we present a transgene-free, highly efficient chemical-induced direct reprogramming approach to generate hepatocyte-like cells from mouse embryonic fibroblasts (MEFs). Using a small molecule cocktail (SMC) as an inducer, MEFs can be directly reprogrammed into hepatocyte-like cells, bypassing the intermediate stages of pluripotent and immature hepatoblasts. These chemical-induced hepatocyte-like cells (ciHeps) closely resemble mature primary hepatocytes in terms of morphology, biological behavior, gene expression patterns, marker expression levels, and hepatic functions. Furthermore, transplanted ciHeps can integrate into the liver, promote liver regeneration, and improve survival rates in mice with acute liver damage. ciHeps can also ameliorate liver fibrosis caused by chronic injuries and enhance liver function. Notably, ciHeps exhibit no tumorigenic potential either in vitro or in vivo. Mechanistically, SMC-induced mesenchymal-to-epithelial transition and suppression of SNAI1 contribute to the fate conversion of fibroblasts into ciHeps. These results indicate that this transgene-free, chemical-induced direct reprogramming technique has the potential to serve as a valuable means of producing alternative hepatocytes for both research and therapeutic purposes. Additionally, this method also sheds light on the direct reprogramming of other cell types under chemical induction.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11121195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138299267","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
A multiplexed time-resolved fluorescence resonance energy transfer ultrahigh-throughput screening assay for targeting the SMAD4-SMAD3-DNA complex. 针对SMAD4-SMAD3-DNA复合物的多路时间分辨荧光共振能量转移超高通量筛选试验
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-04-10 DOI: 10.1093/jmcb/mjad068
Wukun Ouyang, Qianjin Li, Qiankun Niu, Min Qui, Haian Fu, Yuhong Du, Xiulei Mo

The transforming growth factor-beta (TGFβ) signaling pathway plays crucial roles in the establishment of an immunosuppressive tumor microenvironment, making anti-TGFβ agents a significant area of interest in cancer immunotherapy. However, the clinical translation of current anti-TGFβ agents that target upstream cytokines and receptors remains challenging. Therefore, the development of small-molecule inhibitors specifically targeting SMAD4, the downstream master regulator of the TGFβ pathway, would offer an alternative approach with significant therapeutic potential for anti-TGFβ signaling. In this study, we present the development of a cell lysate-based multiplexed time-resolved fluorescence resonance energy transfer (TR-FRET) assay in an ultrahigh-throughput screening (uHTS) 1536-well plate format. This assay enables simultaneous monitoring of the protein‒protein interaction between SMAD4 and SMAD3, as well as the protein‒DNA interaction between SMADs and their consensus DNA-binding motif. The multiplexed TR-FRET assay exhibits high sensitivity, allowing the dynamic analysis of the SMAD4-SMAD3-DNA complex at single-amino acid resolution. Moreover, the multiplexed uHTS assay demonstrates robustness for screening small-molecule inhibitors. Through a pilot screening of an FDA-approved bioactive compound library, we identified gambogic acid and gambogenic acid as potential hit compounds. These proof-of-concept findings underscore the utility of our optimized multiplexed TR-FRET platform for large-scale screening to discover small-molecule inhibitors that target the SMAD4-SMAD3-DNA complex as novel anti-TGFβ signaling agents.

转化生长因子- β (tgf - β)信号通路在建立免疫抑制肿瘤微环境中起着至关重要的作用,这使得抗tgf - β药物成为癌症免疫治疗的一个重要领域。然而,目前针对上游细胞因子和受体的抗tgf β药物的临床翻译仍然具有挑战性。因此,开发专门针对tgf -β通路下游主调控因子SMAD4的小分子抑制剂,将为抗tgf -β信号传导提供一种具有显著治疗潜力的替代方法。在这项研究中,我们提出了一种基于细胞裂解液的多路时间分辨荧光共振能量转移(TR-FRET)的超高通量筛选(uHTS) 1536孔板格式检测方法。该分析能够同时监测SMAD4和SMAD3之间的蛋白质-蛋白质相互作用,以及smad之间的蛋白质- dna相互作用及其一致的dna结合基序。多重TR-FRET测定具有高灵敏度,允许在单氨基酸分辨率下动态分析SMAD4-SMAD3-DNA复合物。此外,多重uHTS试验在筛选小分子抑制剂方面具有稳健性。通过fda批准的生物活性化合物库的试点筛选,我们确定了藤黄酸和藤黄原酸作为潜在的打击化合物。这些概念验证的发现强调了我们优化的多路复用TR-FRET平台在大规模筛选中发现靶向SMAD4-SMAD3-DNA复合物的小分子抑制剂作为新型抗tgf - β信号剂的效用。
{"title":"A multiplexed time-resolved fluorescence resonance energy transfer ultrahigh-throughput screening assay for targeting the SMAD4-SMAD3-DNA complex.","authors":"Wukun Ouyang, Qianjin Li, Qiankun Niu, Min Qui, Haian Fu, Yuhong Du, Xiulei Mo","doi":"10.1093/jmcb/mjad068","DOIUrl":"10.1093/jmcb/mjad068","url":null,"abstract":"<p><p>The transforming growth factor-beta (TGFβ) signaling pathway plays crucial roles in the establishment of an immunosuppressive tumor microenvironment, making anti-TGFβ agents a significant area of interest in cancer immunotherapy. However, the clinical translation of current anti-TGFβ agents that target upstream cytokines and receptors remains challenging. Therefore, the development of small-molecule inhibitors specifically targeting SMAD4, the downstream master regulator of the TGFβ pathway, would offer an alternative approach with significant therapeutic potential for anti-TGFβ signaling. In this study, we present the development of a cell lysate-based multiplexed time-resolved fluorescence resonance energy transfer (TR-FRET) assay in an ultrahigh-throughput screening (uHTS) 1536-well plate format. This assay enables simultaneous monitoring of the protein‒protein interaction between SMAD4 and SMAD3, as well as the protein‒DNA interaction between SMADs and their consensus DNA-binding motif. The multiplexed TR-FRET assay exhibits high sensitivity, allowing the dynamic analysis of the SMAD4-SMAD3-DNA complex at single-amino acid resolution. Moreover, the multiplexed uHTS assay demonstrates robustness for screening small-molecule inhibitors. Through a pilot screening of an FDA-approved bioactive compound library, we identified gambogic acid and gambogenic acid as potential hit compounds. These proof-of-concept findings underscore the utility of our optimized multiplexed TR-FRET platform for large-scale screening to discover small-molecule inhibitors that target the SMAD4-SMAD3-DNA complex as novel anti-TGFβ signaling agents.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11063955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134649204","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
Derivation of zebrafish heart-related haploid cells. 斑马鱼心脏相关单倍体细胞的衍生。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-04-10 DOI: 10.1093/jmcb/mjad077
Siqi Liu, Jia Xu, Yirui Ai, Yunbin Zhang, Shifeng Li, Jinsong Li, Yiping Li
{"title":"Derivation of zebrafish heart-related haploid cells.","authors":"Siqi Liu, Jia Xu, Yirui Ai, Yunbin Zhang, Shifeng Li, Jinsong Li, Yiping Li","doi":"10.1093/jmcb/mjad077","DOIUrl":"10.1093/jmcb/mjad077","url":null,"abstract":"","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11004926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138482406","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
Sex- and age-specific associations between abdominal fat and non-alcoholic fatty liver disease: a prospective cohort study. 腹部脂肪与非酒精性脂肪肝之间的性别和年龄特异性关联:一项前瞻性队列研究
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-04-10 DOI: 10.1093/jmcb/mjad069
Hongli Chen, Yuexing Liu, Dan Liu, Yebei Liang, Zhijun Zhu, Keqing Dong, Huating Li, Yuqian Bao, Jiarui Wu, Xuhong Hou, Weiping Jia

Obesity is closely related to non-alcoholic fatty liver disease (NAFLD). Although sex differences in body fat distribution have been well demonstrated, little is known about the sex-specific associations between adipose tissue and the development of NAFLD. Using community-based cohort data, we evaluated the associations between magnetic resonance imaging quantified areas of abdominal adipose tissue, including visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and incident NAFLD in 2830 participants (1205 males and 1625 females) aged 55-70 years. During a 4.6-year median follow-up, the cumulative incidence rates of NAFLD increased with areas of VAT and SAT both in males and in females. Further analyses showed that the above-mentioned positive associations were stronger in males than in females, especially in participants under 60 years old. In contrast, these sex differences disappeared in those over 60 years old. Furthermore, the risk of developing NAFLD increased non-linearly with increasing fat area in a sex-specific pattern. Additionally, sex-specific potential mediators, such as insulin resistance, lipid metabolism, inflammation, and adipokines, may exist in the associations between adipose tissue and NAFLD. This study showed that the associations between abdominal fat and the risk of NAFLD were stratified by sex and age, highlighting the potential need for sex- and age-specific management of NAFLD.

肥胖与非酒精性脂肪性肝病(NAFLD)密切相关。尽管身体脂肪分布的性别差异已经得到了很好的证明,但关于脂肪组织与NAFLD发展之间的性别特异性关联知之甚少。使用基于社区的队列数据,我们评估了2830名年龄在55-70岁的参与者(1205名男性和1625名女性)腹部脂肪组织的磁共振成像量化区域(包括内脏脂肪组织(VAT)和皮下脂肪组织(SAT))与NAFLD事件之间的关系。在4.6年的中位随访中,男性和女性NAFLD的累积发病率随着VAT和SAT面积的增加而增加。进一步分析表明,上述积极联系在男性中强于女性,尤其是在60岁以下的参与者中。相比之下,这些性别差异在60岁以上的人群中消失了。此外,发生NAFLD的风险随脂肪面积的增加呈非线性增加,且呈性别特异性模式。此外,性别特异性的潜在介质,如胰岛素抵抗、脂质代谢、炎症和脂肪因子,可能存在于脂肪组织和NAFLD之间的关联中。这项研究表明,腹部脂肪与NAFLD风险之间的关系是按性别和年龄分层的,强调了对NAFLD进行性别和年龄特异性管理的潜在需求。
{"title":"Sex- and age-specific associations between abdominal fat and non-alcoholic fatty liver disease: a prospective cohort study.","authors":"Hongli Chen, Yuexing Liu, Dan Liu, Yebei Liang, Zhijun Zhu, Keqing Dong, Huating Li, Yuqian Bao, Jiarui Wu, Xuhong Hou, Weiping Jia","doi":"10.1093/jmcb/mjad069","DOIUrl":"10.1093/jmcb/mjad069","url":null,"abstract":"<p><p>Obesity is closely related to non-alcoholic fatty liver disease (NAFLD). Although sex differences in body fat distribution have been well demonstrated, little is known about the sex-specific associations between adipose tissue and the development of NAFLD. Using community-based cohort data, we evaluated the associations between magnetic resonance imaging quantified areas of abdominal adipose tissue, including visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and incident NAFLD in 2830 participants (1205 males and 1625 females) aged 55-70 years. During a 4.6-year median follow-up, the cumulative incidence rates of NAFLD increased with areas of VAT and SAT both in males and in females. Further analyses showed that the above-mentioned positive associations were stronger in males than in females, especially in participants under 60 years old. In contrast, these sex differences disappeared in those over 60 years old. Furthermore, the risk of developing NAFLD increased non-linearly with increasing fat area in a sex-specific pattern. Additionally, sex-specific potential mediators, such as insulin resistance, lipid metabolism, inflammation, and adipokines, may exist in the associations between adipose tissue and NAFLD. This study showed that the associations between abdominal fat and the risk of NAFLD were stratified by sex and age, highlighting the potential need for sex- and age-specific management of NAFLD.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11161703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138460469","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
Targeting the PD-L1 cytoplasmic domain and its regulatory pathways to enhance cancer immunotherapy. 靶向PD-L1细胞质结构域及其调控途径增强癌症免疫治疗。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-04-10 DOI: 10.1093/jmcb/mjad070
Fangni Chai, Pan Li, Xin Liu, Zhihui Zhou, Haiyan Ren

As a significant member of the immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) plays a critical role in cancer immune escape and has become an important target for cancer immunotherapy. Clinically approved drugs mainly target the extracellular domain of PD-L1. Recently, the small cytoplasmic domain of PD-L1 has been reported to regulate PD-L1 stability and function through multiple pathways. Therefore, the intracellular domain of PD-L1 and its regulatory pathways could be promising targets for cancer therapy, expanding available strategies for combined immunotherapy. Here, we summarize the emerging roles of the PD-L1 cytoplasmic domain and its regulatory pathways. The conserved motifs, homodimerization, and posttranslational modifications of the PD-L1 cytoplasmic domain have been reported to regulate the membrane anchoring, degradation, nuclear translocation, and glycosylation of PD-L1. This summary provides a comprehensive understanding of the functions of the PD-L1 cytoplasmic domain and evaluates the broad prospects for targeted therapy.

程序性细胞死亡1配体1 (programmed cell death 1 ligand 1, PD-L1)作为免疫检查点的重要成员,在肿瘤免疫逃逸中起着至关重要的作用,已成为肿瘤免疫治疗的重要靶点。临床批准的药物主要靶向PD-L1的细胞外结构域。最近,PD-L1的小细胞质结构域被报道通过多种途径调节PD-L1的稳定性和功能。因此,PD-L1的细胞内结构域及其调控途径可能是癌症治疗的有希望的靶点,扩大了联合免疫治疗的可用策略。在这里,我们总结了PD-L1细胞质结构域及其调控途径的新作用。据报道,PD-L1细胞质结构域的保守基序、同二聚化和翻译后修饰可调节PD-L1的膜锚定、降解、核易位和糖基化等。这篇综述提供了对PD-L1细胞质结构域功能的全面了解,并评估了靶向治疗的广阔前景。
{"title":"Targeting the PD-L1 cytoplasmic domain and its regulatory pathways to enhance cancer immunotherapy.","authors":"Fangni Chai, Pan Li, Xin Liu, Zhihui Zhou, Haiyan Ren","doi":"10.1093/jmcb/mjad070","DOIUrl":"10.1093/jmcb/mjad070","url":null,"abstract":"<p><p>As a significant member of the immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) plays a critical role in cancer immune escape and has become an important target for cancer immunotherapy. Clinically approved drugs mainly target the extracellular domain of PD-L1. Recently, the small cytoplasmic domain of PD-L1 has been reported to regulate PD-L1 stability and function through multiple pathways. Therefore, the intracellular domain of PD-L1 and its regulatory pathways could be promising targets for cancer therapy, expanding available strategies for combined immunotherapy. Here, we summarize the emerging roles of the PD-L1 cytoplasmic domain and its regulatory pathways. The conserved motifs, homodimerization, and posttranslational modifications of the PD-L1 cytoplasmic domain have been reported to regulate the membrane anchoring, degradation, nuclear translocation, and glycosylation of PD-L1. This summary provides a comprehensive understanding of the functions of the PD-L1 cytoplasmic domain and evaluates the broad prospects for targeted therapy.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11193063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138295336","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
JunB condensation attenuates vascular endothelial damage under hyperglycemic condition. JunB 缩合可减轻高血糖条件下的血管内皮损伤。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-04-10 DOI: 10.1093/jmcb/mjad072
Xuxia Ren, Zexu Cui, Qiaoqiao Zhang, Zhiguang Su, Wei Xu, Jinhui Wu, Hao Jiang

Endothelial damage is the initial and crucial factor in the occurrence and development of vascular complications in diabetic patients, contributing to morbidity and mortality. Although hyperglycemia has been identified as a damaging effector, the detailed mechanisms remain elusive. In this study, identified by ATAC-seq and RNA-seq, JunB reverses the inhibition of proliferation and the promotion of apoptosis in human umbilical vein endothelial cells treated with high glucose, mainly through the cell cycle and p53 signaling pathways. Furthermore, JunB undergoes phase separation in the nucleus and in vitro, mediated by its intrinsic disordered region and DNA-binding domain. Nuclear localization and condensation behaviors are required for JunB-mediated proliferation and apoptosis. Thus, our study uncovers the roles of JunB and its coacervation in repairing vascular endothelial damage caused by high glucose, elucidating the involvement of phase separation in diabetes and diabetic endothelial dysfunction.

内皮损伤是糖尿病患者血管并发症发生和发展的最初和关键因素,也是导致发病率和死亡率的原因之一。虽然高血糖已被确定为一种损伤效应因子,但其详细机制仍难以捉摸。本研究通过 ATAC-seq 和 RNA-seq 发现,JunB 主要通过细胞周期和 p53 信号通路逆转了高糖处理的人脐静脉内皮细胞的增殖抑制和凋亡促进作用。此外,JunB 在其内在无序区和 DNA 结合域的介导下,会在细胞核内和体外发生相分离。JunB介导的增殖和凋亡需要核定位和凝集行为。因此,我们的研究揭示了 JunB 及其共轭物在修复高糖引起的血管内皮损伤中的作用,阐明了相分离在糖尿病和糖尿病内皮功能障碍中的参与。
{"title":"JunB condensation attenuates vascular endothelial damage under hyperglycemic condition.","authors":"Xuxia Ren, Zexu Cui, Qiaoqiao Zhang, Zhiguang Su, Wei Xu, Jinhui Wu, Hao Jiang","doi":"10.1093/jmcb/mjad072","DOIUrl":"10.1093/jmcb/mjad072","url":null,"abstract":"<p><p>Endothelial damage is the initial and crucial factor in the occurrence and development of vascular complications in diabetic patients, contributing to morbidity and mortality. Although hyperglycemia has been identified as a damaging effector, the detailed mechanisms remain elusive. In this study, identified by ATAC-seq and RNA-seq, JunB reverses the inhibition of proliferation and the promotion of apoptosis in human umbilical vein endothelial cells treated with high glucose, mainly through the cell cycle and p53 signaling pathways. Furthermore, JunB undergoes phase separation in the nucleus and in vitro, mediated by its intrinsic disordered region and DNA-binding domain. Nuclear localization and condensation behaviors are required for JunB-mediated proliferation and apoptosis. Thus, our study uncovers the roles of JunB and its coacervation in repairing vascular endothelial damage caused by high glucose, elucidating the involvement of phase separation in diabetes and diabetic endothelial dysfunction.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11080659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138885133","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
The capsid revolution. 衣壳革命。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-04-10 DOI: 10.1093/jmcb/mjad076
Ian A Taylor, Ariberto Fassati

Lenacapavir, targeting the human immunodeficiency virus type-1 (HIV-1) capsid, is the first-in-class antiretroviral drug recently approved for clinical use. The development of Lenacapavir is attributed to the remarkable progress in our understanding of the capsid protein made during the last few years. Considered little more than a component of the virus shell to be shed early during infection, the capsid has been found to be a key player in the HIV-1 life cycle by interacting with multiple host factors, entering the nucleus, and directing integration. Here, we describe the key advances that led to this 'capsid revolution'.

靶向HIV-1衣壳的Lenacapavir是最近批准用于临床的首个抗逆转录病毒药物。Lenacapavir的开发归功于过去几年我们对衣壳蛋白的理解取得的显着进展。衣壳被认为是在感染早期脱落的病毒外壳的一个组成部分,它通过与多种宿主细胞因子相互作用、进入细胞核并指导整合,在HIV-1生命周期中起着关键作用。在这里,我们描述了导致这场“衣壳革命”的关键进展。
{"title":"The capsid revolution.","authors":"Ian A Taylor, Ariberto Fassati","doi":"10.1093/jmcb/mjad076","DOIUrl":"10.1093/jmcb/mjad076","url":null,"abstract":"<p><p>Lenacapavir, targeting the human immunodeficiency virus type-1 (HIV-1) capsid, is the first-in-class antiretroviral drug recently approved for clinical use. The development of Lenacapavir is attributed to the remarkable progress in our understanding of the capsid protein made during the last few years. Considered little more than a component of the virus shell to be shed early during infection, the capsid has been found to be a key player in the HIV-1 life cycle by interacting with multiple host factors, entering the nucleus, and directing integration. Here, we describe the key advances that led to this 'capsid revolution'.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11193064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138460470","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
The interplay between the muscle and liver in the regulation of glucolipid metabolism. 肌肉和肝脏在调节糖脂代谢中的相互作用。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-04-10 DOI: 10.1093/jmcb/mjad073
Cheng Chen, Liping Xie, Mingliang Zhang, Shama, Kenneth King Yip Cheng, Weiping Jia
{"title":"The interplay between the muscle and liver in the regulation of glucolipid metabolism.","authors":"Cheng Chen, Liping Xie, Mingliang Zhang, Shama, Kenneth King Yip Cheng, Weiping Jia","doi":"10.1093/jmcb/mjad073","DOIUrl":"10.1093/jmcb/mjad073","url":null,"abstract":"","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11078061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138801436","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
Glycogen synthase kinase 3 signaling in neural regeneration in vivo. 糖原合成酶激酶3信号在体内神经再生中的作用。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-04-10 DOI: 10.1093/jmcb/mjad075
Jing Zhang, Shu-Guang Yang, Feng-Quan Zhou

Glycogen synthase kinase 3 (GSK3) signaling plays important and broad roles in regulating neural development in vitro and in vivo. Here, we reviewed recent findings of GSK3-regulated axon regeneration in vivo in both the peripheral and central nervous systems and discussed a few controversial findings in the field. Overall, current evidence indicates that GSK3β signaling serves as an important downstream mediator of the PI3K-AKT pathway to regulate axon regeneration in parallel with the mTORC1 pathway. Specifically, the mTORC1 pathway supports axon regeneration mainly through its role in regulating cap-dependent protein translation, whereas GSK3β signaling might be involved in regulating N6-methyladenosine mRNA methylation-mediated, cap-independent protein translation. In addition, GSK3 signaling also plays a key role in reshaping the neuronal transcriptomic landscape during neural regeneration. Finally, we proposed some research directions to further elucidate the molecular mechanisms underlying the regulatory function of GSK3 signaling and discover novel GSK3 signaling-related therapeutic targets. Together, we hope to provide an updated and insightful overview of how GSK3 signaling regulates neural regeneration in vivo.

糖原合成酶激酶3 (GSK3)信号在体外和体内神经发育调控中发挥着重要而广泛的作用。在这里,我们回顾了gsk3调节外周和中枢神经系统轴突再生的最新发现,并讨论了该领域的一些有争议的发现。总的来说,目前的证据表明,GSK3β信号作为PI3K-AKT通路的重要下游介质,与mTORC1通路平行调节轴突再生。具体来说,mTORC1通路主要通过调节帽依赖性蛋白翻译来支持轴突再生,而GSK3β信号可能参与调节n6 -甲基腺苷(m6A) mRNA甲基化介导的帽非依赖性蛋白翻译。此外,GSK3信号也在神经再生过程中重塑神经元转录组景观中发挥关键作用。最后,我们提出了进一步阐明GSK3信号调控功能的分子机制,发现新的GSK3信号相关治疗靶点的研究方向。总之,我们希望提供GSK3信号如何调节体内神经再生的最新和有见地的概述。
{"title":"Glycogen synthase kinase 3 signaling in neural regeneration in vivo.","authors":"Jing Zhang, Shu-Guang Yang, Feng-Quan Zhou","doi":"10.1093/jmcb/mjad075","DOIUrl":"10.1093/jmcb/mjad075","url":null,"abstract":"<p><p>Glycogen synthase kinase 3 (GSK3) signaling plays important and broad roles in regulating neural development in vitro and in vivo. Here, we reviewed recent findings of GSK3-regulated axon regeneration in vivo in both the peripheral and central nervous systems and discussed a few controversial findings in the field. Overall, current evidence indicates that GSK3β signaling serves as an important downstream mediator of the PI3K-AKT pathway to regulate axon regeneration in parallel with the mTORC1 pathway. Specifically, the mTORC1 pathway supports axon regeneration mainly through its role in regulating cap-dependent protein translation, whereas GSK3β signaling might be involved in regulating N6-methyladenosine mRNA methylation-mediated, cap-independent protein translation. In addition, GSK3 signaling also plays a key role in reshaping the neuronal transcriptomic landscape during neural regeneration. Finally, we proposed some research directions to further elucidate the molecular mechanisms underlying the regulatory function of GSK3 signaling and discover novel GSK3 signaling-related therapeutic targets. Together, we hope to provide an updated and insightful overview of how GSK3 signaling regulates neural regeneration in vivo.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11063957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498637","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
Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia. 受损的dNKAP功能驱动果蝇上皮基因组不稳定和致瘤性生长。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-04-10 DOI: 10.1093/jmcb/mjad078
Ting Guo, Chen Miao, Zhonghua Liu, Jingwei Duan, Yanbin Ma, Xiao Zhang, Weiwei Yang, Maoguang Xue, Qiannan Deng, Pengfei Guo, Yongmei Xi, Xiaohang Yang, Xun Huang, Wanzhong Ge

Mutations or dysregulated expression of NF-kappaB-activating protein (NKAP) family genes have been found in human cancers. How NKAP family gene mutations promote tumor initiation and progression remains to be determined. Here, we characterized dNKAP, the Drosophila homolog of NKAP, and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model. dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics, including tissue overgrowth, cell-invasive behavior, abnormal cell polarity, and cell adhesion defects. dNKAP knockdown causes both R-loop accumulation and DNA damage, indicating the disruption of genome integrity. Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase (JNK)-dependent apoptosis and causes aberrant cell proliferation in distinct cell populations. Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues. Furthermore, JNK signaling is essential for dNKAP depletion-mediated cell invasion. Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways. dNKAP knockdown and oncogenic Ras, Notch, or Yki mutations show synergies in driving tumorigenesis, further supporting the tumor-suppressive role of dNKAP. In summary, this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.

nf - κ b激活蛋白(NKAP)家族基因的突变或表达失调已在人类癌症中被发现。NKAP家族基因突变如何促进肿瘤的发生和发展仍有待确定。在这里,我们对NKAP的果蝇同源物dNKAP进行了表征,并在果蝇上皮肿瘤模型中发现dNKAP功能受损导致基因组不稳定和致瘤性生长。dnkap敲低翼影像盘表现出致瘤性特征,包括组织过度生长、细胞侵袭行为、细胞极性异常和细胞粘附缺陷。dNKAP敲低导致r环积累和DNA损伤,表明基因组完整性被破坏。进一步分析表明,dNKAP敲低可诱导c-Jun n -末端激酶(JNK)依赖性细胞凋亡,并引起不同细胞群细胞增殖的变化。Notch和JAK/STAT信号通路的激活有助于dnkap敲低组织的致瘤性生长。此外,JNK信号对于dNKAP耗竭介导的细胞侵袭至关重要。dnkap敲低组织的转录组分析证实了促进肿瘤发生的信号通路的失调,并揭示了代谢通路的异常调节。dNKAP敲低和致癌的Ras、Notch或Yki突变在驱动肿瘤发生中显示协同作用,进一步支持dNKAP的肿瘤抑制作用。总之,本研究表明,dNKAP通过防止果蝇上皮细胞基因组不稳定发挥肿瘤抑制作用,从而为人类NKAP家族基因在肿瘤发生和发展中的作用提供了新的见解。
{"title":"Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia.","authors":"Ting Guo, Chen Miao, Zhonghua Liu, Jingwei Duan, Yanbin Ma, Xiao Zhang, Weiwei Yang, Maoguang Xue, Qiannan Deng, Pengfei Guo, Yongmei Xi, Xiaohang Yang, Xun Huang, Wanzhong Ge","doi":"10.1093/jmcb/mjad078","DOIUrl":"10.1093/jmcb/mjad078","url":null,"abstract":"<p><p>Mutations or dysregulated expression of NF-kappaB-activating protein (NKAP) family genes have been found in human cancers. How NKAP family gene mutations promote tumor initiation and progression remains to be determined. Here, we characterized dNKAP, the Drosophila homolog of NKAP, and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model. dNKAP-knockdown wing imaginal discs exhibit tumorigenic characteristics, including tissue overgrowth, cell-invasive behavior, abnormal cell polarity, and cell adhesion defects. dNKAP knockdown causes both R-loop accumulation and DNA damage, indicating the disruption of genome integrity. Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase (JNK)-dependent apoptosis and causes aberrant cell proliferation in distinct cell populations. Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP-knockdown tissues. Furthermore, JNK signaling is essential for dNKAP depletion-mediated cell invasion. Transcriptome analysis of dNKAP-knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways. dNKAP knockdown and oncogenic Ras, Notch, or Yki mutations show synergies in driving tumorigenesis, further supporting the tumor-suppressive role of dNKAP. In summary, this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11070879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138498638","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
期刊
Journal of Molecular Cell Biology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1