首页 > 最新文献

Journal of Cell Biology最新文献

英文 中文
AI analysis of super-resolution microscopy: Biological discovery in the absence of ground truth. 超分辨率显微镜的人工智能分析:在缺乏地面实况的情况下发现生物。
IF 7.8 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 Epub Date: 2024-06-12 DOI: 10.1083/jcb.202311073
Ivan R Nabi, Ben Cardoen, Ismail M Khater, Guang Gao, Timothy H Wong, Ghassan Hamarneh

Super-resolution microscopy, or nanoscopy, enables the use of fluorescent-based molecular localization tools to study molecular structure at the nanoscale level in the intact cell, bridging the mesoscale gap to classical structural biology methodologies. Analysis of super-resolution data by artificial intelligence (AI), such as machine learning, offers tremendous potential for the discovery of new biology, that, by definition, is not known and lacks ground truth. Herein, we describe the application of weakly supervised paradigms to super-resolution microscopy and its potential to enable the accelerated exploration of the nanoscale architecture of subcellular macromolecules and organelles.

超分辨率显微镜(或纳米镜)能够利用基于荧光的分子定位工具,研究完整细胞中纳米级别的分子结构,弥补了传统结构生物学方法在中尺度上的差距。通过人工智能(AI)(如机器学习)对超分辨率数据进行分析,为发现新生物学提供了巨大潜力。在此,我们将介绍弱监督范式在超分辨率显微镜中的应用,以及它在加速探索亚细胞大分子和细胞器纳米级结构方面的潜力。
{"title":"AI analysis of super-resolution microscopy: Biological discovery in the absence of ground truth.","authors":"Ivan R Nabi, Ben Cardoen, Ismail M Khater, Guang Gao, Timothy H Wong, Ghassan Hamarneh","doi":"10.1083/jcb.202311073","DOIUrl":"10.1083/jcb.202311073","url":null,"abstract":"<p><p>Super-resolution microscopy, or nanoscopy, enables the use of fluorescent-based molecular localization tools to study molecular structure at the nanoscale level in the intact cell, bridging the mesoscale gap to classical structural biology methodologies. Analysis of super-resolution data by artificial intelligence (AI), such as machine learning, offers tremendous potential for the discovery of new biology, that, by definition, is not known and lacks ground truth. Herein, we describe the application of weakly supervised paradigms to super-resolution microscopy and its potential to enable the accelerated exploration of the nanoscale architecture of subcellular macromolecules and organelles.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11169916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Centrosome age breaks spindle size symmetry even in cells thought to divide symmetrically. 即使在被认为是对称分裂的细胞中,中心体的年龄也会打破纺锤体大小的对称性。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 Epub Date: 2024-07-16 DOI: 10.1083/jcb.202311153
Alexandre Thomas, Patrick Meraldi

Centrosomes are the main microtubule-organizing centers in animal cells. Due to the semiconservative nature of centrosome duplication, the two centrosomes differ in age. In asymmetric stem cell divisions, centrosome age can induce an asymmetry in half-spindle lengths. However, whether centrosome age affects the symmetry of the two half-spindles in tissue culture cells thought to divide symmetrically is unknown. Here, we show that in human epithelial and fibroblastic cell lines centrosome age imposes a mild spindle asymmetry that leads to asymmetric cell daughter sizes. At the mechanistic level, we show that this asymmetry depends on a cenexin-bound pool of the mitotic kinase Plk1, which favors the preferential accumulation on old centrosomes of the microtubule nucleation-organizing proteins pericentrin, γ-tubulin, and Cdk5Rap2, and microtubule regulators TPX2 and ch-TOG. Consistently, we find that old centrosomes have a higher microtubule nucleation capacity. We postulate that centrosome age breaks spindle size symmetry via microtubule nucleation even in cells thought to divide symmetrically.

中心体是动物细胞中主要的微管组织中心。由于中心体复制的半保守性,两个中心体的年龄不同。在非对称干细胞分裂中,中心体年龄可导致半纺锤体长度的非对称性。然而,在被认为是对称分裂的组织培养细胞中,中心体年龄是否会影响两个半纺锤体的对称性尚不清楚。在这里,我们发现在人类上皮细胞和成纤维细胞系中,中心体年龄会造成轻微的纺锤体不对称,从而导致细胞子粒大小不对称。在机理层面,我们发现这种不对称依赖于与有丝分裂激酶 Plk1 结合的 cenexin 池,它有利于微管成核组织蛋白 pericentrin、γ-tubulin 和 Cdk5Rap2 以及微管调节剂 TPX2 和 ch-TOG 在老的中心体上优先积累。同样,我们发现老的中心体具有更高的微管成核能力。我们推测,即使在被认为是对称分裂的细胞中,中心体的年龄也会通过微管成核打破纺锤体大小的对称性。
{"title":"Centrosome age breaks spindle size symmetry even in cells thought to divide symmetrically.","authors":"Alexandre Thomas, Patrick Meraldi","doi":"10.1083/jcb.202311153","DOIUrl":"10.1083/jcb.202311153","url":null,"abstract":"<p><p>Centrosomes are the main microtubule-organizing centers in animal cells. Due to the semiconservative nature of centrosome duplication, the two centrosomes differ in age. In asymmetric stem cell divisions, centrosome age can induce an asymmetry in half-spindle lengths. However, whether centrosome age affects the symmetry of the two half-spindles in tissue culture cells thought to divide symmetrically is unknown. Here, we show that in human epithelial and fibroblastic cell lines centrosome age imposes a mild spindle asymmetry that leads to asymmetric cell daughter sizes. At the mechanistic level, we show that this asymmetry depends on a cenexin-bound pool of the mitotic kinase Plk1, which favors the preferential accumulation on old centrosomes of the microtubule nucleation-organizing proteins pericentrin, γ-tubulin, and Cdk5Rap2, and microtubule regulators TPX2 and ch-TOG. Consistently, we find that old centrosomes have a higher microtubule nucleation capacity. We postulate that centrosome age breaks spindle size symmetry via microtubule nucleation even in cells thought to divide symmetrically.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 8","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11252449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase. 双核人肝细胞是在内膜增生 M 期通过晚期细胞增生退化产生的。
IF 7.8 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 Epub Date: 2024-05-10 DOI: 10.1083/jcb.202403020
Gabriella S Darmasaputra, Cindy C Geerlings, Susana M Chuva de Sousa Lopes, Hans Clevers, Matilde Galli

Binucleated polyploid cells are common in many animal tissues, where they arise by endomitosis, a non-canonical cell cycle in which cells enter M phase but do not undergo cytokinesis. Different steps of cytokinesis have been shown to be inhibited during endomitosis M phase in rodents, but it is currently unknown how human cells undergo endomitosis. In this study, we use fetal-derived human hepatocyte organoids (Hep-Orgs) to investigate how human hepatocytes initiate and execute endomitosis. We find that cells in endomitosis M phase have normal mitotic timings, but lose membrane anchorage to the midbody during cytokinesis, which is associated with the loss of four cortical anchoring proteins, RacGAP1, Anillin, SEPT9, and citron kinase (CIT-K). Moreover, reduction of WNT activity increases the percentage of binucleated cells in Hep-Orgs, an effect that is dependent on the atypical E2F proteins, E2F7 and E2F8. Together, we have elucidated how hepatocytes undergo endomitosis in human Hep-Orgs, providing new insights into the mechanisms of endomitosis in mammals.

双核多倍体细胞在许多动物组织中都很常见,它们是通过内异生产生的,内异生是一种非规范细胞周期,细胞进入 M 期但不进行细胞分裂。在啮齿类动物中,细胞分裂的不同步骤已被证明在内生 M 期受到抑制,但目前还不清楚人类细胞是如何进行内生的。在本研究中,我们利用胎儿衍生的人类肝细胞器官组织(Hep-Orgs)来研究人类肝细胞如何启动和执行内膜形成。我们发现,处于内膜有丝分裂 M 期的细胞具有正常的有丝分裂时间,但在细胞分裂过程中会失去与中体的膜锚定,这与四种皮质锚定蛋白 RacGAP1、Anillin、SEPT9 和柠檬激酶(CIT-K)的缺失有关。此外,减少 WNT 活性会增加 Hep-Orgs 中双核细胞的比例,这种效应依赖于非典型 E2F 蛋白 E2F7 和 E2F8。综上所述,我们阐明了人类 Hep-Orgs 中的肝细胞是如何发生内异症的,从而为哺乳动物的内异症机制提供了新的见解。
{"title":"Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase.","authors":"Gabriella S Darmasaputra, Cindy C Geerlings, Susana M Chuva de Sousa Lopes, Hans Clevers, Matilde Galli","doi":"10.1083/jcb.202403020","DOIUrl":"10.1083/jcb.202403020","url":null,"abstract":"<p><p>Binucleated polyploid cells are common in many animal tissues, where they arise by endomitosis, a non-canonical cell cycle in which cells enter M phase but do not undergo cytokinesis. Different steps of cytokinesis have been shown to be inhibited during endomitosis M phase in rodents, but it is currently unknown how human cells undergo endomitosis. In this study, we use fetal-derived human hepatocyte organoids (Hep-Orgs) to investigate how human hepatocytes initiate and execute endomitosis. We find that cells in endomitosis M phase have normal mitotic timings, but lose membrane anchorage to the midbody during cytokinesis, which is associated with the loss of four cortical anchoring proteins, RacGAP1, Anillin, SEPT9, and citron kinase (CIT-K). Moreover, reduction of WNT activity increases the percentage of binucleated cells in Hep-Orgs, an effect that is dependent on the atypical E2F proteins, E2F7 and E2F8. Together, we have elucidated how hepatocytes undergo endomitosis in human Hep-Orgs, providing new insights into the mechanisms of endomitosis in mammals.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Excessive STAU1 condensate drives mTOR translation and autophagy dysfunction in neurodegeneration. 在神经退行性病变中,过多的 STAU1 冷凝物会驱动 mTOR 翻译和自噬功能障碍。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 Epub Date: 2024-06-24 DOI: 10.1083/jcb.202311127
Ruiqian Zhao, Shijing Huang, Jingyu Li, Aihong Gu, Minjie Fu, Wei Hua, Ying Mao, Qun-Ying Lei, Boxun Lu, Wenyu Wen

The double-stranded RNA-binding protein Staufen1 (STAU1) regulates a variety of physiological and pathological events via mediating RNA metabolism. STAU1 overabundance was observed in tissues from mouse models and fibroblasts from patients with neurodegenerative diseases, accompanied by enhanced mTOR signaling and impaired autophagic flux, while the underlying mechanism remains elusive. Here, we find that endogenous STAU1 forms dynamic cytoplasmic condensate in normal and tumor cell lines, as well as in mouse Huntington's disease knockin striatal cells. STAU1 condensate recruits target mRNA MTOR at its 5'UTR and promotes its translation both in vitro and in vivo, and thus enhanced formation of STAU1 condensate leads to mTOR hyperactivation and autophagy-lysosome dysfunction. Interference of STAU1 condensate normalizes mTOR levels, ameliorates autophagy-lysosome function, and reduces aggregation of pathological proteins in cellular models of neurodegenerative diseases. These findings highlight the importance of balanced phase separation in physiological processes, suggesting that modulating STAU1 condensate may be a strategy to mitigate the progression of neurodegenerative diseases with STAU1 overabundance.

双链 RNA 结合蛋白 Staufen1(STAU1)通过介导 RNA 代谢调控多种生理和病理事件。在小鼠模型的组织和神经退行性疾病患者的成纤维细胞中观察到了 STAU1 的过量存在,并伴随着 mTOR 信号转导的增强和自噬通量的减弱,但其潜在机制仍然难以捉摸。在这里,我们发现内源性 STAU1 在正常细胞系、肿瘤细胞系以及小鼠亨廷顿氏病基因敲除纹状体细胞中形成动态胞质凝聚物。STAU1凝聚物在其5'UTR处招募靶mRNA MTOR并促进其在体外和体内的翻译,因此STAU1凝聚物的形成增强会导致mTOR过度激活和自噬-溶酶体功能障碍。在神经退行性疾病的细胞模型中,干扰 STAU1 冷凝物可使 mTOR 水平恢复正常、改善自噬-溶酶体功能并减少病理蛋白的聚集。这些发现凸显了平衡相分离在生理过程中的重要性,表明调节 STAU1 冷凝物可能是缓解 STAU1 过量导致的神经退行性疾病进展的一种策略。
{"title":"Excessive STAU1 condensate drives mTOR translation and autophagy dysfunction in neurodegeneration.","authors":"Ruiqian Zhao, Shijing Huang, Jingyu Li, Aihong Gu, Minjie Fu, Wei Hua, Ying Mao, Qun-Ying Lei, Boxun Lu, Wenyu Wen","doi":"10.1083/jcb.202311127","DOIUrl":"10.1083/jcb.202311127","url":null,"abstract":"<p><p>The double-stranded RNA-binding protein Staufen1 (STAU1) regulates a variety of physiological and pathological events via mediating RNA metabolism. STAU1 overabundance was observed in tissues from mouse models and fibroblasts from patients with neurodegenerative diseases, accompanied by enhanced mTOR signaling and impaired autophagic flux, while the underlying mechanism remains elusive. Here, we find that endogenous STAU1 forms dynamic cytoplasmic condensate in normal and tumor cell lines, as well as in mouse Huntington's disease knockin striatal cells. STAU1 condensate recruits target mRNA MTOR at its 5'UTR and promotes its translation both in vitro and in vivo, and thus enhanced formation of STAU1 condensate leads to mTOR hyperactivation and autophagy-lysosome dysfunction. Interference of STAU1 condensate normalizes mTOR levels, ameliorates autophagy-lysosome function, and reduces aggregation of pathological proteins in cellular models of neurodegenerative diseases. These findings highlight the importance of balanced phase separation in physiological processes, suggesting that modulating STAU1 condensate may be a strategy to mitigate the progression of neurodegenerative diseases with STAU1 overabundance.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 8","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11194678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Proteasome gene expression is controlled by coordinated functions of multiple transcription factors. 蛋白酶体基因的表达受多种转录因子协调功能的控制。
IF 7.8 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 Epub Date: 2024-05-20 DOI: 10.1083/jcb.202402046
Jennifer E Gilda, Asrafun Nahar, Dharanibalan Kasiviswanathan, Nadav Tropp, Tamar Gilinski, Tamar Lahav, Dina Alexandrovich, Yael Mandel-Gutfreund, Soyeon Park, Shenhav Shemer

Proteasome activity is crucial for cellular integrity, but how tissues adjust proteasome content in response to catabolic stimuli is uncertain. Here, we demonstrate that transcriptional coordination by multiple transcription factors is required to increase proteasome content and activate proteolysis in catabolic states. Using denervated mouse muscle as a model system for accelerated proteolysis in vivo, we reveal that a two-phase transcriptional program activates genes encoding proteasome subunits and assembly chaperones to boost an increase in proteasome content. Initially, gene induction is necessary to maintain basal proteasome levels, and in a more delayed phase (7-10 days after denervation), it stimulates proteasome assembly to meet cellular demand for excessive proteolysis. Intriguingly, the transcription factors PAX4 and α-PALNRF-1 control the expression of proteasome among other genes in a combinatorial manner, driving cellular adaptation to muscle denervation. Consequently, PAX4 and α-PALNRF-1 represent new therapeutic targets to inhibit proteolysis in catabolic diseases (e.g., type-2 diabetes, cancer).

蛋白酶体的活性对细胞的完整性至关重要,但目前还不清楚组织如何调整蛋白酶体的含量以应对分解代谢的刺激。在这里,我们证明了在分解代谢状态下增加蛋白酶体含量和激活蛋白水解需要多个转录因子的转录协调。我们利用失去神经支配的小鼠肌肉作为体内加速蛋白分解的模型系统,揭示了一个两阶段转录程序激活编码蛋白酶体亚基和组装伴侣的基因,以促进蛋白酶体含量的增加。起初,基因诱导是维持蛋白酶体基础水平所必需的,而在更延迟的阶段(去神经支配后 7-10 天),基因诱导刺激蛋白酶体组装,以满足细胞对过度蛋白分解的需求。耐人寻味的是,转录因子 PAX4 和 α-PALNRF-1 以组合方式控制蛋白酶体和其他基因的表达,推动细胞适应肌肉去神经化。因此,PAX4 和 α-PALNRF-1 是抑制分解代谢疾病(如 2 型糖尿病、癌症)中蛋白酶解的新治疗靶点。
{"title":"Proteasome gene expression is controlled by coordinated functions of multiple transcription factors.","authors":"Jennifer E Gilda, Asrafun Nahar, Dharanibalan Kasiviswanathan, Nadav Tropp, Tamar Gilinski, Tamar Lahav, Dina Alexandrovich, Yael Mandel-Gutfreund, Soyeon Park, Shenhav Shemer","doi":"10.1083/jcb.202402046","DOIUrl":"10.1083/jcb.202402046","url":null,"abstract":"<p><p>Proteasome activity is crucial for cellular integrity, but how tissues adjust proteasome content in response to catabolic stimuli is uncertain. Here, we demonstrate that transcriptional coordination by multiple transcription factors is required to increase proteasome content and activate proteolysis in catabolic states. Using denervated mouse muscle as a model system for accelerated proteolysis in vivo, we reveal that a two-phase transcriptional program activates genes encoding proteasome subunits and assembly chaperones to boost an increase in proteasome content. Initially, gene induction is necessary to maintain basal proteasome levels, and in a more delayed phase (7-10 days after denervation), it stimulates proteasome assembly to meet cellular demand for excessive proteolysis. Intriguingly, the transcription factors PAX4 and α-PALNRF-1 control the expression of proteasome among other genes in a combinatorial manner, driving cellular adaptation to muscle denervation. Consequently, PAX4 and α-PALNRF-1 represent new therapeutic targets to inhibit proteolysis in catabolic diseases (e.g., type-2 diabetes, cancer).</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11104393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Regulation of cell function and identity by cellular senescence. 细胞衰老对细胞功能和特性的调节。
IF 7.8 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 Epub Date: 2024-06-12 DOI: 10.1083/jcb.202401112
Anda Huna, Amélie Massemin, Gabriela Makulyte, Jean-Michel Flaman, Nadine Martin, David Bernard

During aging and in some contexts, like embryonic development, wound healing, and diseases such as cancer, senescent cells accumulate and play a key role in different pathophysiological functions. A long-held belief was that cellular senescence decreased normal cell functions, given the loss of proliferation of senescent cells. This view radically changed following the discovery of the senescence-associated secretory phenotype (SASP), factors released by senescent cells into their microenvironment. There is now accumulating evidence that cellular senescence also promotes gain-of-function effects by establishing, reinforcing, or changing cell identity, which can have a beneficial or deleterious impact on pathophysiology. These effects may involve both proliferation arrest and autocrine SASP production, although they largely remain to be defined. Here, we provide a historical overview of the first studies on senescence and an insight into emerging trends regarding the effects of senescence on cell identity.

在衰老过程中,以及在胚胎发育、伤口愈合和癌症等疾病的某些情况下,衰老细胞会不断积累,并在不同的病理生理功能中发挥关键作用。长期以来,人们一直认为细胞衰老会降低细胞的正常功能,因为衰老细胞失去了增殖能力。随着衰老相关分泌表型(SASP)的发现--衰老细胞向其微环境释放的因子--这种观点发生了根本改变。现在有越来越多的证据表明,细胞衰老还能通过建立、强化或改变细胞特性来促进功能增益效应,从而对病理生理学产生有益或有害的影响。这些效应可能涉及增殖停滞和自分泌 SASP 的产生,尽管它们在很大程度上仍有待界定。在此,我们将对有关衰老的首次研究进行历史性概述,并深入探讨有关衰老对细胞特性影响的新趋势。
{"title":"Regulation of cell function and identity by cellular senescence.","authors":"Anda Huna, Amélie Massemin, Gabriela Makulyte, Jean-Michel Flaman, Nadine Martin, David Bernard","doi":"10.1083/jcb.202401112","DOIUrl":"10.1083/jcb.202401112","url":null,"abstract":"<p><p>During aging and in some contexts, like embryonic development, wound healing, and diseases such as cancer, senescent cells accumulate and play a key role in different pathophysiological functions. A long-held belief was that cellular senescence decreased normal cell functions, given the loss of proliferation of senescent cells. This view radically changed following the discovery of the senescence-associated secretory phenotype (SASP), factors released by senescent cells into their microenvironment. There is now accumulating evidence that cellular senescence also promotes gain-of-function effects by establishing, reinforcing, or changing cell identity, which can have a beneficial or deleterious impact on pathophysiology. These effects may involve both proliferation arrest and autocrine SASP production, although they largely remain to be defined. Here, we provide a historical overview of the first studies on senescence and an insight into emerging trends regarding the effects of senescence on cell identity.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11169915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Dual protection by Bcp1 and Rkm1 ensures incorporation of uL14 into pre-60S ribosomal subunits. Bcp1 和 Rkm1 的双重保护确保了 uL14 与前 60S 核糖体亚基的结合。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 Epub Date: 2024-07-15 DOI: 10.1083/jcb.202306117
Min-Chi Yeh, Ning-Hsiang Hsu, Hao-Yu Chu, Cheng-Han Yang, Pang-Hung Hsu, Chi-Chi Chou, Jing-Ting Shie, Wei-Ming Lee, Meng-Chiao Ho, Kai-Yin Lo

Eukaryotic ribosomal proteins contain extended regions essential for translation coordination. Dedicated chaperones stabilize the associated ribosomal proteins. We identified Bcp1 as the chaperone of uL14 in Saccharomyces cerevisiae. Rkm1, the lysine methyltransferase of uL14, forms a ternary complex with Bcp1 and uL14 to protect uL14. Rkm1 is transported with uL14 by importins to the nucleus, and Bcp1 disassembles Rkm1 and importin from uL14 simultaneously in a RanGTP-independent manner. Molecular docking, guided by crosslinking mass spectrometry and validated by a low-resolution cryo-EM map, reveals the correlation between Bcp1, Rkm1, and uL14, demonstrating the protection model. In addition, the ternary complex also serves as a surveillance point, whereas incorrect uL14 is retained on Rkm1 and prevented from loading to the pre-60S ribosomal subunits. This study reveals the molecular mechanism of how uL14 is protected and quality checked by serial steps to ensure its safe delivery from the cytoplasm until its incorporation into the 60S ribosomal subunit.

真核生物核糖体蛋白含有翻译协调所必需的延伸区域。专用的伴侣蛋白能稳定相关的核糖体蛋白。我们发现 Bcp1 是酿酒酵母中 uL14 的伴侣蛋白。uL14的赖氨酸甲基转移酶Rkm1与Bcp1和uL14形成三元复合物,保护uL14。Rkm1 通过导入蛋白与 uL14 一起被运输到细胞核,Bcp1 以一种不依赖于 RanGTP 的方式同时将 Rkm1 和导入蛋白从 uL14 中分解。以交联质谱为指导并通过低分辨率冷冻电镜图谱验证的分子对接揭示了 Bcp1、Rkm1 和 uL14 之间的相关性,证明了保护模式。此外,三元复合物也是一个监控点,而不正确的uL14则被保留在Rkm1上,无法加载到前60S核糖体亚基上。这项研究揭示了uL14如何通过一系列步骤受到保护和质量检查的分子机制,以确保其从细胞质安全输送到60S核糖体亚基。
{"title":"Dual protection by Bcp1 and Rkm1 ensures incorporation of uL14 into pre-60S ribosomal subunits.","authors":"Min-Chi Yeh, Ning-Hsiang Hsu, Hao-Yu Chu, Cheng-Han Yang, Pang-Hung Hsu, Chi-Chi Chou, Jing-Ting Shie, Wei-Ming Lee, Meng-Chiao Ho, Kai-Yin Lo","doi":"10.1083/jcb.202306117","DOIUrl":"10.1083/jcb.202306117","url":null,"abstract":"<p><p>Eukaryotic ribosomal proteins contain extended regions essential for translation coordination. Dedicated chaperones stabilize the associated ribosomal proteins. We identified Bcp1 as the chaperone of uL14 in Saccharomyces cerevisiae. Rkm1, the lysine methyltransferase of uL14, forms a ternary complex with Bcp1 and uL14 to protect uL14. Rkm1 is transported with uL14 by importins to the nucleus, and Bcp1 disassembles Rkm1 and importin from uL14 simultaneously in a RanGTP-independent manner. Molecular docking, guided by crosslinking mass spectrometry and validated by a low-resolution cryo-EM map, reveals the correlation between Bcp1, Rkm1, and uL14, demonstrating the protection model. In addition, the ternary complex also serves as a surveillance point, whereas incorrect uL14 is retained on Rkm1 and prevented from loading to the pre-60S ribosomal subunits. This study reveals the molecular mechanism of how uL14 is protected and quality checked by serial steps to ensure its safe delivery from the cytoplasm until its incorporation into the 60S ribosomal subunit.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 8","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11248248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Stable GDP-tubulin islands rescue dynamic microtubules. 稳定的 GDP-微管蛋白岛可挽救动态微管。
IF 4.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 Epub Date: 2024-05-17 DOI: 10.1083/jcb.202307074
Nassiba Bagdadi, Juliette Wu, Julie Delaroche, Laurence Serre, Christian Delphin, Manon De Andrade, Marion Carcel, Homaira Nawabi, Benoît Pinson, Claire Vérin, Yohann Couté, Sylvie Gory-Fauré, Annie Andrieux, Virginie Stoppin-Mellet, Isabelle Arnal

Microtubules are dynamic polymers that interconvert between phases of growth and shrinkage, yet they provide structural stability to cells. Growth involves hydrolysis of GTP-tubulin to GDP-tubulin, which releases energy that is stored within the microtubule lattice and destabilizes it; a GTP cap at microtubule ends is thought to prevent GDP subunits from rapidly dissociating and causing catastrophe. Here, using in vitro reconstitution assays, we show that GDP-tubulin, usually considered inactive, can itself assemble into microtubules, preferentially at the minus end, and promote persistent growth. GDP-tubulin-assembled microtubules are highly stable, displaying no detectable spontaneous shrinkage. Strikingly, islands of GDP-tubulin within dynamic microtubules stop shrinkage events and promote rescues. Microtubules thus possess an intrinsic capacity for stability, independent of accessory proteins. This finding provides novel mechanisms to explain microtubule dynamics.

微管是一种动态聚合物,可在生长和收缩两个阶段之间相互转换,但却能为细胞提供结构稳定性。生长过程中,GTP-微管蛋白水解为 GDP-微管蛋白,释放出储存在微管晶格中的能量,从而破坏微管晶格的稳定性;微管末端的 GTP 盖被认为能防止 GDP 亚基迅速解离并导致灾难。在这里,我们利用体外重组实验表明,通常被认为是无活性的 GDP-微管蛋白本身可以组装成微管,优先组装在负端,并促进持续生长。GDP-微管蛋白组装的微管高度稳定,不会出现可检测到的自发收缩。令人吃惊的是,动态微管中的 GDP-微管蛋白岛能阻止收缩事件并促进挽救。因此,微管具有内在的稳定性,不受附属蛋白的影响。这一发现为解释微管动力学提供了新的机制。
{"title":"Stable GDP-tubulin islands rescue dynamic microtubules.","authors":"Nassiba Bagdadi, Juliette Wu, Julie Delaroche, Laurence Serre, Christian Delphin, Manon De Andrade, Marion Carcel, Homaira Nawabi, Benoît Pinson, Claire Vérin, Yohann Couté, Sylvie Gory-Fauré, Annie Andrieux, Virginie Stoppin-Mellet, Isabelle Arnal","doi":"10.1083/jcb.202307074","DOIUrl":"10.1083/jcb.202307074","url":null,"abstract":"<p><p>Microtubules are dynamic polymers that interconvert between phases of growth and shrinkage, yet they provide structural stability to cells. Growth involves hydrolysis of GTP-tubulin to GDP-tubulin, which releases energy that is stored within the microtubule lattice and destabilizes it; a GTP cap at microtubule ends is thought to prevent GDP subunits from rapidly dissociating and causing catastrophe. Here, using in vitro reconstitution assays, we show that GDP-tubulin, usually considered inactive, can itself assemble into microtubules, preferentially at the minus end, and promote persistent growth. GDP-tubulin-assembled microtubules are highly stable, displaying no detectable spontaneous shrinkage. Strikingly, islands of GDP-tubulin within dynamic microtubules stop shrinkage events and promote rescues. Microtubules thus possess an intrinsic capacity for stability, independent of accessory proteins. This finding provides novel mechanisms to explain microtubule dynamics.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11101955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Tailored assemblies of COPII proteins in secretion. 分泌过程中 COPII 蛋白的定制组装。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 Epub Date: 2024-07-03 DOI: 10.1083/jcb.202404013
Vivek Malhotra

Export of secretory cargoes from the endoplasmic reticulum (ER) requires COPII proteins, which were first identified for their ability to coat small vesicles that bud from the ER. Recent data indicate that COPII proteins can also organize into a collar at the necks of tubules, as well as phase-separate into liquid-like condensates. Thus, COPII assemblies seem to be tailored to accommodate variations in the size and quantities of cargo secreted.

从内质网(ER)导出分泌货物需要 COPII 蛋白,人们最初发现 COPII 蛋白能够包裹从 ER 萌发的小囊泡。最近的数据表明,COPII 蛋白还能在小管的颈部组织成环,以及相分离成液体状凝聚体。因此,COPII 的组装似乎是量身定制的,以适应分泌货物的大小和数量的变化。
{"title":"Tailored assemblies of COPII proteins in secretion.","authors":"Vivek Malhotra","doi":"10.1083/jcb.202404013","DOIUrl":"10.1083/jcb.202404013","url":null,"abstract":"<p><p>Export of secretory cargoes from the endoplasmic reticulum (ER) requires COPII proteins, which were first identified for their ability to coat small vesicles that bud from the ER. Recent data indicate that COPII proteins can also organize into a collar at the necks of tubules, as well as phase-separate into liquid-like condensates. Thus, COPII assemblies seem to be tailored to accommodate variations in the size and quantities of cargo secreted.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 8","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11222725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks. DBF4 而不是 DRF1 是复制叉上 CDC7 激酶的关键调节因子。
IF 7.8 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-08-05 Epub Date: 2024-06-12 DOI: 10.1083/jcb.202402144
Anja Göder, Chrystelle Antoinat Maric, Michael D Rainey, Aisling O'Connor, Chiara Cazzaniga, Daniel Shamavu, Jean-Charles Cadoret, Corrado Santocanale

CDC7 kinase is crucial for DNA replication initiation and is involved in fork processing and replication stress response. Human CDC7 requires the binding of either DBF4 or DRF1 for its activity. However, it is unclear whether the two regulatory subunits target CDC7 to a specific set of substrates, thus having different biological functions, or if they act redundantly. Using genome editing technology, we generated isogenic cell lines deficient in either DBF4 or DRF1: these cells are viable but present signs of genomic instability, indicating that both can independently support CDC7 for bulk DNA replication. Nonetheless, DBF4-deficient cells show altered replication efficiency, partial deficiency in MCM helicase phosphorylation, and alterations in the replication timing of discrete genomic regions. Notably, we find that CDC7 function at replication forks is entirely dependent on DBF4 and not on DRF1. Thus, DBF4 is the primary regulator of CDC7 activity, mediating most of its functions in unperturbed DNA replication and upon replication interference.

CDC7 激酶对 DNA 复制的启动至关重要,并参与叉处理和复制应激反应。人类 CDC7 的活性需要与 DBF4 或 DRF1 结合。然而,目前还不清楚这两个调控亚基是将 CDC7 定位于一组特定的底物,从而具有不同的生物学功能,还是它们的作用是多余的。利用基因组编辑技术,我们生成了缺乏 DBF4 或 DRF1 的同源细胞系:这些细胞可以存活,但有基因组不稳定的迹象,表明它们都能独立支持 CDC7 进行大量 DNA 复制。然而,DBF4 缺陷细胞显示出复制效率的改变、MCM 螺旋酶磷酸化的部分缺陷以及离散基因组区域复制时间的改变。值得注意的是,我们发现 CDC7 在复制叉上的功能完全依赖于 DBF4 而不是 DRF1。因此,DBF4 是 CDC7 活性的主要调节因子,在未受干扰的 DNA 复制和复制干扰时介导 CDC7 的大部分功能。
{"title":"DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks.","authors":"Anja Göder, Chrystelle Antoinat Maric, Michael D Rainey, Aisling O'Connor, Chiara Cazzaniga, Daniel Shamavu, Jean-Charles Cadoret, Corrado Santocanale","doi":"10.1083/jcb.202402144","DOIUrl":"10.1083/jcb.202402144","url":null,"abstract":"<p><p>CDC7 kinase is crucial for DNA replication initiation and is involved in fork processing and replication stress response. Human CDC7 requires the binding of either DBF4 or DRF1 for its activity. However, it is unclear whether the two regulatory subunits target CDC7 to a specific set of substrates, thus having different biological functions, or if they act redundantly. Using genome editing technology, we generated isogenic cell lines deficient in either DBF4 or DRF1: these cells are viable but present signs of genomic instability, indicating that both can independently support CDC7 for bulk DNA replication. Nonetheless, DBF4-deficient cells show altered replication efficiency, partial deficiency in MCM helicase phosphorylation, and alterations in the replication timing of discrete genomic regions. Notably, we find that CDC7 function at replication forks is entirely dependent on DBF4 and not on DRF1. Thus, DBF4 is the primary regulator of CDC7 activity, mediating most of its functions in unperturbed DNA replication and upon replication interference.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11169917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 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