首页 > 最新文献

Journal of Cell Biology最新文献

英文 中文
Nuclear poly-glutamine aggregates rupture the nuclear envelope and hinder its repair. 核聚谷氨酰胺聚集体会破坏核包膜,阻碍其修复。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-16 DOI: 10.1083/jcb.202307142
Giel Korsten, Miriam Osinga, Robin A Pelle, Albert K Serweta, Baukje Hoogenberg, Harm H Kampinga, Lukas C Kapitein

Huntington's disease (HD) is caused by a polyglutamine expansion of the huntingtin protein, resulting in the formation of polyglutamine aggregates. The mechanisms of toxicity that result in the complex HD pathology remain only partially understood. Here, we show that nuclear polyglutamine aggregates induce nuclear envelope (NE) blebbing and ruptures that are often repaired incompletely. These ruptures coincide with disruptions of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair. Furthermore, we found that NE repair factors often accumulated near nuclear aggregates, consistent with stalled repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntington's disease and other polyglutamine diseases.

亨廷顿氏病(Huntington's disease,HD)是由亨廷丁蛋白的多聚谷氨酰胺扩增导致多聚谷氨酰胺聚集体的形成引起的。导致复杂的 HD 病理的毒性机制仍只有部分了解。在这里,我们展示了核聚谷氨酰胺聚集体会诱发核包膜(NE)出血和破裂,而这种破裂往往不能完全修复。这些破裂与核薄层的破坏同时发生,并导致薄层瘢痕的形成。膨胀显微镜能够解析核聚集体的超微结构,并发现多聚谷氨酰胺纤维粘附在破裂部位的细胞膜上,这表明了一种不完全修复的机制。此外,我们还发现 NE 修复因子经常聚集在核聚集体附近,这与修复停滞一致。这些发现表明,核聚Q聚集体诱导的NE完整性丧失是亨廷顿氏病和其他多聚谷氨酰胺疾病的潜在诱因。
{"title":"Nuclear poly-glutamine aggregates rupture the nuclear envelope and hinder its repair.","authors":"Giel Korsten, Miriam Osinga, Robin A Pelle, Albert K Serweta, Baukje Hoogenberg, Harm H Kampinga, Lukas C Kapitein","doi":"10.1083/jcb.202307142","DOIUrl":"10.1083/jcb.202307142","url":null,"abstract":"<p><p>Huntington's disease (HD) is caused by a polyglutamine expansion of the huntingtin protein, resulting in the formation of polyglutamine aggregates. The mechanisms of toxicity that result in the complex HD pathology remain only partially understood. Here, we show that nuclear polyglutamine aggregates induce nuclear envelope (NE) blebbing and ruptures that are often repaired incompletely. These ruptures coincide with disruptions of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair. Furthermore, we found that NE repair factors often accumulated near nuclear aggregates, consistent with stalled repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntington's disease and other polyglutamine diseases.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 11","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988073","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
Distinct roles of Kif6 and Kif9 in mammalian ciliary trafficking and motility. Kif6和Kif9在哺乳动物纤毛运输和运动中的不同作用
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-19 DOI: 10.1083/jcb.202312060
Chuyu Fang, Xinwen Pan, Di Li, Wei Chen, Ying Huang, Yawen Chen, Luan Li, Qi Gao, Xin Liang, Dong Li, Xueliang Zhu, Xiumin Yan

Ciliary beat and intraflagellar transport depend on dynein and kinesin motors. The kinesin-9 family members Kif6 and Kif9 are implicated in motile cilia motilities across protists and mammals. How they function and whether they act redundantly, however, remain unclear. Here, we show that Kif6 and Kif9 play distinct roles in mammals. Kif6 forms puncta that move bidirectionally along axonemes, whereas Kif9 appears to oscillate regionally on the ciliary central apparatus. Consistently, only Kif6 displays microtubule-based motor activity in vitro, and its ciliary localization requires its ATPase activity. Kif6 deficiency in mice disrupts coordinated ciliary beat across ependymal tissues and impairs cerebrospinal fluid flow, resulting in severe hydrocephalus and high mortality. Kif9 deficiency causes mild hydrocephalus without obviously affecting the ciliary beat or the lifespan. Kif6-/- and Kif9-/- males are infertile but exhibit oligozoospermia with poor sperm motility and defective forward motion of sperms, respectively. These results suggest Kif6 as a motor for cargo transport and Kif9 as a central apparatus regulator.

纤毛搏动和纤毛内运输依赖于动力蛋白和驱动蛋白马达。驱动蛋白-9 家族成员 Kif6 和 Kif9 与原生动物和哺乳动物的纤毛运动有关。然而,它们是如何起作用的以及它们是否起冗余作用仍不清楚。在这里,我们发现 Kif6 和 Kif9 在哺乳动物中发挥着不同的作用。Kif6 形成的点沿着轴丝双向移动,而 Kif9 似乎在纤毛中心器上的区域内摆动。一致的是,只有 Kif6 在体外显示出基于微管的运动活性,其纤毛定位需要其 ATPase 活性。小鼠缺乏 Kif6 会破坏上皮组织中协调的睫状肌搏动,并损害脑脊液流动,导致严重脑积水和高死亡率。Kif9 缺乏会导致轻度脑积水,但不会明显影响睫状肌搏动或寿命。Kif6-/- 和 Kif9-/- 雄性不育,但分别表现出精子活力差和精子前向运动缺陷的少精子症。这些结果表明 Kif6 是货物运输的马达,而 Kif9 则是中央装置的调节器。
{"title":"Distinct roles of Kif6 and Kif9 in mammalian ciliary trafficking and motility.","authors":"Chuyu Fang, Xinwen Pan, Di Li, Wei Chen, Ying Huang, Yawen Chen, Luan Li, Qi Gao, Xin Liang, Dong Li, Xueliang Zhu, Xiumin Yan","doi":"10.1083/jcb.202312060","DOIUrl":"10.1083/jcb.202312060","url":null,"abstract":"<p><p>Ciliary beat and intraflagellar transport depend on dynein and kinesin motors. The kinesin-9 family members Kif6 and Kif9 are implicated in motile cilia motilities across protists and mammals. How they function and whether they act redundantly, however, remain unclear. Here, we show that Kif6 and Kif9 play distinct roles in mammals. Kif6 forms puncta that move bidirectionally along axonemes, whereas Kif9 appears to oscillate regionally on the ciliary central apparatus. Consistently, only Kif6 displays microtubule-based motor activity in vitro, and its ciliary localization requires its ATPase activity. Kif6 deficiency in mice disrupts coordinated ciliary beat across ependymal tissues and impairs cerebrospinal fluid flow, resulting in severe hydrocephalus and high mortality. Kif9 deficiency causes mild hydrocephalus without obviously affecting the ciliary beat or the lifespan. Kif6-/- and Kif9-/- males are infertile but exhibit oligozoospermia with poor sperm motility and defective forward motion of sperms, respectively. These results suggest Kif6 as a motor for cargo transport and Kif9 as a central apparatus regulator.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 11","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000013","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
Aurora B controls anaphase onset and error-free chromosome segregation in trypanosomes. 极光 B 控制着锥虫无丝分裂期的开始和无差错染色体分离。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-28 DOI: 10.1083/jcb.202401169
Daniel Ballmer, Hua Jane Lou, Midori Ishii, Benjamin E Turk, Bungo Akiyoshi

Kinetochores form the interface between chromosomes and spindle microtubules and are thus under tight control by a complex regulatory circuitry. The Aurora B kinase plays a central role within this circuitry by destabilizing improper kinetochore-microtubule attachments and relaying the attachment status to the spindle assembly checkpoint. Intriguingly, Aurora B is conserved even in kinetoplastids, a group of early-branching eukaryotes which possess a unique set of kinetochore proteins. It remains unclear how their kinetochores are regulated to ensure faithful chromosome segregation. Here, we show in Trypanosoma brucei that Aurora B activity controls the metaphase-to-anaphase transition through phosphorylation of the divergent Bub1-like protein KKT14. Depletion of KKT14 overrides the metaphase arrest resulting from Aurora B inhibition, while expression of non-phosphorylatable KKT14 delays anaphase onset. Finally, we demonstrate that re-targeting Aurora B to the outer kinetochore suffices to promote mitotic exit but causes extensive chromosome missegregation in anaphase. Our results indicate that Aurora B and KKT14 are involved in an unconventional circuitry controlling cell cycle progression in trypanosomes.

动点形成染色体与纺锤体微管之间的界面,因此受到复杂的调控电路的严格控制。极光 B 激酶在这一电路中起着核心作用,它能破坏不正常的动点核心-微管连接的稳定性,并将连接状态传递给纺锤体组装检查点。耐人寻味的是,极光 B 甚至在真核细胞中也是保守的,真核细胞是一类早期分支真核生物,拥有一套独特的动点核心蛋白。目前仍不清楚它们的动点如何调控以确保染色体的忠实分离。在这里,我们在布氏锥虫中发现,极光 B 的活性通过磷酸化不同的 Bub1 样蛋白 KKT14 来控制着色期到无色期的转变。KKT14的耗竭会推翻极光B抑制导致的无丝分裂期停滞,而不可磷酸化的KKT14的表达会延迟无丝分裂期的开始。最后,我们证明将 Aurora B 重新定向到外侧动点足以促进有丝分裂的退出,但在无丝分裂期会导致广泛的染色体错聚。我们的研究结果表明,极光 B 和 KKT14 参与了控制锥虫细胞周期进展的非常规电路。
{"title":"Aurora B controls anaphase onset and error-free chromosome segregation in trypanosomes.","authors":"Daniel Ballmer, Hua Jane Lou, Midori Ishii, Benjamin E Turk, Bungo Akiyoshi","doi":"10.1083/jcb.202401169","DOIUrl":"10.1083/jcb.202401169","url":null,"abstract":"<p><p>Kinetochores form the interface between chromosomes and spindle microtubules and are thus under tight control by a complex regulatory circuitry. The Aurora B kinase plays a central role within this circuitry by destabilizing improper kinetochore-microtubule attachments and relaying the attachment status to the spindle assembly checkpoint. Intriguingly, Aurora B is conserved even in kinetoplastids, a group of early-branching eukaryotes which possess a unique set of kinetochore proteins. It remains unclear how their kinetochores are regulated to ensure faithful chromosome segregation. Here, we show in Trypanosoma brucei that Aurora B activity controls the metaphase-to-anaphase transition through phosphorylation of the divergent Bub1-like protein KKT14. Depletion of KKT14 overrides the metaphase arrest resulting from Aurora B inhibition, while expression of non-phosphorylatable KKT14 delays anaphase onset. Finally, we demonstrate that re-targeting Aurora B to the outer kinetochore suffices to promote mitotic exit but causes extensive chromosome missegregation in anaphase. Our results indicate that Aurora B and KKT14 are involved in an unconventional circuitry controlling cell cycle progression in trypanosomes.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 11","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11354203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080364","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
Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity. 乳化作用可稳定 TFEB,从而提高自噬和溶酶体活性。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-28 DOI: 10.1083/jcb.202308099
Yewei Huang, Gan Luo, Kesong Peng, Yue Song, Yusha Wang, Hongtao Zhang, Jin Li, Xiangmin Qiu, Maomao Pu, Xinchang Liu, Chao Peng, Dante Neculai, Qiming Sun, Tianhua Zhou, Pintong Huang, Wei Liu

The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells.

转录因子 TFEB 是溶酶体生物发生和自噬的主要调节因子。越来越多的证据表明,翻译后修饰在调节 TFEB 活性方面发挥着至关重要的作用。在这里,我们发现乳酸分子可以对 TFEB 进行共价修饰,导致其乳化和稳定。从机理上讲,K91处的乳化可阻止TFEB与E3泛素连接酶WWP2相互作用,从而抑制TFEB的泛素化和蛋白酶体降解,导致TFEB活性和自噬通量增加。利用针对乳化 K91 的特异性抗体,在临床人类胰腺癌样本中观察到了增强的 TFEB 乳化作用。我们的研究结果表明,乳化是一种新型的 TFEB 调节模式,TFEB 的乳化可能与快速增殖细胞(如癌细胞)的高水平自噬有关。
{"title":"Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.","authors":"Yewei Huang, Gan Luo, Kesong Peng, Yue Song, Yusha Wang, Hongtao Zhang, Jin Li, Xiangmin Qiu, Maomao Pu, Xinchang Liu, Chao Peng, Dante Neculai, Qiming Sun, Tianhua Zhou, Pintong Huang, Wei Liu","doi":"10.1083/jcb.202308099","DOIUrl":"10.1083/jcb.202308099","url":null,"abstract":"<p><p>The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 11","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11354204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080365","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
Purinergic signaling through the P2Y2 receptor regulates osteocytes' mechanosensitivity. 通过 P2Y2 受体的嘌呤能信号调节骨细胞的机械敏感性
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-30 DOI: 10.1083/jcb.202403005
Amit Chougule, Chunbin Zhang, Nickolas Vinokurov, Devin Mendez, Elizabeth Vojtisek, Chenjun Shi, Jitao Zhang, Joseph Gardinier

Osteocytes' response to dynamic loading plays a crucial role in regulating the bone mass but quickly becomes saturated such that downstream induction of bone formation plateaus. The underlying mechanisms that downregulate osteocytes' sensitivity and overall response to loading remain unknown. In other cell types, purinergic signaling through the P2Y2 receptor has the potential to downregulate the sensitivity to loading by modifying cell stiffness through actin polymerization and cytoskeleton organization. Herein, we examined the role of P2Y2 activation in regulating osteocytes' mechanotransduction using a P2Y2 knockout cell line alongside conditional knockout mice. Our findings demonstrate that the absence of P2Y2 expression in MLO-Y4 cells prevents actin polymerization while increasing the sensitivity to fluid flow-induced shear stress. Deleting osteocytes' P2Y2 expression in conditional-knockout mice enabled bone formation to increase when increasing the duration of exercise. Overall, P2Y2 activation under loading produces a negative feedback loop, limiting osteocytes' response to continuous loading by shifting the sensitivity to mechanical strain through actin stress fiber formation.

成骨细胞对动态负荷的反应在调节骨量方面起着至关重要的作用,但很快就会饱和,从而使下游骨形成诱导作用趋于平稳。下调骨细胞对负荷的敏感性和整体反应的潜在机制仍不清楚。在其他细胞类型中,通过 P2Y2 受体发出的嘌呤能信号有可能通过肌动蛋白聚合和细胞骨架组织改变细胞硬度,从而下调对负荷的敏感性。在此,我们使用 P2Y2 基因敲除细胞系和条件性基因敲除小鼠研究了 P2Y2 激活在调节骨细胞机械传导中的作用。我们的研究结果表明,MLO-Y4 细胞中 P2Y2 表达的缺失会阻止肌动蛋白聚合,同时增加对流体流动诱导的剪切应力的敏感性。在条件性基因敲除小鼠中删除骨细胞的 P2Y2 表达,可使骨形成在延长运动时间时增加。总之,P2Y2 在负荷下激活会产生负反馈回路,通过肌动蛋白应力纤维的形成改变骨细胞对机械应变的敏感性,从而限制骨细胞对持续负荷的反应。
{"title":"Purinergic signaling through the P2Y2 receptor regulates osteocytes' mechanosensitivity.","authors":"Amit Chougule, Chunbin Zhang, Nickolas Vinokurov, Devin Mendez, Elizabeth Vojtisek, Chenjun Shi, Jitao Zhang, Joseph Gardinier","doi":"10.1083/jcb.202403005","DOIUrl":"10.1083/jcb.202403005","url":null,"abstract":"<p><p>Osteocytes' response to dynamic loading plays a crucial role in regulating the bone mass but quickly becomes saturated such that downstream induction of bone formation plateaus. The underlying mechanisms that downregulate osteocytes' sensitivity and overall response to loading remain unknown. In other cell types, purinergic signaling through the P2Y2 receptor has the potential to downregulate the sensitivity to loading by modifying cell stiffness through actin polymerization and cytoskeleton organization. Herein, we examined the role of P2Y2 activation in regulating osteocytes' mechanotransduction using a P2Y2 knockout cell line alongside conditional knockout mice. Our findings demonstrate that the absence of P2Y2 expression in MLO-Y4 cells prevents actin polymerization while increasing the sensitivity to fluid flow-induced shear stress. Deleting osteocytes' P2Y2 expression in conditional-knockout mice enabled bone formation to increase when increasing the duration of exercise. Overall, P2Y2 activation under loading produces a negative feedback loop, limiting osteocytes' response to continuous loading by shifting the sensitivity to mechanical strain through actin stress fiber formation.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 11","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107803","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
Histone H4 acetylation differentially modulates proliferation in adult oligodendrocyte progenitors. 组蛋白 H4 乙酰化对成年少突胶质细胞祖细胞的增殖有不同的调节作用。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-12 DOI: 10.1083/jcb.202308064
David K Dansu, Ipek Selcen, Sami Sauma, Emily Prentice, Dennis Huang, Meng Li, Sarah Moyon, Patrizia Casaccia

Adult oligodendrocyte progenitors (aOPCs) generate myelinating oligodendrocytes like neonatal progenitors (nOPCs), and they also display unique functional features. Here, using unbiased histone proteomics analysis and ChIP sequencing analysis of PDGFRα+ OPCs sorted from neonatal and adult Pdgfra-H2B-EGFP reporter mice, we identify the activating H4K8ac histone mark as enriched in the aOPCs. We detect increased occupancy of the H4K8ac activating mark at chromatin locations corresponding to genes related to the progenitor state (e.g., Hes5, Gpr17), metabolic processes (e.g., Txnip, Ptdgs), and myelin components (e.g., Cnp, Mog). aOPCs showed higher levels of transcripts related to lipid metabolism and myelin, and lower levels of transcripts related to cell cycle and proliferation compared with nOPCs. In addition, pharmacological inhibition of histone acetylation decreased the expression of the H4K8ac target genes in aOPCs and decreased their proliferation. Overall, this study identifies acetylation of the histone H4K8 as a regulator of the proliferative capacity of aOPCs.

成人少突胶质细胞祖细胞(aOPCs)会像新生儿祖细胞(nOPCs)一样生成髓鞘化少突胶质细胞,而且它们还显示出独特的功能特征。在这里,我们利用无偏组蛋白组学分析和 ChIP 测序分析从新生小鼠和成年 Pdgfra-H2B-EGFP 报告小鼠中分拣出的 PDGFRα+ OPCs,确定了活化 H4K8ac 组蛋白标记在 aOPCs 中的富集。我们在与祖细胞状态(如 Hes5、Gpr17)、代谢过程(如 Txnip、Ptdgs)和髓鞘成分(如 Cnp、Mog)相关的基因相对应的染色质位置检测到 H4K8ac 激活标记的占据增加。此外,药物抑制组蛋白乙酰化可降低 aOPCs 中 H4K8ac 靶基因的表达,并减少其增殖。总之,本研究发现组蛋白 H4K8 的乙酰化是 aOPCs 增殖能力的调节因子。
{"title":"Histone H4 acetylation differentially modulates proliferation in adult oligodendrocyte progenitors.","authors":"David K Dansu, Ipek Selcen, Sami Sauma, Emily Prentice, Dennis Huang, Meng Li, Sarah Moyon, Patrizia Casaccia","doi":"10.1083/jcb.202308064","DOIUrl":"10.1083/jcb.202308064","url":null,"abstract":"<p><p>Adult oligodendrocyte progenitors (aOPCs) generate myelinating oligodendrocytes like neonatal progenitors (nOPCs), and they also display unique functional features. Here, using unbiased histone proteomics analysis and ChIP sequencing analysis of PDGFRα+ OPCs sorted from neonatal and adult Pdgfra-H2B-EGFP reporter mice, we identify the activating H4K8ac histone mark as enriched in the aOPCs. We detect increased occupancy of the H4K8ac activating mark at chromatin locations corresponding to genes related to the progenitor state (e.g., Hes5, Gpr17), metabolic processes (e.g., Txnip, Ptdgs), and myelin components (e.g., Cnp, Mog). aOPCs showed higher levels of transcripts related to lipid metabolism and myelin, and lower levels of transcripts related to cell cycle and proliferation compared with nOPCs. In addition, pharmacological inhibition of histone acetylation decreased the expression of the H4K8ac target genes in aOPCs and decreased their proliferation. Overall, this study identifies acetylation of the histone H4K8 as a regulator of the proliferative capacity of aOPCs.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 11","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916810","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
Coordination of force-generating actin-based modules stabilizes and remodels membranes in vivo. 以肌动蛋白为基础的发力模块的协调可稳定和重塑体内膜。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-22 DOI: 10.1083/jcb.202401091
Marco Heydecker, Akiko Shitara, Desu Chen, Duy T Tran, Andrius Masedunskas, Muhibullah S Tora, Seham Ebrahim, Mark A Appaduray, Jorge Luis Galeano Niño, Abhishek Bhardwaj, Kedar Narayan, Edna C Hardeman, Peter W Gunning, Roberto Weigert

Membrane remodeling drives a broad spectrum of cellular functions, and it is regulated through mechanical forces exerted on the membrane by cytoplasmic complexes. Here, we investigate how actin filaments dynamically tune their structure to control the active transfer of membranes between cellular compartments with distinct compositions and biophysical properties. Using intravital subcellular microscopy in live rodents we show that a lattice composed of linear filaments stabilizes the granule membrane after fusion with the plasma membrane and a network of branched filaments linked to the membranes by Ezrin, a regulator of membrane tension, initiates and drives to completion the integration step. Our results highlight how the actin cytoskeleton tunes its structure to adapt to dynamic changes in the biophysical properties of membranes.

膜重塑驱动着广泛的细胞功能,它通过细胞质复合物对膜施加的机械力进行调节。在这里,我们研究了肌动蛋白丝如何动态调整其结构,以控制具有不同成分和生物物理特性的细胞成分之间膜的主动转移。通过在活体啮齿动物体内进行亚细胞内显微镜观察,我们发现由线性丝组成的晶格在颗粒膜与质膜融合后起到稳定作用,而由膜张力调节因子 Ezrin 连接到膜上的分支丝网络则启动并推动完成整合步骤。我们的研究结果突显了肌动蛋白细胞骨架如何调整其结构以适应膜的生物物理特性的动态变化。
{"title":"Coordination of force-generating actin-based modules stabilizes and remodels membranes in vivo.","authors":"Marco Heydecker, Akiko Shitara, Desu Chen, Duy T Tran, Andrius Masedunskas, Muhibullah S Tora, Seham Ebrahim, Mark A Appaduray, Jorge Luis Galeano Niño, Abhishek Bhardwaj, Kedar Narayan, Edna C Hardeman, Peter W Gunning, Roberto Weigert","doi":"10.1083/jcb.202401091","DOIUrl":"10.1083/jcb.202401091","url":null,"abstract":"<p><p>Membrane remodeling drives a broad spectrum of cellular functions, and it is regulated through mechanical forces exerted on the membrane by cytoplasmic complexes. Here, we investigate how actin filaments dynamically tune their structure to control the active transfer of membranes between cellular compartments with distinct compositions and biophysical properties. Using intravital subcellular microscopy in live rodents we show that a lattice composed of linear filaments stabilizes the granule membrane after fusion with the plasma membrane and a network of branched filaments linked to the membranes by Ezrin, a regulator of membrane tension, initiates and drives to completion the integration step. Our results highlight how the actin cytoskeleton tunes its structure to adapt to dynamic changes in the biophysical properties of membranes.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 11","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017579","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
Unbiased MD simulations identify lipid binding sites in lipid transfer proteins. 无偏差 MD 模拟确定脂质转移蛋白中的脂质结合位点。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-06 DOI: 10.1083/jcb.202312055
Sriraksha Srinivasan, Daniel Álvarez, Arun T John Peter, Stefano Vanni

The characterization of lipid binding to lipid transfer proteins (LTPs) is fundamental to understand their molecular mechanism. However, several structures of LTPs, and notably those proposed to act as bridges between membranes, do not provide the precise location of their endogenous lipid ligands. To address this limitation, computational approaches are a powerful alternative methodology, but they are often limited by the high flexibility of lipid substrates. Here, we develop a protocol based on unbiased coarse-grain molecular dynamics simulations in which lipids placed away from the protein can spontaneously bind to LTPs. This approach accurately determines binding pockets in LTPs and provides a working hypothesis for the lipid entry pathway. We apply this approach to characterize lipid binding to bridge LTPs of the Vps13-Atg2 family, for which the lipid localization inside the protein is currently unknown. Overall, our work paves the way to determine binding pockets and entry pathways for several LTPs in an inexpensive, fast, and accurate manner.

要了解脂质转移蛋白(LTPs)的分子机理,就必须确定其与脂质结合的特性。然而,一些 LTPs 的结构,尤其是那些被认为在膜之间起桥梁作用的 LTPs,并没有提供其内源性脂质配体的精确位置。为了解决这一限制,计算方法是一种强大的替代方法,但它们往往受到脂质底物高度灵活性的限制。在这里,我们开发了一种基于无偏粗粒度分子动力学模拟的方案,在这种模拟中,远离蛋白质的脂质可以自发地与 LTP 结合。这种方法能准确确定 LTPs 中的结合口袋,并为脂质进入途径提供一个工作假设。我们运用这种方法描述了脂质与 Vps13-Atg2 家族桥 LTPs 结合的特征,目前还不知道脂质在蛋白质内部的定位。总之,我们的工作为以廉价、快速和准确的方式确定几种 LTPs 的结合口袋和进入途径铺平了道路。
{"title":"Unbiased MD simulations identify lipid binding sites in lipid transfer proteins.","authors":"Sriraksha Srinivasan, Daniel Álvarez, Arun T John Peter, Stefano Vanni","doi":"10.1083/jcb.202312055","DOIUrl":"10.1083/jcb.202312055","url":null,"abstract":"<p><p>The characterization of lipid binding to lipid transfer proteins (LTPs) is fundamental to understand their molecular mechanism. However, several structures of LTPs, and notably those proposed to act as bridges between membranes, do not provide the precise location of their endogenous lipid ligands. To address this limitation, computational approaches are a powerful alternative methodology, but they are often limited by the high flexibility of lipid substrates. Here, we develop a protocol based on unbiased coarse-grain molecular dynamics simulations in which lipids placed away from the protein can spontaneously bind to LTPs. This approach accurately determines binding pockets in LTPs and provides a working hypothesis for the lipid entry pathway. We apply this approach to characterize lipid binding to bridge LTPs of the Vps13-Atg2 family, for which the lipid localization inside the protein is currently unknown. Overall, our work paves the way to determine binding pockets and entry pathways for several LTPs in an inexpensive, fast, and accurate manner.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 11","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893508","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
INPP4B promotes PDAC aggressiveness via PIKfyve and TRPML-1-mediated lysosomal exocytosis. INPP4B通过PIKfyve和TRPML-1介导的溶酶体外渗促进PDAC的侵袭性。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-09 DOI: 10.1083/jcb.202401012
Golam T Saffi, Lydia To, Nicholas Kleine, Ché M P Melo, Keyue Chen, Gizem Genc, K C Daniel Lee, Jonathan Tak-Sum Chow, Gun Ho Jang, Steven Gallinger, Roberto J Botelho, Leonardo Salmena

Aggressive solid malignancies, including pancreatic ductal adenocarcinoma (PDAC), can exploit lysosomal exocytosis to modify the tumor microenvironment, enhance motility, and promote invasiveness. However, the molecular pathways through which lysosomal functions are co-opted in malignant cells remain poorly understood. In this study, we demonstrate that inositol polyphosphate 4-phosphatase, Type II (INPP4B) overexpression in PDAC is associated with PDAC progression. We show that INPP4B overexpression promotes peripheral dispersion and exocytosis of lysosomes resulting in increased migratory and invasive potential of PDAC cells. Mechanistically, INPP4B overexpression drives the generation of PtdIns(3,5)P2 on lysosomes in a PIKfyve-dependent manner, which directs TRPML-1 to trigger the release of calcium ions (Ca2+). Our findings offer a molecular understanding of the prognostic significance of INPP4B overexpression in PDAC through the discovery of a novel oncogenic signaling axis that orchestrates migratory and invasive properties of PDAC via the regulation of lysosomal phosphoinositide homeostasis.

包括胰腺导管腺癌(PDAC)在内的侵袭性实体恶性肿瘤可利用溶酶体外泌来改变肿瘤微环境、增强运动性和促进侵袭性。然而,人们对溶酶体功能在恶性细胞中的分子途径仍然知之甚少。在这项研究中,我们证明了肌醇多磷酸4-磷酸酶II型(INPP4B)在PDAC中的过表达与PDAC的进展有关。我们发现,INPP4B 的过表达会促进溶酶体的外周弥散和外排,从而导致 PDAC 细胞的迁移和侵袭潜力增加。从机理上讲,INPP4B 过表达以 PIKfyve 依赖性方式驱动溶酶体上 PtdIns(3,5)P2 的生成,从而引导 TRPML-1 触发钙离子(Ca2+)的释放。我们的研究发现了一个新的致癌信号轴,它通过调节溶酶体磷酸肌醇的平衡来协调 PDAC 的迁移和侵袭特性,从而从分子角度理解了 INPP4B 过表达在 PDAC 中的预后意义。
{"title":"INPP4B promotes PDAC aggressiveness via PIKfyve and TRPML-1-mediated lysosomal exocytosis.","authors":"Golam T Saffi, Lydia To, Nicholas Kleine, Ché M P Melo, Keyue Chen, Gizem Genc, K C Daniel Lee, Jonathan Tak-Sum Chow, Gun Ho Jang, Steven Gallinger, Roberto J Botelho, Leonardo Salmena","doi":"10.1083/jcb.202401012","DOIUrl":"10.1083/jcb.202401012","url":null,"abstract":"<p><p>Aggressive solid malignancies, including pancreatic ductal adenocarcinoma (PDAC), can exploit lysosomal exocytosis to modify the tumor microenvironment, enhance motility, and promote invasiveness. However, the molecular pathways through which lysosomal functions are co-opted in malignant cells remain poorly understood. In this study, we demonstrate that inositol polyphosphate 4-phosphatase, Type II (INPP4B) overexpression in PDAC is associated with PDAC progression. We show that INPP4B overexpression promotes peripheral dispersion and exocytosis of lysosomes resulting in increased migratory and invasive potential of PDAC cells. Mechanistically, INPP4B overexpression drives the generation of PtdIns(3,5)P2 on lysosomes in a PIKfyve-dependent manner, which directs TRPML-1 to trigger the release of calcium ions (Ca2+). Our findings offer a molecular understanding of the prognostic significance of INPP4B overexpression in PDAC through the discovery of a novel oncogenic signaling axis that orchestrates migratory and invasive properties of PDAC via the regulation of lysosomal phosphoinositide homeostasis.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 11","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11317760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906711","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
Near millimolar concentration of nucleosomes in mitotic chromosomes from late prometaphase into anaphase. 从有丝分裂后期到无丝分裂期,有丝分裂染色体中的核小体浓度接近毫摩尔。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-26 DOI: 10.1083/jcb.202403165
Fernanda Cisneros-Soberanis, Eva L Simpson, Alison J Beckett, Nina Pucekova, Samuel Corless, Natalia Y Kochanova, Ian A Prior, Daniel G Booth, William C Earnshaw

Chromosome compaction is a key feature of mitosis and critical for accurate chromosome segregation. However, a precise quantitative analysis of chromosome geometry during mitotic progression is lacking. Here, we use volume electron microscopy to map, with nanometer precision, chromosomes from prometaphase through telophase in human RPE1 cells. During prometaphase, chromosomes acquire a smoother surface, their arms shorten, and the primary centromeric constriction is formed. The chromatin is progressively compacted, ultimately reaching a remarkable nucleosome concentration of over 750 µM in late prometaphase that remains relatively constant during metaphase and early anaphase. Surprisingly, chromosomes then increase their volume in late anaphase prior to deposition of the nuclear envelope. The plateau of total chromosome volume from late prometaphase through early anaphase described here is consistent with proposals that the final stages of chromatin condensation in mitosis involve a limit density, such as might be expected for a process involving phase separation.

染色体压实是有丝分裂的一个关键特征,也是染色体准确分离的关键。然而,目前还缺乏对有丝分裂过程中染色体几何形状的精确定量分析。在这里,我们使用体电子显微镜以纳米级精度绘制了人类 RPE1 细胞从有丝分裂后期到端期的染色体图谱。在端粒期,染色体表面变得更加光滑,染色体臂缩短,并形成初级中心粒收缩。染色质逐渐压缩,最终在原核后期达到超过 750 µM 的显著核小体浓度,并在分裂后期和无核初期保持相对稳定。令人惊讶的是,染色体在核包膜沉积之前的无丝分裂后期体积会增大。这里描述的染色体总体积从有丝分裂后期到无丝分裂初期的高原现象,与有丝分裂中染色质凝聚的最后阶段涉及极限密度的建议是一致的,如涉及相分离的过程所预期的那样。
{"title":"Near millimolar concentration of nucleosomes in mitotic chromosomes from late prometaphase into anaphase.","authors":"Fernanda Cisneros-Soberanis, Eva L Simpson, Alison J Beckett, Nina Pucekova, Samuel Corless, Natalia Y Kochanova, Ian A Prior, Daniel G Booth, William C Earnshaw","doi":"10.1083/jcb.202403165","DOIUrl":"10.1083/jcb.202403165","url":null,"abstract":"<p><p>Chromosome compaction is a key feature of mitosis and critical for accurate chromosome segregation. However, a precise quantitative analysis of chromosome geometry during mitotic progression is lacking. Here, we use volume electron microscopy to map, with nanometer precision, chromosomes from prometaphase through telophase in human RPE1 cells. During prometaphase, chromosomes acquire a smoother surface, their arms shorten, and the primary centromeric constriction is formed. The chromatin is progressively compacted, ultimately reaching a remarkable nucleosome concentration of over 750 µM in late prometaphase that remains relatively constant during metaphase and early anaphase. Surprisingly, chromosomes then increase their volume in late anaphase prior to deposition of the nuclear envelope. The plateau of total chromosome volume from late prometaphase through early anaphase described here is consistent with proposals that the final stages of chromatin condensation in mitosis involve a limit density, such as might be expected for a process involving phase separation.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":"223 11","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055694","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