首页 > 最新文献

Journal of Cell Biology最新文献

英文 中文
Migrasomes: Biogenesis, physiological roles, and therapeutic potentials. 移行体:生物生成、生理作用和治疗潜力。
IF 7.8 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-14 DOI: 10.1083/jcb.202403051
Haifeng Jiao,Li Yu
Migrasomes, vesicular structures discovered in migrating cells, arise from the junctions or tips of retraction fibers, and gradually grow to microscale vesicles. Migrasomes have garnered attention for their role in intercellular communication and potential therapeutic implications. This review presents an overview of recent advances in migrasome biology, covering the mechanisms of migrasome biogenesis, essential physiological roles, and their association with various diseases, alongside potential therapeutic applications. Furthermore, we share our perspectives on potential future directions in the study of migrasomes and highlight the challenges that remain in this developing area of research.
迁移体(Migrasomes)是在迁移细胞中发现的囊泡结构,它产生于牵引纤维的连接处或顶端,并逐渐成长为微型囊泡。移行体因其在细胞间通信中的作用和潜在的治疗意义而备受关注。本综述概述了移行体生物学的最新进展,涵盖了移行体的生物生成机制、基本生理作用、与各种疾病的关联以及潜在的治疗应用。此外,我们还分享了我们对移行体研究未来潜在方向的看法,并强调了这一不断发展的研究领域所面临的挑战。
{"title":"Migrasomes: Biogenesis, physiological roles, and therapeutic potentials.","authors":"Haifeng Jiao,Li Yu","doi":"10.1083/jcb.202403051","DOIUrl":"https://doi.org/10.1083/jcb.202403051","url":null,"abstract":"Migrasomes, vesicular structures discovered in migrating cells, arise from the junctions or tips of retraction fibers, and gradually grow to microscale vesicles. Migrasomes have garnered attention for their role in intercellular communication and potential therapeutic implications. This review presents an overview of recent advances in migrasome biology, covering the mechanisms of migrasome biogenesis, essential physiological roles, and their association with various diseases, alongside potential therapeutic applications. Furthermore, we share our perspectives on potential future directions in the study of migrasomes and highlight the challenges that remain in this developing area of research.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fluorescence lifetime sorting reveals tunable enzyme interactions within cytoplasmic condensates. 荧光寿命分选揭示了细胞质凝聚体内可调的酶相互作用。
IF 7.8 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-14 DOI: 10.1083/jcb.202311105
Leyla E Fahim,Joshua M Marcus,Noah D Powell,Zachary A Ralston,Katherine Walgamotte,Eleonora Perego,Giuseppe Vicidomini,Alessandro Rossetta,Jason E Lee
Ribonucleoprotein (RNP) condensates partition RNA and protein into multiple liquid phases. The multiphasic feature of condensate-enriched components creates experimental challenges for distinguishing membraneless condensate functions from the surrounding dilute phase. We combined fluorescence lifetime imaging microscopy (FLIM) with phasor plot filtering and segmentation to resolve condensates from the dilute phase. Condensate-specific lifetimes were used to track protein-protein interactions by measuring FLIM-Förster resonance energy transfer (FRET). We used condensate FLIM-FRET to evaluate whether mRNA decapping complex subunits can form decapping-competent interactions within P-bodies. Condensate FLIM-FRET revealed the presence of core subunit interactions within P-bodies under basal conditions and the disruption of interactions between the decapping enzyme (Dcp2) and a critical cofactor (Dcp1A) during oxidative stress. Our results show a context-dependent plasticity of the P-body interaction network, which can be rewired within minutes in response to stimuli. Together, our FLIM-based approaches provide investigators with an automated and rigorous method to uncover and track essential protein-protein interaction dynamics within RNP condensates in live cells.
核糖核蛋白(RNP)凝聚体将 RNA 和蛋白质分隔成多个液相。冷凝物富集成分的多相特征给区分无膜冷凝物功能和周围稀释相带来了实验挑战。我们将荧光寿命成像显微镜(FLIM)与相位图过滤和分割相结合,从稀释相中分辨出冷凝物。通过测量 FLIM-Förster 共振能量转移 (FRET),凝集物的特异性寿命被用于跟踪蛋白质与蛋白质之间的相互作用。我们利用凝集物 FLIM-FRET 来评估 mRNA 解旋复合物亚基是否能在 P 体内形成解旋作用。冷凝物 FLIM-FRET 揭示了在基础条件下 P 体内存在的核心亚基相互作用,以及在氧化应激过程中解旋酶(Dcp2)与关键辅助因子(Dcp1A)之间相互作用的破坏。我们的研究结果表明,P-body 相互作用网络具有上下文相关的可塑性,它可以在几分钟内根据刺激重新布线。总之,我们基于 FLIM 的方法为研究人员提供了一种自动化的严谨方法,用于发现和跟踪活细胞中 RNP 凝聚物内重要的蛋白质-蛋白质相互作用动态。
{"title":"Fluorescence lifetime sorting reveals tunable enzyme interactions within cytoplasmic condensates.","authors":"Leyla E Fahim,Joshua M Marcus,Noah D Powell,Zachary A Ralston,Katherine Walgamotte,Eleonora Perego,Giuseppe Vicidomini,Alessandro Rossetta,Jason E Lee","doi":"10.1083/jcb.202311105","DOIUrl":"https://doi.org/10.1083/jcb.202311105","url":null,"abstract":"Ribonucleoprotein (RNP) condensates partition RNA and protein into multiple liquid phases. The multiphasic feature of condensate-enriched components creates experimental challenges for distinguishing membraneless condensate functions from the surrounding dilute phase. We combined fluorescence lifetime imaging microscopy (FLIM) with phasor plot filtering and segmentation to resolve condensates from the dilute phase. Condensate-specific lifetimes were used to track protein-protein interactions by measuring FLIM-Förster resonance energy transfer (FRET). We used condensate FLIM-FRET to evaluate whether mRNA decapping complex subunits can form decapping-competent interactions within P-bodies. Condensate FLIM-FRET revealed the presence of core subunit interactions within P-bodies under basal conditions and the disruption of interactions between the decapping enzyme (Dcp2) and a critical cofactor (Dcp1A) during oxidative stress. Our results show a context-dependent plasticity of the P-body interaction network, which can be rewired within minutes in response to stimuli. Together, our FLIM-based approaches provide investigators with an automated and rigorous method to uncover and track essential protein-protein interaction dynamics within RNP condensates in live cells.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
StableMARK-decorated microtubules in cells have expanded lattices. 细胞中经 StableMARK 装饰的微管具有扩展的晶格。
IF 7.8 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-10 DOI: 10.1083/jcb.202206143
Leanne de Jager,Klara I Jansen,Robin Hoogebeen,Anna Akhmanova,Lukas C Kapitein,Friedrich Förster,Stuart C Howes
Microtubules are crucial in cells and are regulated by various mechanisms like posttranslational modifications, microtubule-associated proteins, and tubulin isoforms. Recently, the conformation of the microtubule lattice has also emerged as a potential regulatory factor, but it has remained unclear to what extent different lattices co-exist within the cell. Using cryo-electron tomography, we find that, while most microtubules have a compacted lattice (∼41 Å monomer spacing), approximately a quarter of the microtubules displayed more expanded lattice spacings. The addition of the microtubule-stabilizing agent Taxol increased the lattice spacing of all microtubules, consistent with results on reconstituted microtubules. Furthermore, correlative cryo-light and electron microscopy revealed that the stable subset of microtubules labeled by StableMARK, a marker for stable microtubules, predominantly displayed a more expanded lattice spacing (∼41.9 Å), further suggesting a close connection between lattice expansion and microtubule stability. The coexistence of different lattices and their correlation with stability implicate lattice spacing as an important factor in establishing specific microtubule subsets.
微管在细胞中至关重要,并受到翻译后修饰、微管相关蛋白和微管蛋白异构体等各种机制的调控。最近,微管晶格的构象也成为一个潜在的调控因素,但目前仍不清楚细胞内不同晶格共存的程度。利用低温电子断层扫描技术,我们发现虽然大多数微管具有紧凑的晶格(单体间距∼41 Å),但大约四分之一的微管显示出更大的晶格间距。加入微管稳定剂紫杉醇后,所有微管的晶格间距都有所增加,这与重组微管的结果一致。此外,相关的冷冻光镜和电子显微镜显示,用稳定微管标记物 StableMARK 标记的稳定微管亚群主要显示出更大的晶格间距(∼41.9 Å),这进一步表明晶格扩张与微管稳定性之间存在密切联系。不同晶格的共存及其与稳定性的相关性表明,晶格间距是建立特定微管亚集的一个重要因素。
{"title":"StableMARK-decorated microtubules in cells have expanded lattices.","authors":"Leanne de Jager,Klara I Jansen,Robin Hoogebeen,Anna Akhmanova,Lukas C Kapitein,Friedrich Förster,Stuart C Howes","doi":"10.1083/jcb.202206143","DOIUrl":"https://doi.org/10.1083/jcb.202206143","url":null,"abstract":"Microtubules are crucial in cells and are regulated by various mechanisms like posttranslational modifications, microtubule-associated proteins, and tubulin isoforms. Recently, the conformation of the microtubule lattice has also emerged as a potential regulatory factor, but it has remained unclear to what extent different lattices co-exist within the cell. Using cryo-electron tomography, we find that, while most microtubules have a compacted lattice (∼41 Å monomer spacing), approximately a quarter of the microtubules displayed more expanded lattice spacings. The addition of the microtubule-stabilizing agent Taxol increased the lattice spacing of all microtubules, consistent with results on reconstituted microtubules. Furthermore, correlative cryo-light and electron microscopy revealed that the stable subset of microtubules labeled by StableMARK, a marker for stable microtubules, predominantly displayed a more expanded lattice spacing (∼41.9 Å), further suggesting a close connection between lattice expansion and microtubule stability. The coexistence of different lattices and their correlation with stability implicate lattice spacing as an important factor in establishing specific microtubule subsets.","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
T cells use focal adhesions to pull themselves through confined environments. T 细胞利用病灶粘附力使自己穿过封闭的环境。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-06-18 DOI: 10.1083/jcb.202310067
Alexia Caillier, David Oleksyn, Deborah J Fowell, Jim Miller, Patrick W Oakes

Immune cells are highly dynamic and able to migrate through environments with diverse biochemical and mechanical compositions. Their migration has classically been defined as amoeboid under the assumption that it is integrin independent. Here, we show that activated primary Th1 T cells require both confinement and extracellular matrix proteins to migrate efficiently. This migration is mediated through small and dynamic focal adhesions that are composed of the same proteins associated with canonical mesenchymal cell focal adhesions, such as integrins, talin, and vinculin. These focal adhesions, furthermore, localize to sites of contractile traction stresses, enabling T cells to pull themselves through confined spaces. Finally, we show that Th1 T cells preferentially follow tracks of other T cells, suggesting that these adhesions modify the extracellular matrix to provide additional environmental guidance cues. These results demonstrate not only that the boundaries between amoeboid and mesenchymal migration modes are ambiguous, but that integrin-mediated focal adhesions play a key role in T cell motility.

免疫细胞具有高度动态性,能够在具有不同生化和机械成分的环境中迁移。根据独立于整合素的假设,它们的迁移通常被定义为非膜性迁移。在这里,我们发现活化的原发性 Th1 T 细胞需要封闭和细胞外基质蛋白才能有效迁移。这种迁移是通过小而动态的局灶粘附介导的,局灶粘附由与典型间充质细胞局灶粘附相关的相同蛋白组成,如整合素、塔林和长链蛋白。此外,这些局灶粘附还定位在收缩牵引应力的部位,使 T 细胞能将自己拉过狭窄的空间。最后,我们发现 Th1 T 细胞会优先追随其他 T 细胞的轨迹,这表明这些粘附改变了细胞外基质,从而提供了额外的环境引导线索。这些结果不仅证明了非变形和间质迁移模式之间的界限模糊不清,而且证明了整合素介导的局灶粘附在 T 细胞运动中起着关键作用。
{"title":"T cells use focal adhesions to pull themselves through confined environments.","authors":"Alexia Caillier, David Oleksyn, Deborah J Fowell, Jim Miller, Patrick W Oakes","doi":"10.1083/jcb.202310067","DOIUrl":"10.1083/jcb.202310067","url":null,"abstract":"<p><p>Immune cells are highly dynamic and able to migrate through environments with diverse biochemical and mechanical compositions. Their migration has classically been defined as amoeboid under the assumption that it is integrin independent. Here, we show that activated primary Th1 T cells require both confinement and extracellular matrix proteins to migrate efficiently. This migration is mediated through small and dynamic focal adhesions that are composed of the same proteins associated with canonical mesenchymal cell focal adhesions, such as integrins, talin, and vinculin. These focal adhesions, furthermore, localize to sites of contractile traction stresses, enabling T cells to pull themselves through confined spaces. Finally, we show that Th1 T cells preferentially follow tracks of other T cells, suggesting that these adhesions modify the extracellular matrix to provide additional environmental guidance cues. These results demonstrate not only that the boundaries between amoeboid and mesenchymal migration modes are ambiguous, but that integrin-mediated focal adhesions play a key role in T cell motility.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11187980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419273","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
Calorie restriction activates a gastric Notch-FOXO1 pathway to expand ghrelin cells. 卡路里限制会激活胃 Notch-FOXO1 通路,从而扩大胃泌素细胞。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-07-03 DOI: 10.1083/jcb.202305093
Wendy M McKimpson, Sophia Spiegel, Maria Mukhanova, Michael Kraakman, Wen Du, Takumi Kitamoto, Junjie Yu, Zhaobin Deng, Utpal Pajvani, Domenico Accili

Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF-03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation.

限制卡路里摄入会延长寿命。在卡路里限制对特定组织的保护作用中,对胃肠道的影响仍不清楚。我们报告了限制卡路里摄入的小鼠胃中嗜铬粒蛋白 A 阳性(+)细胞数量的增加,其中包括嗜食性胃泌素+细胞。这种效应伴随着Notch靶标Hes1和Notch配体Jag1的增加,并通过使用γ-分泌酶抑制剂DAPT阻断Notch而逆转。原代培养物和转基因报告小鼠表明,内分泌细胞数量的增加是由于Lgr5+干细胞和Neurog3+内分泌祖细胞增殖的改变。与肠道不同的是,卡路里限制减少了胃Lgr5+干细胞,而内分泌祖细胞的FOXO1/Neurog3+亚群则以Notch依赖性方式增加。此外,FOXO1的激活足以促进独立于Notch的内分泌细胞分化。Notch抑制剂PF-03084014或胃泌素受体拮抗剂GHRP-6可逆转小鼠热量限制的表型效应。替扎帕肽还能扩大小鼠的胃泌素+细胞。总之,卡路里限制促进了Notch依赖性、FOXO1调控的胃内分泌细胞分化。
{"title":"Calorie restriction activates a gastric Notch-FOXO1 pathway to expand ghrelin cells.","authors":"Wendy M McKimpson, Sophia Spiegel, Maria Mukhanova, Michael Kraakman, Wen Du, Takumi Kitamoto, Junjie Yu, Zhaobin Deng, Utpal Pajvani, Domenico Accili","doi":"10.1083/jcb.202305093","DOIUrl":"10.1083/jcb.202305093","url":null,"abstract":"<p><p>Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF-03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11222742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492064","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
UBAP2L contributes to formation of P-bodies and modulates their association with stress granules. UBAP2L 有助于 P 型体的形成,并能调节它们与应激颗粒的结合。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-07-15 DOI: 10.1083/jcb.202307146
Claire L Riggs, Nancy Kedersha, Misheel Amarsanaa, Safiyah Noor Zubair, Pavel Ivanov, Paul Anderson

Stress triggers the formation of two distinct cytoplasmic biomolecular condensates: stress granules (SGs) and processing bodies (PBs), both of which may contribute to stress-responsive translation regulation. Though PBs can be present constitutively, stress can increase their number and size and lead to their interaction with stress-induced SGs. The mechanism of such interaction, however, is largely unknown. Formation of canonical SGs requires the RNA binding protein Ubiquitin-Associated Protein 2-Like (UBAP2L), which is a central SG node protein in the RNA-protein interaction network of SGs and PBs. UBAP2L binds to the essential SG and PB proteins G3BP and DDX6, respectively. Research on UBAP2L has mostly focused on its role in SGs, but not its connection to PBs. We find that UBAP2L is not solely an SG protein but also localizes to PBs in certain conditions, contributes to PB biogenesis and SG-PB interactions, and can nucleate hybrid granules containing SG and PB components in cells. These findings inform a new model for SG and PB formation in the context of UBAP2L's role.

应激会引发两种不同的细胞质生物分子凝聚体的形成:应激颗粒(SGs)和加工体(PBs),它们都可能有助于应激反应翻译调控。虽然 PBs 可组成性存在,但应激可增加它们的数量和大小,并导致它们与应激诱导的 SGs 相互作用。然而,这种相互作用的机制在很大程度上还不清楚。典型 SG 的形成需要 RNA 结合蛋白类泛素相关蛋白 2(Ubiquitin-Associated Protein 2-Like,UBAP2L),它是 SG 与 PB 的 RNA 蛋白相互作用网络中的核心节点蛋白。UBAP2L 分别与重要的 SG 和 PB 蛋白 G3BP 和 DDX6 结合。对 UBAP2L 的研究主要集中在它在 SG 中的作用,而没有关注它与 PB 的联系。我们发现,UBAP2L 不仅仅是一种 SG 蛋白,在某些条件下还会定位到 PB,促进 PB 的生物生成和 SG-PB 的相互作用,并能在细胞中核化含有 SG 和 PB 成分的混合颗粒。这些发现为 UBAP2L 的作用背景下 SG 和 PB 的形成提供了一个新模型。
{"title":"UBAP2L contributes to formation of P-bodies and modulates their association with stress granules.","authors":"Claire L Riggs, Nancy Kedersha, Misheel Amarsanaa, Safiyah Noor Zubair, Pavel Ivanov, Paul Anderson","doi":"10.1083/jcb.202307146","DOIUrl":"10.1083/jcb.202307146","url":null,"abstract":"<p><p>Stress triggers the formation of two distinct cytoplasmic biomolecular condensates: stress granules (SGs) and processing bodies (PBs), both of which may contribute to stress-responsive translation regulation. Though PBs can be present constitutively, stress can increase their number and size and lead to their interaction with stress-induced SGs. The mechanism of such interaction, however, is largely unknown. Formation of canonical SGs requires the RNA binding protein Ubiquitin-Associated Protein 2-Like (UBAP2L), which is a central SG node protein in the RNA-protein interaction network of SGs and PBs. UBAP2L binds to the essential SG and PB proteins G3BP and DDX6, respectively. Research on UBAP2L has mostly focused on its role in SGs, but not its connection to PBs. We find that UBAP2L is not solely an SG protein but also localizes to PBs in certain conditions, contributes to PB biogenesis and SG-PB interactions, and can nucleate hybrid granules containing SG and PB components in cells. These findings inform a new model for SG and PB formation in the context of UBAP2L's role.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11248227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616524","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
A force-sensitive mutation reveals a non-canonical role for dynein in anaphase progression. 力敏感突变揭示了dynein在无丝分裂进程中的非典型作用。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-07-01 DOI: 10.1083/jcb.202310022
David Salvador-Garcia, Li Jin, Andrew Hensley, Mert Gölcük, Emmanuel Gallaud, Sami Chaaban, Fillip Port, Alessio Vagnoni, Vicente José Planelles-Herrero, Mark A McClintock, Emmanuel Derivery, Andrew P Carter, Régis Giet, Mert Gür, Ahmet Yildiz, Simon L Bullock

The diverse roles of the dynein motor in shaping microtubule networks and cargo transport complicate in vivo analysis of its functions significantly. To address this issue, we have generated a series of missense mutations in Drosophila Dynein heavy chain. We show that mutations associated with human neurological disease cause a range of defects, including impaired cargo trafficking in neurons. We also describe a novel microtubule-binding domain mutation that specifically blocks the metaphase-anaphase transition during mitosis in the embryo. This effect is independent from dynein's canonical role in silencing the spindle assembly checkpoint. Optical trapping of purified dynein complexes reveals that this mutation only compromises motor performance under load, a finding rationalized by the results of all-atom molecular dynamics simulations. We propose that dynein has a novel function in anaphase progression that depends on it operating in a specific load regime. More broadly, our work illustrates how in vivo functions of motors can be dissected by manipulating their mechanical properties.

肌球蛋白马达在塑造微管网络和货物运输方面的作用多种多样,这使得对其功能的体内分析变得非常复杂。为了解决这个问题,我们在果蝇Dynein重链中产生了一系列错义突变。我们发现,与人类神经系统疾病相关的突变会导致一系列缺陷,包括神经元中的货物运输受损。我们还描述了一种新型微管结合域突变,它能特异性地阻断胚胎有丝分裂过程中的移行期-无丝分裂期转变。这种效应与动力蛋白在沉默纺锤体组装检查点中的典型作用无关。对纯化的动力蛋白复合物进行的光学捕获显示,这种突变只在负载条件下影响电机性能,全原子分子动力学模拟的结果也证明了这一发现的合理性。我们提出,dynein 在无丝分裂进程中具有一种新的功能,这种功能取决于它在特定的负载条件下运行。更广泛地说,我们的工作说明了如何通过操纵电机的机械特性来剖析其体内功能。
{"title":"A force-sensitive mutation reveals a non-canonical role for dynein in anaphase progression.","authors":"David Salvador-Garcia, Li Jin, Andrew Hensley, Mert Gölcük, Emmanuel Gallaud, Sami Chaaban, Fillip Port, Alessio Vagnoni, Vicente José Planelles-Herrero, Mark A McClintock, Emmanuel Derivery, Andrew P Carter, Régis Giet, Mert Gür, Ahmet Yildiz, Simon L Bullock","doi":"10.1083/jcb.202310022","DOIUrl":"10.1083/jcb.202310022","url":null,"abstract":"<p><p>The diverse roles of the dynein motor in shaping microtubule networks and cargo transport complicate in vivo analysis of its functions significantly. To address this issue, we have generated a series of missense mutations in Drosophila Dynein heavy chain. We show that mutations associated with human neurological disease cause a range of defects, including impaired cargo trafficking in neurons. We also describe a novel microtubule-binding domain mutation that specifically blocks the metaphase-anaphase transition during mitosis in the embryo. This effect is independent from dynein's canonical role in silencing the spindle assembly checkpoint. Optical trapping of purified dynein complexes reveals that this mutation only compromises motor performance under load, a finding rationalized by the results of all-atom molecular dynamics simulations. We propose that dynein has a novel function in anaphase progression that depends on it operating in a specific load regime. More broadly, our work illustrates how in vivo functions of motors can be dissected by manipulating their mechanical properties.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468236","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
Dynamic interaction of REEP5-MFN1/2 enables mitochondrial hitchhiking on tubular ER. REEP5-MFN1/2 的动态相互作用使线粒体能够在管状 ER 上搭便车。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-08-12 DOI: 10.1083/jcb.202304031
Shue Chen, Yang Sun, Yuling Qin, Lan Yang, Zhenhua Hao, Zhihao Xu, Mikael Björklund, Wei Liu, Zhi Hong

Mitochondrial functions can be regulated by membrane contact sites with the endoplasmic reticulum (ER). These mitochondria-ER contact sites (MERCs) are functionally heterogeneous and maintained by various tethers. Here, we found that REEP5, an ER tubule-shaping protein, interacts with Mitofusins 1/2 to mediate mitochondrial distribution throughout the cytosol by a new transport mechanism, mitochondrial "hitchhiking" with tubular ER on microtubules. REEP5 depletion led to reduced tethering and increased perinuclear localization of mitochondria. Conversely, increasing REEP5 expression facilitated mitochondrial distribution throughout the cytoplasm. Rapamycin-induced irreversible REEP5-MFN1/2 interaction led to mitochondrial hyperfusion, implying that the dynamic release of mitochondria from tethering is necessary for normal mitochondrial distribution and dynamics. Functionally, disruption of MFN2-REEP5 interaction dynamics by forced dimerization or silencing REEP5 modulated the production of mitochondrial reactive oxygen species (ROS). Overall, our results indicate that dynamic REEP5-MFN1/2 interaction mediates cytosolic distribution and connectivity of the mitochondrial network by "hitchhiking" and this process regulates mitochondrial ROS, which is vital for multiple physiological functions.

线粒体的功能可以通过与内质网(ER)的膜接触点来调节。这些线粒体-ER接触位点(MERCs)在功能上是异质的,由不同的系链维持。在这里,我们发现ER小管塑形蛋白REEP5与Mitofusins 1/2相互作用,通过一种新的运输机制--线粒体在微管上与管状ER "搭便车"--介导线粒体在整个细胞质中的分布。耗尽 REEP5 会导致线粒体的系链减少和核周定位增加。相反,增加 REEP5 的表达则有利于线粒体在整个细胞质中的分布。雷帕霉素诱导的 REEP5-MFN1/2 不可逆相互作用导致线粒体过度融合,这意味着线粒体从系链中动态释放是线粒体正常分布和动态变化的必要条件。从功能上讲,通过强迫二聚化或沉默 REEP5 来破坏 MFN2-REEP5相互作用的动态,可调节线粒体活性氧(ROS)的产生。总之,我们的研究结果表明,REEP5-MFN1/2的动态相互作用通过 "搭便车 "介导线粒体网络的胞浆分布和连接,这一过程调节线粒体ROS,而ROS对多种生理功能至关重要。
{"title":"Dynamic interaction of REEP5-MFN1/2 enables mitochondrial hitchhiking on tubular ER.","authors":"Shue Chen, Yang Sun, Yuling Qin, Lan Yang, Zhenhua Hao, Zhihao Xu, Mikael Björklund, Wei Liu, Zhi Hong","doi":"10.1083/jcb.202304031","DOIUrl":"10.1083/jcb.202304031","url":null,"abstract":"<p><p>Mitochondrial functions can be regulated by membrane contact sites with the endoplasmic reticulum (ER). These mitochondria-ER contact sites (MERCs) are functionally heterogeneous and maintained by various tethers. Here, we found that REEP5, an ER tubule-shaping protein, interacts with Mitofusins 1/2 to mediate mitochondrial distribution throughout the cytosol by a new transport mechanism, mitochondrial \"hitchhiking\" with tubular ER on microtubules. REEP5 depletion led to reduced tethering and increased perinuclear localization of mitochondria. Conversely, increasing REEP5 expression facilitated mitochondrial distribution throughout the cytoplasm. Rapamycin-induced irreversible REEP5-MFN1/2 interaction led to mitochondrial hyperfusion, implying that the dynamic release of mitochondria from tethering is necessary for normal mitochondrial distribution and dynamics. Functionally, disruption of MFN2-REEP5 interaction dynamics by forced dimerization or silencing REEP5 modulated the production of mitochondrial reactive oxygen species (ROS). Overall, our results indicate that dynamic REEP5-MFN1/2 interaction mediates cytosolic distribution and connectivity of the mitochondrial network by \"hitchhiking\" and this process regulates mitochondrial ROS, which is vital for multiple physiological functions.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11318672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916809","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
De novo lipid synthesis and polarized prenylation drive cell invasion through basement membrane. 新的脂质合成和极化的前酰化推动细胞侵入基底膜。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-07-15 DOI: 10.1083/jcb.202402035
Kieop Park, Aastha Garde, Siddharthan B Thendral, Adam W J Soh, Qiuyi Chi, David R Sherwood

To breach the basement membrane, cells in development and cancer use large, transient, specialized lipid-rich membrane protrusions. Using live imaging, endogenous protein tagging, and cell-specific RNAi during Caenorhabditis elegans anchor cell (AC) invasion, we demonstrate that the lipogenic SREBP transcription factor SBP-1 drives the expression of the fatty acid synthesis enzymes POD-2 and FASN-1 prior to invasion. We show that phospholipid-producing LPIN-1 and sphingomyelin synthase SMS-1, which use fatty acids as substrates, produce lysosome stores that build the AC's invasive protrusion, and that SMS-1 also promotes protrusion localization of the lipid raft partitioning ZMP-1 matrix metalloproteinase. Finally, we discover that HMG-CoA reductase HMGR-1, which generates isoprenoids for prenylation, localizes to the ER and enriches in peroxisomes at the AC invasive front, and that the final transmembrane prenylation enzyme, ICMT-1, localizes to endoplasmic reticulum exit sites that dynamically polarize to deliver prenylated GTPases for protrusion formation. Together, these results reveal a collaboration between lipogenesis and a polarized lipid prenylation system that drives invasive protrusion formation.

为了突破基底膜,细胞在发育和癌变过程中会使用大型、瞬时、特化的富脂膜突起。在秀丽隐杆线虫锚细胞(AC)入侵过程中,我们利用实时成像、内源蛋白标记和细胞特异性 RNAi 技术证明,在入侵之前,脂质生成 SREBP 转录因子 SBP-1 驱动脂肪酸合成酶 POD-2 和 FASN-1 的表达。我们还发现,以脂肪酸为底物的磷脂生产酶 LPIN-1 和鞘磷脂合成酶 SMS-1,可产生溶酶体储存,从而构建 AC 的侵袭性突起,SMS-1 还可促进脂筏分区 ZMP-1 基质金属蛋白酶的突起定位。最后,我们发现,HMG-CoA 还原酶 HMGR-1 能生成用于前炔化的异丙肾上腺素,它能定位到 ER 并富集在 AC 侵袭前沿的过氧物酶体中,最后一种跨膜前炔化酶 ICMT-1 能定位到内质网出口位点,这些位点能动态极化,为突起的形成提供前炔化 GTP 酶。这些结果共同揭示了脂肪生成与极化脂质前酰化系统之间的协作,这种协作推动了侵袭性突起的形成。
{"title":"De novo lipid synthesis and polarized prenylation drive cell invasion through basement membrane.","authors":"Kieop Park, Aastha Garde, Siddharthan B Thendral, Adam W J Soh, Qiuyi Chi, David R Sherwood","doi":"10.1083/jcb.202402035","DOIUrl":"10.1083/jcb.202402035","url":null,"abstract":"<p><p>To breach the basement membrane, cells in development and cancer use large, transient, specialized lipid-rich membrane protrusions. Using live imaging, endogenous protein tagging, and cell-specific RNAi during Caenorhabditis elegans anchor cell (AC) invasion, we demonstrate that the lipogenic SREBP transcription factor SBP-1 drives the expression of the fatty acid synthesis enzymes POD-2 and FASN-1 prior to invasion. We show that phospholipid-producing LPIN-1 and sphingomyelin synthase SMS-1, which use fatty acids as substrates, produce lysosome stores that build the AC's invasive protrusion, and that SMS-1 also promotes protrusion localization of the lipid raft partitioning ZMP-1 matrix metalloproteinase. Finally, we discover that HMG-CoA reductase HMGR-1, which generates isoprenoids for prenylation, localizes to the ER and enriches in peroxisomes at the AC invasive front, and that the final transmembrane prenylation enzyme, ICMT-1, localizes to endoplasmic reticulum exit sites that dynamically polarize to deliver prenylated GTPases for protrusion formation. Together, these results reveal a collaboration between lipogenesis and a polarized lipid prenylation system that drives invasive protrusion formation.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11248228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616523","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-organized plasma membrane infoldings linked to growth of a cortical actin domain. 中心体组织的质膜内折与皮质肌动蛋白结构域的生长有关。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-10-07 Epub Date: 2024-06-27 DOI: 10.1083/jcb.202403115
Rebecca Tam, Tony J C Harris

Regulated cell shape change requires the induction of cortical cytoskeletal domains. Often, local changes to plasma membrane (PM) topography are involved. Centrosomes organize cortical domains and can affect PM topography by locally pulling the PM inward. Are these centrosome effects coupled? At the syncytial Drosophila embryo cortex, centrosome-induced actin caps grow into dome-like compartments for mitoses. We found the nascent cap to be a collection of PM folds and tubules formed over the astral centrosomal MT array. The localized infoldings require centrosome and dynein activities, and myosin-based surface tension prevents them elsewhere. Centrosome-engaged PM infoldings become specifically enriched with an Arp2/3 induction pathway. Arp2/3 actin network growth between the infoldings counterbalances centrosomal pulling forces and disperses the folds for actin cap expansion. Abnormal domain topography with either centrosome or Arp2/3 disruption correlates with decreased exocytic vesicle association. Together, our data implicate centrosome-organized PM infoldings in coordinating Arp2/3 network growth and exocytosis for cortical domain assembly.

调节细胞形状的变化需要诱导皮质细胞骨架结构域。这通常涉及质膜(PM)形貌的局部变化。中心体组织皮质结构域,可通过局部向内拉动质膜来影响质膜的形貌。这些中心体效应是耦合的吗?在合胞果蝇胚胎皮层,中心体诱导的肌动蛋白帽生长为有丝分裂的圆顶状区室。我们发现新生帽是星形中心体 MT 阵列上形成的 PM 褶皱和小管的集合。局部的折叠需要中心体和动力蛋白的活动,而肌球蛋白的表面张力会阻止它们在其他地方形成。中心体参与的PM内陷通过Arp2/3诱导途径变得特别丰富。褶皱之间的 Arp2/3 肌动蛋白网络生长抵消了中心体的拉力,并分散了褶皱以促进肌动蛋白帽的扩张。中心粒或 Arp2/3 中断导致的异常结构域拓扑与外ocytic囊泡结合减少有关。总之,我们的数据表明,中心体组织的 PM 折叠协调了 Arp2/3 网络的生长和皮质结构域组装的外泌作用。
{"title":"Centrosome-organized plasma membrane infoldings linked to growth of a cortical actin domain.","authors":"Rebecca Tam, Tony J C Harris","doi":"10.1083/jcb.202403115","DOIUrl":"10.1083/jcb.202403115","url":null,"abstract":"<p><p>Regulated cell shape change requires the induction of cortical cytoskeletal domains. Often, local changes to plasma membrane (PM) topography are involved. Centrosomes organize cortical domains and can affect PM topography by locally pulling the PM inward. Are these centrosome effects coupled? At the syncytial Drosophila embryo cortex, centrosome-induced actin caps grow into dome-like compartments for mitoses. We found the nascent cap to be a collection of PM folds and tubules formed over the astral centrosomal MT array. The localized infoldings require centrosome and dynein activities, and myosin-based surface tension prevents them elsewhere. Centrosome-engaged PM infoldings become specifically enriched with an Arp2/3 induction pathway. Arp2/3 actin network growth between the infoldings counterbalances centrosomal pulling forces and disperses the folds for actin cap expansion. Abnormal domain topography with either centrosome or Arp2/3 disruption correlates with decreased exocytic vesicle association. Together, our data implicate centrosome-organized PM infoldings in coordinating Arp2/3 network growth and exocytosis for cortical domain assembly.</p>","PeriodicalId":15211,"journal":{"name":"Journal of Cell Biology","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141457101","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