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Altered Ca2+ responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes. 弗里德赖希共济失调样小脑星形胶质细胞钙反应和抗氧化特性的改变。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-09 DOI: 10.1242/jcs.263446
Chiara Marullo, Laura Croci, Iris Giupponi, Claudia Rivoletti, Sofia Zuffetti, Barbara Bettegazzi, Ottavio Cremona, Paola Giunti, Alessandro Ambrosi, Filippo Casoni, Gian Giacomo Consalez, Franca Codazzi

Friedreich's ataxia (FRDA) is a neurodegenerative disorder characterized by severe neurological signs, affecting the peripheral and central nervous system, caused by reduced frataxin protein (FXN) levels. Although several studies have highlighted cellular dysfunctions in neurons, there is limited information on the effects of FXN depletion in astrocytes and on the potential non-cell autonomous mechanisms affecting neurons in FRDA. In this study, we generated a model of FRDA cerebellar astrocytes to unveil phenotypic alterations that might contribute to cerebellar atrophy. We treated primary cerebellar astrocytes with an RNA interference-based approach, to achieve a reduction of FXN comparable to that observed in individuals with FRDA. These FRDA-like astrocytes display some typical features of the disease, such as an increase of oxidative stress and a depletion of glutathione content. Moreover, FRDA-like astrocytes exhibit decreased Ca2+ responses to purinergic stimuli. Our findings shed light on cellular changes caused by FXN downregulation in cerebellar astrocytes, likely impairing their complex interaction with neurons. The potentially impaired ability to provide neuronal cells with glutathione or to release neuromodulators in a Ca2+-dependent manner could affect neuronal function, contributing to neurodegeneration.

弗里德赖希共济失调(FRDA)是一种神经退行性疾病,其特征是严重的神经症状,影响周围和中枢神经系统,由frataxin蛋白(FXN)水平降低引起。虽然一些研究强调了神经元的细胞功能障碍,但关于星形胶质细胞中FXN消耗的影响以及影响FRDA神经元的潜在非细胞自主机制的信息有限。在这项研究中,我们建立了一个FRDA小脑星形胶质细胞模型,以揭示可能导致小脑萎缩的表型改变。我们采用基于RNA干扰的方法治疗原发性小脑星形胶质细胞,以实现与患者观察到的FXN减少相当。这些frda样星形胶质细胞表现出该疾病的一些典型特征,如氧化应激增加和谷胱甘肽含量减少。此外,frda样星形胶质细胞对嘌呤能刺激的钙反应降低。我们的发现揭示了小脑星形胶质细胞中FXN下调引起的细胞变化,可能损害了它们与神经元的复杂相互作用。为神经元细胞提供谷胱甘肽或以钙依赖的方式释放神经调节剂的潜在能力受损可能影响神经元功能,导致神经变性。
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引用次数: 0
The co-chaperone DNAJA2 buffers proteasomal degradation of cytosolic proteins with missense mutations. 共伴侣DNAJA2缓冲错义突变的胞质蛋白的蛋白酶体降解。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-10 DOI: 10.1242/jcs.262019
Heather A Baker, Jonathan P Bernardini, Veronika Csizmók, Angel Madero, Shriya Kamat, Hailey Eng, Jessica Lacoste, Faith A Yeung, Sophie Comyn, Elizabeth Hui, Gaetano Calabrese, Brian Raught, Mikko Taipale, Thibault Mayor

Mutations can disrupt the native function of protein by causing misfolding, which is generally handled by an intricate protein quality control network. To better understand the triaging mechanisms for misfolded cytosolic proteins, we screened a human mutation library to identify a panel of unstable mutations. The degradation of these mutated cytosolic proteins is largely dependent on the ubiquitin proteasome system. Using BioID proximity labelling, we found that the co-chaperones DNAJA1 and DNAJA2 are key interactors with one of the mutated proteins. Notably, the absence of DNAJA2 increases the turnover of the mutant but not the wild-type protein. Our work indicates that specific missense mutations in cytosolic proteins can promote enhanced interactions with molecular chaperones. Assessment of the broader panel of cytosolic mutant proteins shows that the co-chaperone DNAJA2 exhibits two distinct behaviours - acting to stabilize a wide array of cytosolic proteins, including wild-type variants, and to specifically 'buffer' some mutant proteins to reduce their turnover. Our work illustrates how distinct elements of the protein homeostasis network are utilized in the presence of a cytosolic misfolded protein.

突变可以通过导致错误折叠来破坏蛋白质的天然功能,这通常是由复杂的蛋白质质量控制网络处理的。为了更好地了解错误折叠的细胞质蛋白的分类机制,我们筛选了一个人类突变文库来鉴定一组不稳定突变。这些突变细胞质蛋白的降解在很大程度上依赖于泛素蛋白酶体系统。使用BioID接近标记,我们发现共同伴侣DNAJA1和DNAJA2是其中一个突变蛋白的关键相互作用物。值得注意的是,DNAJA2的缺失增加了突变体的周转率,而不是野生型蛋白的周转率。我们的工作表明,细胞质蛋白中的特定错义突变可以促进与分子伴侣的相互作用增强。对更广泛的细胞质突变蛋白的评估表明,共同伴侣DNAJA2表现出两种不同的行为:稳定包括野生型变异在内的大量细胞质蛋白,并特异性地“缓冲”一些突变蛋白以减少它们的周转。我们的工作说明了在细胞质错误折叠蛋白存在的情况下,蛋白质动态平衡网络的不同元素是如何被利用的。
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引用次数: 0
PIKFYVE inhibition induces endosome- and lysosome-derived vacuole enlargement via ammonium accumulation. 抑制 PIKFYVE 可通过铵积累诱导内膜体和溶酶体衍生的液泡增大。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-10 DOI: 10.1242/jcs.262236
Junsuke Uwada, Hitomi Nakazawa, Takeshi Kiyoi, Takashi Yazawa, Ikunobu Muramatsu, Takayoshi Masuoka

FYVE-type zinc finger-containing phosphoinositide kinase (PIKFYVE), which is essential for phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2] production, is an important regulator of lysosomal homeostasis. PIKFYVE dysfunction leads to cytoplasmic vacuolization; however, the underlying mechanism remains unknown. In this study, we explored the cause of vacuole enlargement upon PIKFYVE inhibition in DU145 prostate cancer cells. Enlargement of vacuoles upon PIKFYVE inhibition required glutamine and its metabolism by glutaminases. Addition of ammonia, a metabolite of glutamine, was sufficient to enlarge vacuoles via PIKFYVE inhibition. Moreover, PIKFYVE inhibition led to intracellular ammonium accumulation. Endosome-lysosome permeabilization resulted in ammonium leakage from the cells, indicating ammonium accumulation in the endosomes and lysosomes. Ammonium accumulation and vacuole expansion were suppressed by the lysosomal lumen neutralization. It is therefore assumed that PIKFYVE inhibition interferes with the efflux of NH4+, which formed through protonation of NH3 in the lysosomal lumen, leading to osmotic swelling of vacuoles. Notably, glutamine or ammonium is required for PIKFYVE inhibition-induced suppression of lysosomal function and autophagic flux. In conclusion, this study shows that PIKFYVE inhibition disrupts lysosomal homeostasis via ammonium accumulation.

FYVE 型含锌指磷脂激酶(PIKFYVE)对 PtdIns(3,5)P2 的产生至关重要,是溶酶体稳态的重要调节因子。PIKFYVE 功能障碍会导致细胞质空泡化,但其潜在机制仍不清楚。在这项研究中,我们探讨了抑制 PIKFYVE 后 DU145 前列腺癌细胞空泡增大的原因。抑制 PIKFYVE 导致的液泡增大需要谷氨酰胺及其在谷氨酰胺酶作用下的代谢。加入谷氨酰胺的代谢产物氨足以通过抑制 PIKFYVE 使液泡增大。此外,抑制 PIKFYVE 会导致细胞内氨的积累。内膜体-溶酶体渗透导致铵从细胞中渗出,表明铵在内膜体和溶酶体中积累。溶酶体内腔中和抑制了铵的积累和液泡的扩大。因此推测 PIKFYVE 抑制干扰了 NH4+ 的外流,NH4+ 在溶酶体腔内质子化 NH3,导致液泡渗透膨胀。值得注意的是,谷氨酰胺或铵是 PIKFYVE 抑制引起的溶酶体功能和自噬通量抑制所必需的。总之,本研究表明,PIKfyve 抑制会通过铵积累破坏溶酶体的稳态。
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引用次数: 0
The Ras-related nuclear GTPase RAN1 ensures pollen size and tube growth by maintaining the actin cytoskeleton. 与 Ras 相关的核 GTPase RAN1 可通过维持肌动蛋白细胞骨架来确保花粉的大小和花粉管的生长。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-02 DOI: 10.1242/jcs.261920
Yihao Li, Yuwan Zhao, Haining Zhang, Peiwei Liu, Haiyun Ren

Controlling organ size in plants is a complex biological process influenced by various factors, including gene expression, genome ploidy and environmental conditions. Despite its importance for plant growth and development, the mechanisms underlying organ size regulation remain unknown. Here, we investigated the role of RAN1, a member of the Ras-related nuclear GTPase family, in regulating pollen size. A RAN1 knockdown mutant (ran1-1) exhibited a significant reduction in pollen size, accompanied by impaired germination and reduced pollen tube growth. RAN1 mutation caused disruptions in actin filament organization, such as aberrant structure of actin collar due to the dysregulation of expression of actin-binding proteins. Furthermore, we identified that mutation of the transcription activator SHORT HYPOCOTYL UNDER BLUE1 (SHB1) showed similar but milder phenotypes in pollen compared to ran1-1. Genetic evidence suggested that SHB1 acts downstream of RAN1. Transient expression assays in leaves showed that SHB1 was largely retained in the cytoplasm of the ran1-1 mutant, potentially affecting the expression of actin-binding proteins. These findings highlight the pivotal role of RAN1 in modulating pollen size and development, providing valuable insights into cell size regulation.

植物器官大小的控制是一个复杂的生物学过程,受多种因素的影响,包括基因表达、基因组倍性和环境条件。尽管它对植物生长发育很重要,但器官大小调节的机制尚不清楚。在此,我们研究了RAN1在花粉大小调控中的作用,RAN1是ras相关核GTPases家族的成员。RAN1敲低突变体(RAN1 -1)表现出花粉大小显著减少,同时萌发受损和花粉管生长减少。RAN1突变导致肌动蛋白结合蛋白表达失调,导致肌动蛋白丝组织破坏,如肌动蛋白颈圈结构异常。此外,我们鉴定了转录激活子SHB1 (BLUE1下的短下胚轴),与ran1-1相比,其突变在花粉中表现出相似但更温和的表型。遗传证据表明SHB1作用于RAN1的下游。叶片中的瞬时表达分析表明,SHB1在ran1-1突变体的细胞质中大部分保留,可能影响肌动蛋白结合蛋白的表达。这些发现强调了RAN1在调节花粉大小和发育中的关键作用,为细胞大小调节提供了有价值的见解。
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引用次数: 0
Biochemical and biophysical mechanisms macrophages use to tune phagocytic appetite. 巨噬细胞调节吞噬食欲的生化和生物物理机制。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-03 DOI: 10.1242/jcs.263513
Annalise Bond, Meghan A Morrissey

Macrophages phagocytose, or eat, pathogens, dead cells and cancer cells. To activate phagocytosis, macrophages recognize 'eat me' signals like IgG and phosphatidylserine on the target cell surface. Macrophages must carefully adjust their phagocytic appetite to ignore non-specific or transient eat me signal exposure on healthy cells while still rapidly recognizing pathogens and debris. Depending on the context, macrophages can increase their appetite for phagocytosis, to prioritize an effective immune response, or decrease their appetite, to avoid damage to healthy tissue during homeostasis. In this Review, we discuss the biochemical and biophysical mechanisms that macrophages employ to increase or decrease their sensitivity or capacity for phagocytosis. We discuss evidence that macrophages tune their sensitivity via several mechanisms, including altering the balance of activating and inhibitory receptor expression, altering the availability of activating receptors, as well as influencing their clustering and mobility, and modulating inhibitory receptor location. We also highlight how membrane availability limits the capacity of macrophages for phagocytosis and discuss potential mechanisms to promote membrane recycling and increase phagocytic capacity. Overall, this Review highlights recent work detailing the molecular toolkit that macrophages use to alter their appetite.

巨噬细胞吞噬或吃掉病原体、死亡细胞和癌细胞。为了激活吞噬功能,巨噬细胞会识别 "吃我 "信号,如目标细胞表面的 IgG 和磷脂酰丝氨酸。巨噬细胞必须仔细调整其吞噬欲望,以忽略健康细胞上的非特异性或瞬时 "吃我 "信号,同时仍能快速识别病原体和碎屑。根据具体情况,巨噬细胞可以增加其吞噬欲望,以优先考虑有效的免疫反应,或者降低其吞噬欲望,以避免在平衡过程中对健康组织造成损害。在本综述中,我们将讨论巨噬细胞提高或降低其吞噬敏感性或能力的生化和生物物理机制。我们讨论了巨噬细胞通过几种机制调整其敏感性的证据,包括改变激活受体和抑制受体表达的平衡、改变激活受体的可用性以及影响它们的聚集和流动性,以及调节抑制受体的位置。我们还强调了膜的可用性如何限制巨噬细胞的吞噬能力,并讨论了促进膜循环和提高吞噬能力的潜在机制。总之,本综述重点介绍了近期的研究工作,详细说明了巨噬细胞用于改变其食欲的分子工具包。
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引用次数: 0
Quantitative approaches for studying G protein-coupled receptor signalling and pharmacology. G蛋白偶联受体信号传导和药理学的定量研究方法。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-15 DOI: 10.1242/jcs.263434
Abigail Pearce, Theo Redfern-Nichols, Edward Wills, Matthew Rosa, Iga Manulak, Claudia Sisk, Xianglin Huang, Peace Atakpa-Adaji, David L Prole, Graham Ladds

G protein-coupled receptor (GPCR) signalling pathways underlie numerous physiological processes, are implicated in many diseases and are major targets for therapeutics. There are more than 800 GPCRs, which together transduce a vast array of extracellular stimuli into a variety of intracellular signals via heterotrimeric G protein activation and multiple downstream effectors. A key challenge in cell biology research and the pharmaceutical industry is developing tools that enable the quantitative investigation of GPCR signalling pathways to gain mechanistic insights into the varied cellular functions and pharmacology of GPCRs. Recent progress in this area has been rapid and extensive. In this Review, we provide a critical overview of these new, state-of-the-art approaches to investigate GPCR signalling pathways. These include novel sensors, Förster or bioluminescence resonance energy transfer assays, libraries of tagged G proteins and transcriptional reporters. These approaches enable improved quantitative studies of different stages of GPCR signalling, including GPCR activation, G protein activation, second messenger (cAMP and Ca2+) signalling, β-arrestin recruitment and the internalisation and intracellular trafficking of GPCRs.

G蛋白偶联受体(GPCR)信号通路是许多生理过程的基础,与许多疾病有关,是治疗的主要靶点。有超过800种gpcr,它们通过异源三聚体G蛋白激活和多种下游效应物将大量细胞外刺激转化为各种细胞内信号。细胞生物学研究和制药行业面临的一个关键挑战是开发工具,使GPCR信号通路的定量研究能够获得GPCR不同细胞功能和药理学的机制见解。最近在这一领域取得了迅速和广泛的进展。在这篇综述中,我们提供了这些新的,最先进的方法来研究GPCR信号通路的关键概述。这些包括新型传感器,Förster或生物发光共振能量转移测定,标记G蛋白文库和转录报告。这些方法能够改进GPCR信号传导不同阶段的定量研究,包括GPCR激活、G蛋白激活、第二信使(cAMP和Ca2+)信号传导、β-阻滞蛋白募集以及GPCR的内化和细胞内运输。
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引用次数: 0
Phosphorylation on serine 72 modulates Rab7A palmitoylation and retromer recruitment. 丝氨酸 72 上的磷酸化调节 Rab7A 棕榈酰化和 retromer 招募。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2025-01-08 DOI: 10.1242/jcs.262177
Graziana Modica, Laura Tejeda-Valencia, Etienne Sauvageau, Seda Yasa, Juliette Maes, Olga Skorobogata, Stephane Lefrancois

Rab7A has a key role in regulating membrane trafficking at late endosomes. By interacting with several different effectors, this small GTPase controls late endosome mobility, orchestrates fusion events between late endosomes and lysosomes, and participates in the formation of and regulates the fusion between autophagosomes and lysosomes. Rab7A is also responsible for the spatiotemporal recruitment of retromer, which is required for the endosome-to-trans-Golgi network retrieval of cargo receptors such as sortilin (SORT1) and CI-MPR (also known as IGF2R). Recently, several post-translational modifications have been shown to modulate Rab7A functions, including palmitoylation, ubiquitination and phosphorylation. Here, we show that phosphorylation of Rab7A at serine 72 is important to modulate its interaction with retromer, as the non-phosphorylatable Rab7AS72A mutant is not able to interact with and recruit retromer to late endosomes. We have previously shown that Rab7A palmitoylation is also required for efficient retromer recruitment. We found that palmitoylation of Rab7AS72A is reduced compared to that of the wild-type protein, suggesting an interplay between S72 phosphorylation and palmitoylation in regulating the Rab7A-retromer interaction. Finally, we identify NEK7 as a kinase required to phosphorylate Rab7A to promote retromer binding and recruitment.

Rab7A 在调节晚期内体的膜贩运方面起着关键作用。通过与几种不同的效应物相互作用,这种小 GTPase 可控制晚期内体的流动性,协调晚期内体与溶酶体之间的融合事件,并参与形成和调节自噬体与溶酶体之间的融合。Rab7A 还负责 retromer 的时空招募,而 retromer 是内质体到 TGN 检索货物受体(如 sortilin 和 CI-MPR)所必需的。最近有研究表明,几种翻译后修饰可调节 Rab7A 的功能,包括棕榈酰化、泛素化和磷酸化。我们在这里发现,Rab7A 在丝氨酸 72 处的磷酸化对调节其与 retromer 的相互作用非常重要,因为不可磷酸化的 Rab7AS72A 突变体无法与 retromer 相互作用并将其招募到晚期内体。我们之前已经证明,Rab7A棕榈酰化也是有效招募 retromer 的必要条件。我们发现,与野生型蛋白相比,Rab7AS72A 的棕榈酰化减少了,这表明 S72 磷酸化和棕榈酰化在调节 Rab7A 与 retromer 的相互作用中相互作用。最后,我们确定 NEK7 是使 Rab7A 磷酸化以促进 retromer 结合和招募所需的激酶。
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引用次数: 0
Ankyrin-B is required for the establishment and maintenance of lens cytoarchitecture, mechanics and clarity. Ankyrin-B 是建立和维持晶状体细胞结构、力学和透明度所必需的。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-12-15 Epub Date: 2024-12-18 DOI: 10.1242/jcs.262349
Rupalatha Maddala, Ariana Allen, Nikolai P Skiba, Ponugoti Vasantha Rao

The transparent ocular lens is essential for vision because it focuses light onto the retina. Despite recognition of the importance of its unique cellular architecture and mechanical properties, the molecular mechanisms governing these attributes remain elusive. This study aims to elucidate the role of ankyrin-B (AnkB, encoded by ANK2), a membrane scaffolding protein, in lens cytoarchitecture, growth and function using a conditional knockout (cKO) mouse model. The AnkB cKO mouse has no defects in lens morphogenesis but exhibited changes that supported a global role for AnkB in maintenance of lens clarity, size, cytoarchitecture, membrane organization and stiffness. Notably, absence of AnkB led to nuclear cataract formation, which was evident from postnatal day 16. AnkB cKO lens fibers exhibit progressive disruption in membrane organization of the spectrin-actin cytoskeleton, cell adhesion proteins and channel proteins; loss and degradation of several membrane proteins [such as NrCAM. N-cadherin (CDH2) and aquaporin-0 (also known as MIP)]; along with a disorganized plasma membrane and impaired membrane interdigitations. Furthermore, absence of AnkB led to decreased lens stiffness. Collectively, these results illustrate the essential role for AnkB in lens architecture, growth and function through its involvement in membrane skeletal and protein organization and stability.

透明的眼球晶状体能将光线聚焦到视网膜上,对视觉至关重要。尽管人们认识到晶状体独特的细胞结构和机械特性的重要性,但支配这些特性的分子机制仍然难以捉摸。本研究旨在利用条件性基因敲除(cKO)小鼠模型,阐明膜支架蛋白 ankyrin-B(AnkB)在晶状体细胞结构、生长和功能中的作用。AnkB cKO小鼠在晶状体形态发生方面没有缺陷,但表现出的变化支持了AnkB在维持晶状体清晰度、大小、细胞结构、膜组织和硬度方面的整体作用。值得注意的是,AnkB 的缺失会导致核白内障的形成,从 P16 开始就很明显。AnkB cKO 的晶状体纤维表现出谱系蛋白-肌动蛋白细胞骨架、细胞粘附蛋白和通道蛋白的膜组织逐渐破坏,多种膜蛋白(如 NrCAM、N-cadherin 和 aquaporin-0)丢失和降解,同时质膜紊乱,膜间连接受损。此外,缺乏 AnkB 会导致晶状体硬度下降。总之,这些结果说明了 AnkB 通过参与膜骨架和蛋白质的组织与稳定,在晶状体的结构、生长和功能中发挥着重要作用。
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引用次数: 0
Apical integrins as a switchable target to regulate the epithelial barrier. 顶端整合素是调节上皮屏障的可切换目标。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-12-15 Epub Date: 2024-12-20 DOI: 10.1242/jcs.263580
Raven J Peterson, Ryan C Reed, Colin R Zamecnik, Marwa A Sallam, Joel A Finbloom, Francisco J Martinez, Joshua M Levy, Aekkacha Moonwiriyakit, Tejal A Desai, Michael Koval

Tight junctions regulate epithelial barrier function and have been shown to be influenced by multiple classes of proteins. Apical integrins have been identified as potential regulators of epithelial barrier function; however, only indirect approaches have been used to measure integrin regulation of the epithelial barrier. Here, we used polymeric nanowires conjugated with anti-integrin β1 antibodies to specifically target apically localized integrins in either their closed or open conformation. Barrier regulation by apical integrins was found to be conformation specific. Nanowires targeting integrins in the closed conformation increased epithelial permeability and caused zonula occludens-1 (ZO-1, also known as TJP1) to change from a linear to a ruffled morphology. Claudin-2 and claudin-4 colocalized with ZO-1 and were also ruffled; however, claudin-1 and claudin-7 remained linear. Ruffling was dependent on myosin light chain kinases (MLCKs) and Rho kinases (ROCKs). Conversely, targeting integrins in the open conformation decreased epithelial permeability and made junctions more linearized. Anti-integrin β1 nanowires differentially affected actin and talin (analyzed using pan-talin antibodies), depending on whether they contained activating or inhibitory antibodies. Thus, apical integrins can act as a conformation-sensitive switch that regulates epithelial barrier function.

紧密连接调节上皮屏障功能,并已证明受到多种蛋白质的影响。顶端整合素已被确定为上皮屏障功能的潜在调控因子,但目前只有间接的方法用于测量整合素对上皮屏障的调控。在这里,我们使用与抗整合素β1抗体结合的聚合物纳米线,特异性地靶向封闭或开放构象的顶端定位整合素。研究发现,顶端整合素对屏障的调节具有构象特异性。以封闭构象整合素为靶的纳米线增加了上皮细胞的通透性,并使闭锁带-1(ZO-1)从线性形态变为皱褶形态。Claudin-2和claudin-4与ZO-1共定位,也呈皱褶状,但claudin-1和claudin-7仍呈线状。褶皱依赖于肌球蛋白轻链(MLCK)和 Rho 激酶(ROCK)。相反,以开放构象的整合素为靶标会降低上皮的通透性,并使连接更加线性化。抗整合素β1纳米线对肌动蛋白和滑蛋白的影响各不相同,这取决于它们是否含有激活或抑制抗体。因此,顶端整合素可作为一种构象敏感开关,调节上皮屏障功能。
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引用次数: 0
Fantastic proteins and where to find them - histones, in the nucleus and beyond. 奇妙的蛋白质以及在哪里可以找到它们——组蛋白,在细胞核内外。
IF 3.3 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-12-15 Epub Date: 2024-12-20 DOI: 10.1242/jcs.262071
Johanna Grinat, Noah P Shriever, Maria A Christophorou

Animal genomes are packaged into chromatin, a highly dynamic macromolecular structure of DNA and histone proteins organised into nucleosomes. This accommodates packaging of lengthy genomic sequences within the physical confines of the nucleus while also enabling precise regulation of access to genetic information. However, histones existed before chromatin and have lesser-known functions beyond genome regulation. Most notably, histones are potent antimicrobial agents, and the release of chromatin to the extracellular space is a defence mechanism nearly as ancient and widespread as chromatin itself. Histone sequences have changed very little throughout evolution, suggesting the possibility that some of their 'non-canonical' functions are at play in parallel or in concert with their genome regulatory functions. In this Review, we take an evolutionary perspective of histone, nuclear chromatin and extracellular chromatin biology and describe the known extranuclear and extracellular functions of histones. We detail molecular mechanisms of chromatin release and extracellular chromatin sensing, and we discuss their roles in physiology and disease. Finally, we present evidence and give a perspective on the potential of extracellular histones to act as bioactive, cell modulatory factors.

动物基因组被包装成染色质,染色质是一种高度动态的DNA和组蛋白大分子结构,被组织成核小体。这可以在细胞核的物理范围内容纳长基因组序列的包装,同时也可以精确调节获取遗传信息的途径。然而,组蛋白在染色质之前就存在了,并且除了基因组调控之外,还有一些鲜为人知的功能。最值得注意的是,组蛋白是有效的抗菌剂,将染色质释放到细胞外空间是一种防御机制,几乎和染色质本身一样古老和广泛。组蛋白序列在整个进化过程中变化很小,这表明它们的一些“非规范”功能可能与它们的基因组调节功能并行或协同发挥作用。在这篇综述中,我们从组蛋白、核染色质和细胞外染色质生物学的进化角度,描述了已知的组蛋白的核外和细胞外功能。我们详细介绍了染色质释放和细胞外染色质传感的分子机制,并讨论了它们在生理和疾病中的作用。最后,我们提出了证据,并给出了细胞外组蛋白作为生物活性细胞调节因子的潜力的观点。
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