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Fine-tuning stress responses by auxiliary feedback loops that sense damage repair. 通过感知损伤修复的辅助反馈回路微调应激反应
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-12-02 Epub Date: 2024-11-15 DOI: 10.1083/jcb.202410205
Axel Mogk, Fabian den Brave

Mogk and den Brave discuss exciting results from a comprehensive screen of heat shock response components in yeast, published in this issue by Pincus and colleagues (https://doi.org/10.1083/jcb.202401082). Their work reveals modulatory regulatory loops that fine-tune the timing of the shutdown of this highly conserved pathway.

Mogk 和 den Brave 讨论了 Pincus 及其同事在本期(https://doi.org/10.1083/jcb.202401082)上发表的全面筛选酵母热休克反应成分的令人兴奋的结果。他们的工作揭示了微调这一高度保守途径关闭时机的调节环路。
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引用次数: 0
Migratory autolysosome disposal mitigates lysosome damage. 迁移性自溶体处理减轻了溶酶体损伤。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-12-02 Epub Date: 2024-09-30 DOI: 10.1083/jcb.202403195
Takami Sho, Ying Li, Haifeng Jiao, Li Yu

Lysosomes, essential for intracellular degradation and recycling, employ damage-control strategies such as lysophagy and membrane repair mechanisms to maintain functionality and cellular homeostasis. Our study unveils migratory autolysosome disposal (MAD), a response to lysosomal damage where cells expel LAMP1-LC3 positive structures via autolysosome exocytosis, requiring autophagy machinery, SNARE proteins, and cell migration. This mechanism, crucial for mitigating lysosomal damage, underscores the role of cell migration in lysosome damage control and facilitates the release of small extracellular vesicles, highlighting the intricate relationship between cell migration, organelle quality control, and extracellular vesicle release.

溶酶体是细胞内降解和再循环的关键,它采用溶酶吞噬和膜修复机制等损伤控制策略来维持功能和细胞稳态。我们的研究揭示了迁移性自溶体处理(MAD),这是一种对溶酶体损伤的反应,细胞通过自溶体外排排出 LAMP1-LC3 阳性结构,需要自噬机制、SNARE 蛋白和细胞迁移。这一机制对减轻溶酶体损伤至关重要,它强调了细胞迁移在溶酶体损伤控制中的作用,并促进了细胞外小囊泡的释放,凸显了细胞迁移、细胞器质量控制和细胞外小囊泡释放之间错综复杂的关系。
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引用次数: 0
Preserve or destroy: Orphan protein proteostasis and the heat shock response. 保存还是毁灭孤儿蛋白蛋白稳态与热休克反应
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-12-02 Epub Date: 2024-11-15 DOI: 10.1083/jcb.202407123
Asif Ali, Sarah Paracha, David Pincus

Most eukaryotic genes encode polypeptides that are either obligate members of hetero-stoichiometric complexes or clients of organelle-targeting pathways. Proteins in these classes can be released from the ribosome as "orphans"-newly synthesized proteins not associated with their stoichiometric binding partner(s) and/or not targeted to their destination organelle. Here we integrate recent findings suggesting that although cells selectively degrade orphan proteins under homeostatic conditions, they can preserve them in chaperone-regulated biomolecular condensates during stress. These orphan protein condensates activate the heat shock response (HSR) and represent subcellular sites where the chaperones induced by the HSR execute their functions. Reversible condensation of orphan proteins may broadly safeguard labile precursors during stress.

大多数真核生物基因所编码的多肽要么是异源-同源复合物的必须成员,要么是细胞器靶向途径的客户。这些类别中的蛋白质可以作为 "孤儿 "从核糖体中释放出来--新合成的蛋白质与其按比例结合的伙伴没有联系和/或没有靶向其目的细胞器。在这里,我们整合了最近的研究结果,这些结果表明,虽然细胞在平衡状态下会选择性地降解孤儿蛋白,但在应激状态下,它们可以将孤儿蛋白保存在伴侣调节的生物分子凝聚体中。这些孤蛋白凝集体激活了热休克反应(HSR),并代表了由热休克反应诱导的伴侣蛋白执行其功能的亚细胞位点。孤岛蛋白的可逆缩聚可在应激期间广泛保护易变前体。
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引用次数: 0
Mitochondrial-derived compartments are multilamellar domains that encase membrane cargo and cytosol. 线粒体源性区室是一个多纤层结构域,可容纳膜货物和细胞膜。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-13 DOI: 10.1083/jcb.202307035
Zachary N Wilson, Matt West, Alyssa M English, Greg Odorizzi, Adam L Hughes

Preserving the health of the mitochondrial network is critical to cell viability and longevity. To do so, mitochondria employ several membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and compartments (MDCs) to selectively remove portions of the organelle. In contrast to well-characterized MDVs, the distinguishing features of MDC formation and composition remain unclear. Here, we used electron tomography to observe that MDCs form as large, multilamellar domains that generate concentric spherical compartments emerging from mitochondrial tubules at ER-mitochondria contact sites. Time-lapse fluorescence microscopy of MDC biogenesis revealed that mitochondrial membrane extensions repeatedly elongate, coalesce, and invaginate to form these compartments that encase multiple layers of membrane. As such, MDCs strongly sequester portions of the outer mitochondrial membrane, securing membrane cargo into a protected domain, while also enclosing cytosolic material within the MDC lumen. Collectively, our results provide a model for MDC formation and describe key features that distinguish MDCs from other previously identified mitochondrial structures and cargo-sorting domains.

保持线粒体网络的健康对细胞的活力和寿命至关重要。为此,线粒体采用了多种膜重塑机制,包括形成线粒体衍生囊泡 (MDV) 和区室 (MDC),以选择性地移除细胞器的一部分。与表征明确的 MDVs 不同,MDCs 形成和组成的显著特征仍不清楚。在这里,我们利用电子断层扫描技术观察到,MDCs 以大型多纤毛结构域的形式形成,在 ER 线粒体与线粒体的接触部位产生从线粒体小管出现的同心球形隔室。对 MDC 生物发生过程的延时荧光显微镜观察发现,线粒体膜延伸部分反复伸长、凝聚和内陷,形成了这些包裹多层膜的区室。因此,MDCs 能强力封闭线粒体外膜的一部分,将膜货物固定在一个受保护的区域内,同时也将细胞质封闭在 MDC 内腔中。总之,我们的研究结果为 MDC 的形成提供了一个模型,并描述了将 MDC 与之前发现的其他线粒体结构和货物分类域区分开来的关键特征。
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引用次数: 0
A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell-cell contacts. 脂质转运 ER 蛋白 TMEM24 和 C2CD2 与带 4.1 在细胞-细胞接触处的复合物。
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.202311137
Ben Johnson, Maria Iuliano, TuKiet T Lam, Thomas Biederer, Pietro V De Camilli

Junctions between the ER and plasma membrane (PM) are implicated in calcium homeostasis, non-vesicular lipid transfer, and other cellular functions. Two ER proteins that function both as tethers to the PM via a polybasic C-terminus motif and as phospholipid transporters are brain-enriched TMEM24 (C2CD2L) and its paralog C2CD2. We report that both proteins also form a complex with band 4.1 family members, which in turn bind PM proteins including cell adhesion molecules such as SynCAM 1. This complex enriches TMEM24 and C2CD2 containing ER/PM junctions at sites of cell contacts. Dynamic properties of TMEM24-dependent ER/PM junctions are impacted when band 4.1 is part of the junction, as TMEM24 at cell-adjacent ER/PM junctions is not shed from the PM by calcium rise, unlike TMEM24 at non-cell adjacent junctions. Lipid transport between the ER and the PM by TMEM24 and C2CD2 at sites where cells, including neurons, contact other cells may participate in adaptive responses to cell contact-dependent signaling.

ER和质膜(PM)之间的连接与钙平衡、非囊泡脂质转移和其他细胞功能有关。脑富集的 TMEM24(C2CD2L)及其同源物 C2CD2 是两种既能通过多基态 C 端基团与质膜连接又能作为磷脂转运体的 ER 蛋白。我们报告说,这两种蛋白还与带状 4.1 家族成员形成复合物,而带状 4.1 家族成员又与包括细胞粘附分子(如 SynCAM 1)在内的 PM 蛋白结合。这种复合物在细胞接触部位富集了含有 ER/PM 连接的 TMEM24 和 C2CD2。当带 4.1 成为连接点的一部分时,依赖 TMEM24 的 ER/PM 连接点的动态特性会受到影响,因为细胞相邻 ER/PM 连接点上的 TMEM24 不会因钙升高而从 PM 上脱落,这与非细胞相邻连接点上的 TMEM24 不同。在细胞(包括神经元)与其他细胞接触的部位,TMEM24 和 C2CD2 在 ER 和 PM 之间的脂质运输可能参与了对细胞接触依赖性信号的适应性反应。
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引用次数: 0
Cyclin B3 is a dominant fast-acting cyclin that drives rapid early embryonic mitoses. 细胞周期蛋白 B3 是一种显性快速作用细胞周期蛋白,它能驱动早期胚胎的快速有丝分裂。
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.202308034
Pablo Lara-Gonzalez, Smriti Variyar, Shabnam Moghareh, Anh Cao Ngoc Nguyen, Amrutha Kizhedathu, Jacqueline Budrewicz, Aleesa Schlientz, Neha Varshney, Andrew Bellaart, Karen Oegema, Lee Bardwell, Arshad Desai

Mitosis in early embryos often proceeds at a rapid pace, but how this pace is achieved is not understood. Here, we show that cyclin B3 is the dominant driver of rapid embryonic mitoses in the C. elegans embryo. Cyclins B1 and B2 support slow mitosis (NEBD to anaphase ∼600 s), but the presence of cyclin B3 dominantly drives the approximately threefold faster mitosis observed in wildtype. Multiple mitotic events are slowed down in cyclin B1 and B2-driven mitosis, and cyclin B3-associated Cdk1 H1 kinase activity is ∼25-fold more active than cyclin B1-associated Cdk1. Addition of cyclin B1 to fast cyclin B3-only mitosis introduces an ∼60-s delay between completion of chromosome alignment and anaphase onset; this delay, which is important for segregation fidelity, is dependent on inhibitory phosphorylation of the anaphase activator Cdc20. Thus, cyclin B3 dominance, coupled to a cyclin B1-dependent delay that acts via Cdc20 phosphorylation, sets the rapid pace and ensures mitotic fidelity in the early C. elegans embryo.

早期胚胎的有丝分裂通常以很快的速度进行,但这种速度是如何实现的尚不清楚。在这里,我们发现细胞周期蛋白 B3 是优雅小鼠胚胎快速有丝分裂的主要驱动力。细胞周期蛋白 B1 和 B2 支持缓慢的有丝分裂(从 NEBD 到无丝分裂 ∼600 秒),但细胞周期蛋白 B3 的存在主导性地推动了野生型中观察到的约三倍快的有丝分裂。在细胞周期蛋白 B1 和 B2 驱动的有丝分裂过程中,多个有丝分裂事件被减慢,细胞周期蛋白 B3 相关的 Cdk1 H1 激酶活性比细胞周期蛋白 B1 相关的 Cdk1 活性高 25 倍。在仅有细胞周期蛋白 B3 的快速有丝分裂中加入细胞周期蛋白 B1,会在染色体排列完成和无丝分裂开始之间产生 60 秒的延迟;这种延迟对分离的保真度非常重要,它依赖于无丝分裂激活剂 Cdc20 的抑制性磷酸化。因此,细胞周期蛋白 B3 的优势加上细胞周期蛋白 B1 依赖性延迟(通过 Cdc20 磷酸化起作用),为早期秀丽隐杆线虫胚胎的有丝分裂设定了快节奏,并确保了有丝分裂的保真度。
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引用次数: 0
Nesprin-2 coordinates opposing microtubule motors during nuclear migration in neurons. 神经元核迁移过程中,Nesprin-2 可协调对立的微管马达。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-08 DOI: 10.1083/jcb.202405032
Chuying Zhou, You Kure Wu, Fumiyoshi Ishidate, Takahiro K Fujiwara, Mineko Kengaku

Nuclear migration is critical for the proper positioning of neurons in the developing brain. It is known that bidirectional microtubule motors are required for nuclear transport, yet the mechanism of the coordination of opposing motors is still under debate. Using mouse cerebellar granule cells, we demonstrate that Nesprin-2 serves as a nucleus-motor adaptor, coordinating the interplay of kinesin-1 and dynein. Nesprin-2 recruits dynein-dynactin-BicD2 independently of the nearby kinesin-binding LEWD motif. Both motor binding sites are required to rescue nuclear migration defects caused by the loss of function of Nesprin-2. In an intracellular cargo transport assay, the Nesprin-2 fragment encompassing the motor binding sites generates persistent movements toward both microtubule minus and plus ends. Nesprin-2 drives bidirectional cargo movements over a prolonged period along perinuclear microtubules, which advance during the migration of neurons. We propose that Nesprin-2 keeps the nucleus mobile by coordinating opposing motors, enabling continuous nuclear transport along advancing microtubules in migrating cells.

核迁移对于神经元在发育中大脑的正确定位至关重要。众所周知,核迁移需要双向微管马达,但对立马达的协调机制仍有争议。我们利用小鼠小脑颗粒细胞证明,Nesprin-2 可作为核运动适配器,协调驱动蛋白-1 和动力蛋白的相互作用。Nesprin-2能够独立于附近的驱动蛋白结合LEWD基团而招募动力蛋白-动力蛋白-BicD2。要挽救 Nesprin-2 功能缺失导致的核迁移缺陷,这两个马达结合位点都是必需的。在细胞内货物运输试验中,包含马达结合位点的Nesprin-2片段会产生向微管负端和正端的持续运动。在神经元迁移过程中,Nesprin-2驱动货物沿着核周微管长期双向移动。我们认为,Nesprin-2 通过协调相反的马达使细胞核保持移动,从而使细胞核在迁移过程中沿着前进的微管持续运输。
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引用次数: 0
Racing through C. elegans mitosis using cyclin B3. 利用细胞周期蛋白 B3 在秀丽隐杆线虫有丝分裂过程中飞驰。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-10-28 DOI: 10.1083/jcb.202410007
Andreas Boland, Julia Kamenz

Racecar drivers use left-foot braking, i.e., simultaneously engaging brake and throttle, to carefully balance acceleration and traction when navigating chicanes. In this issue, Lara-Gonzalez et al. (https://doi.org/10.1083/jcb.202308034) show that C. elegans embryos employ the molecular equivalent of left-foot braking to faithfully speed through mitosis.

赛车手在通过弯道时会使用左脚制动,即同时踩下刹车和油门,以小心平衡加速度和牵引力。在本期杂志中,Lara-Gonzalez 等人(https://doi.org/10.1083/jcb.202308034)展示了 elegans 胚胎采用相当于左脚刹车的分子方式,以忠实地加速完成有丝分裂。
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引用次数: 0
How condensed are mitotic chromosomes? 有丝分裂染色体的浓缩程度如何?
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-10-14 DOI: 10.1083/jcb.202409044
Hide A Konishi, Hironori Funabiki

Chromosomes undergo dramatic compaction during mitosis, but accurately measuring their volume has been challenging. Employing serial block face scanning electron microscopy, Cisneros-Soberanis et al. (https://doi.org/10.1083/jcb.202403165) report that mitotic chromosomes compact to a nucleosome concentration of ∼760 µM.

染色体在有丝分裂过程中会发生急剧压缩,但准确测量其体积一直是个难题。Cisneros-Soberanis 等人(https://doi.org/10.1083/jcb.202403165)利用序列块面扫描电子显微镜报告说,有丝分裂染色体压实到核小体浓度为 ∼ 760 µM。
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引用次数: 0
Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane. 线粒体衍生区从线粒体外膜中清除多余的蛋白质。
IF 7.4 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-11-04 Epub Date: 2024-08-13 DOI: 10.1083/jcb.202307036
Zachary N Wilson, Sai Sangeetha Balasubramaniam, Sara Wong, Max-Hinderk Schuler, Mitchell J Wopat, Adam L Hughes

The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a mitochondrial remodeling mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here, we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are incorporated into MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface.

线粒体外膜(OMM)形成了一个边界,它可以导入大部分线粒体蛋白质组,同时清除无关或受损的蛋白质。线粒体外膜如何感知异常蛋白并进行重塑以保持线粒体外膜的完整性仍是一个未解之谜。此前,我们发现了一种称为线粒体衍生区室(MDC)的线粒体重塑机制,它能清除线粒体蛋白质组的一个子集。在这里,我们发现 MDCs 能特异性地封存只定位于 OMM 的蛋白质,从而解释了线粒体蛋白质是如何被选择性地纳入 MDCs 的。值得注意的是,选择性分拣进入 MDC 也发生在 OMM 内,因为除非 TOM 复合物的组装受损,否则外膜转运酶(TOM)复合物的亚基会被排除在 MDC 之外。考虑到线粒体膜蛋白或尾部锚定膜蛋白在 OMM 中的过载会诱导 MDCs 形成并封存这些蛋白,我们认为 MDCs 的一个功能性作用是创建一个富含 OMM 的陷阱,将多余的蛋白从线粒体表面分离并封存。
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引用次数: 0
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