Here, there, and everywhere: The importance of ER membrane contact sites.
Here, there, and everywhere: The importance of ER membrane contact sites.
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DOI：
10.1126/science.aan5835
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发表时间：
2018-08-03
期刊：
影响因子：
--
通讯作者：
Voeltz GK
中科院分区：
文献类型：
--
作者：
Wu H;Carvalho P;Voeltz GK
真核细胞的特征是存在不同种类的膜结合细胞器，每个细胞器都有专门的功能。大多数细胞器在细胞中有多个拷贝。相反，每个细胞只含有一个内质网（ER）。然而，ER由膜池和小管的精心制作的网络组成，其延伸遍及整个细胞并占据细胞质体积的大部分。虽然这些细胞器中的生化反应和过程的区室化具有明显的优势，但它也对它们的协调活动提出了挑战，需要调节细胞器间通信的机制。然而，这些仍然难以捉摸，典型的教科书漫画仍然描绘了孤立的细胞器，漂浮在细胞质海洋中。过去的十年从根本上改变了这一观点，不同细胞器之间的膜接触位点（MCS）被带到中心舞台，作为细胞内稳态所必需的细胞器间通信的主要，高度调节的途径。细胞器接触的存在很久以前就被认识到了。然而，这些结构的重要性仍然不清楚。显微镜分辨率的最新进展和独特荧光团的发展大大提高了我们研究细胞器间MCSs的能力。ER MCSs与其他细胞器和质膜的三维结构可以通过电子显微镜（EM）以纳米分辨率可视化。多光谱活细胞荧光显微镜显示随着时间的推移和对刺激的反应的MCS的行为。这些数据共同揭示了MCSs的一般特征。例如，EM已经揭示了MCSs是紧密相对的和栓系的，但不是融合的膜; MCSs以10 - 30nm间隔开;并且核糖体在这些位点被排除在ER表面之外。荧光显微镜观察表明，细胞器在沿着微管沿着移动时可以保持附着在ER小管上。这些工具与经典的分子生物学和生物化学工具的组合已经确定了与几种MCS有关的分子，并阐明了它们的功能，包括细胞器之间的脂质和离子转运以及细胞器定位和分裂。MCS是正常细胞生理学的核心。此外，几种MCSs蛋白与各种疾病相关：Seipin、Protrudin和Spastin与遗传性痉挛性截瘫相关; VAPA和VAPB与肌萎缩侧索硬化相关; Dnm 2和Mfn2与夏科玛丽牙相关; Stim1和Orai 1与管状聚集性肌病相关; ACBD 5与视网膜营养不良相关。MCSs功能缺陷是否直接或间接导致这些疾病仍有待探讨。最近的进展已经开始确定一些调节MCSs形成的分子机制。剖析这些因素的作用，将加强我们对MCSs的整合性质的理解。不同显微镜技术的进步将使我们能够跟踪多个因素在MCSs同时在真实的时间和高分辨率，这可能有助于我们获得更详细的了解MCSs生物学及其相关的生理过程。我们教科书上细胞器的形象已经改变了。而不是孤立的细胞隔室，现在出现的图片显示细胞器在很大程度上是相互依赖的结构，可以通过膜接触位点（MCS）进行通信。MCS是相对的细胞器被束缚但不融合的场所。MCS提供了一个混合的位置，两种不同细胞器的工具包可以一起工作，以执行重要的细胞功能，如脂质和离子转移，信号传导和细胞器分裂。在这里，我们集中在MCS涉及内质网（ER），细胞器形成广泛的网络池和小管。我们将强调如何动态ER网络调节过多的细胞过程，通过MCS与各种细胞器和质膜（PM）。Fig. 0.内质网（ER）膜接触位点（MCS）与其他细胞器和质膜（PM）。内质网与线粒体、高尔基体、核内体、过氧化物酶体、脂滴和颗粒膜形成微囊藻细胞。这些MCS是紧密相对的，但不是融合的膜，含有各种分子机器。定位于这些MCSs的因子介导重要的细胞过程，包括脂质和离子交换、细胞器定位和生物发生。
The defining feature of eukaryotic cells is the presence of membranebound organelles of diverse kinds, each with specialized functions. Most organelles have multiple copies in cells. In contrast, each cell contains only one endoplasmic reticulum (ER). However, the ER consists of an elaborated network of membrane cisternae and tubules that extends throughout the cell and occupies a large fraction of the cytoplasmic volume. While compartmentalization of biochemical reactions and processes in these organelles has obvious advantages, it also poses challenges for their coordinated activity, requiring mechanisms for regulated inter-organelle communication. However, these have remained elusive and the quintessential textbook cartoon still pictures organelles in isolation, floating in a cytoplasmic sea. The last decade radically changed this view and membrane contact sites (MCSs) between different organelles were brought to the center stage as prime, highly regulated routes for inter-organelle communication essential for cell homeostasis. The presence of organelle contacts was recognized long ago. However, the significance of these structures remained unclear. Recent advances in the resolution of microscopy and the development of unique fluorophores have dramatically advanced our ability to study inter-organelle MCSs. The 3D structure of ER MCSs with other organelles and the plasma membrane can be visualized at nanometer resolution by electron microscopy (EM). Multi-spectral live-cell fluorescence microscopy displays the behavior of MCSs over time and in response to stimuli. Together these data have revealed the general features of MCSs. For example, EM has revealed that MCSs are closely opposed and tethered, but not fused membranes; MCSs are spaced at 10-30nm; and ribosomes are excluded from the ER surface at these sites. Fluorescence microscopy demonstrates that organelles can remain attached to ER tubules as they traffic along microtubules. The combinations of these tools with classical molecular biology and biochemical tools have identified molecules implicated in several MCSs and elucidated their functions, including lipid and ion transport between organelles and organelles positioning and division. MCSs are central to normal cell physiology. Moreover, several MCSs proteins are linked to various diseases: Seipin, Protrudin, and Spastin to hereditary spastic paraplegia; VAPA and VAPB to amyotrophic lateral sclerosis; Dnm2 and Mfn2 to charcot marie tooth; Stim1 and Orai1 to tubular aggregate myopathy; and ACBD5 to retinal dystrophy. Whether defects in MCSs functions cause these diseases directly or indirectly remain to be explored. Recent progress has begun to identify some of the molecular machineries that regulate MCSs formation. Dissecting roles of these factors will strengthen our understanding of the integrative nature of MCSs. The advancement of diverse microscopy techniques will allow us to track multiple factors at MCSs simultaneously in real time and in high resolution, and this may help us gain a more detailed view of MCSs biology and their related physiological processes. Our textbook image of organelles has changed. Instead of isolated cellular compartments, the picture now emerging shows organelles as largely interdependent structures that can communicate through membrane contact sites (MCSs). MCSs are sites where opposing organelles are tethered but do not fuse. MCSs provide a hybrid location where the toolkits of two different organelles can work together to perform vital cellular functions, such as lipid and ion transfer, signaling, and organelle division. Here we concentrate on MCSs involving the endoplasmic reticulum (ER), an organelle forming an extensive network of cisternae and tubules. We will highlight how the dynamic ER network regulates a plethora of cellular processes through MCSs with various organelles and with the plasma membrane (PM). Fig. 0. Endoplasmic reticulum (ER) membrane contacts sites (MCSs) with other organelles and the plasma membrane (PM). The ER forms MCSs with mitochondria, Golgi, endosomes, peroxisomes, lipid droplets and the PM. These MCSs are closely opposed but not fused membranes containing various molecular machineries. Factors localized to these MCSs mediate essential cellular processes including lipid and ion exchange, organelle positioning and biogenesis.
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DOI：
10.1083/jcb.201609033
发表时间：
2017-05-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Allison R;Edgar JR;Pearson G;Rizo T;Newton T;Günther S;Berner F;Hague J;Connell JW;Winkler J;Lippincott-Schwartz J;Beetz C;Winner B;Reid E
通讯作者：
Reid E
影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
影响因子：
8.8
作者：
Elbaz-Alon Y;Eisenberg-Bord M;Shinder V;Stiller SB;Shimoni E;Wiedemann N;Geiger T;Schuldiner M
通讯作者：
Schuldiner M
影响因子：
64.8
作者：
Fan G;Baker ML;Wang Z;Baker MR;Sinyagovskiy PA;Chiu W;Ludtke SJ;Serysheva II
通讯作者：
Serysheva II
影响因子：
21.3
作者：
Bleazard, W;McCaffery, JM;Shaw, JM
通讯作者：
Shaw, JM