A model for the self-organization of vesicular flux and protein distributions in the Golgi apparatus.
A model for the self-organization of vesicular flux and protein distributions in the Golgi apparatus.
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DOI：
10.1371/journal.pcbi.1003125
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发表时间：
2013
影响因子：
4.3
通讯作者：
Müsch A
中科院分区：
文献类型：
--
作者：
Ispolatov I;Müsch A
通过囊泡交换产生两个不相同的膜隔室被认为需要两种类型的囊泡，其由选择性募集货物的不同胞质外被指定，以及两种膜结合的SNARE对，其指定融合并且对每种类型的囊泡的亲和力不同。哺乳动物高尔基复合体由6-8个不同的池组成，这些池经历逐渐成熟和替换，但只有两个SNARE对。我们提出了一个模型，解释了如何不同的组成高尔基池可以产生两个，甚至一个单一的陷阱对和一个囊泡外套。老化脑池中活性SNARE浓度的衰减为顺式反式SNARE梯度提供了种子，顺式反式SNARE梯度产生主要的逆行囊泡通量，这进一步增强了梯度。这种通量反过来又产生了观察到的高尔基体酶的不均匀稳态分布，这些酶相互竞争并与SNARE竞争并入运输囊泡。我们分析表明，稳态陷阱浓度随池数呈指数衰减。速率方程的数值解再现了实验观察到的SNARE梯度，在顺式、中间和反式中重叠的酶峰，以及报道的跨越高尔基体的囊泡性质的变化：起源于较年轻的脑池的囊泡主要含有高尔基体酶和富集在这些脑池中的SNARE，并通过内质网（ER）广泛地再循环，而另一个囊泡亚群含有在较老的脑池中普遍存在的高尔基体蛋白，并且几乎不能到达ER。我们已经开发了一个定量模型来解决细胞生物学中的一个基本问题：高尔基体，一个由多个交换囊泡的脑池组成的细胞器，如何稳定地保持其不均匀的蛋白质组成，面对持续的脑池老化和替换，以及货物的进出。我们不假设任何先验极性内高尔基体或方向性的泡交通。随着年龄的增长，高尔基体池不可避免地失去了指定囊泡融合的活性蛋白质，即SNARE分子，从而打破了隔室之间的对称性，并为定向囊泡运输建立了“种子”。在老的脑池中SNARE浓度的这种小的降低然后通过SNARE的逐渐更定向的囊泡运输而进一步自我增强。酶竞争掺入主要是逆行融合囊泡反过来产生重叠，但不同的固定酶峰。应用这些一般机制的融合不对称性和竞争性囊泡加载的实际情况中堆叠的哺乳动物高尔基体，我们再现了实验观察到的分布的两个陷阱对，在高尔基体中操作，酶峰在顺式，中间和反式cisterectin。我们相信，我们的研究尝试了第一个自洽的解释极性在高尔基堆栈。
The generation of two non-identical membrane compartments via exchange of vesicles is considered to require two types of vesicles specified by distinct cytosolic coats that selectively recruit cargo, and two membrane-bound SNARE pairs that specify fusion and differ in their affinities for each type of vesicles. The mammalian Golgi complex is composed of 6–8 non-identical cisternae that undergo gradual maturation and replacement yet features only two SNARE pairs. We present a model that explains how distinct composition of Golgi cisternae can be generated with two and even a single SNARE pair and one vesicle coat. A decay of active SNARE concentration in aging cisternae provides the seed for a cis trans SNARE gradient that generates the predominantly retrograde vesicle flux which further enhances the gradient. This flux in turn yields the observed inhomogeneous steady-state distribution of Golgi enzymes, which compete with each other and with the SNAREs for incorporation into transport vesicles. We show analytically that the steady state SNARE concentration decays exponentially with the cisterna number. Numerical solutions of rate equations reproduce the experimentally observed SNARE gradients, overlapping enzyme peaks in cis, medial and trans and the reported change in vesicle nature across the Golgi: Vesicles originating from younger cisternae mostly contain Golgi enzymes and SNAREs enriched in these cisternae and extensively recycle through the Endoplasmic Reticulum (ER), while the other subpopulation of vesicles contains Golgi proteins prevalent in older cisternae and hardly reaches the ER. We have developed a quantitative model to address a fundamental question in cell biology: How does the Golgi apparatus, an organelle composed of multiple cisternae that exchange vesicles, steadily maintains its inhomogeneous protein composition in the face of ongoing cisternal aging and replacement, and cargo entry and exit. We do not assume any a priori polarity within the Golgi apparatus or directionality of vesicular traffic. The Golgi cisternae inevitably lose active proteins that specify vesicle fusion, the SNARE molecules, as they age, thus breaking the symmetry between compartments and establishing the “seed” for directional vesicular transport. This small decrease in SNARE concentration in older cisternae is then further self-enhanced by the progressively more directional vesicular transport of SNAREs. Competition of enzymes for incorporation into predominantly retrograde-fusing vesicles in turn generates overlapping but distinct stationary enzyme peaks. Applying these general mechanisms of fusion asymmetry and competitive vesicle loading to the actual situation in the stacked mammalian Golgi, we reproduced the experimentally observed distributions of the two SNARE pairs that operate in the Golgi, and enzyme peaks in cis, medial and trans cisternae. We believe that our study attempts the first self-consistent explanation for the polarity in the Golgi stack.
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