Falahati Hanieh, Wu Yumei, Fang Mumu, De Camilli Pietro
Departments of Neuroscience and of Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, CT 06510, USA.
Departments of Neuroscience and of Cell Biology, Howard Hughes Medical Institute, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, CT 06510, USA.
Curr Biol. 2025 Jan 20;35(2):265-276.e4. doi: 10.1016/j.cub.2024.11.010. Epub 2024 Dec 2.
The endoplasmic reticulum (ER) is a continuous cellular endomembrane network that displays focal specializations. Most notable examples of such specializations include the spine apparatus of neuronal dendrites and the cisternal organelle of axonal initial segments. Both organelles exhibit stacks of smooth ER sheets with a narrow lumen, interconnected by a dense protein matrix. The actin-binding protein synaptopodin is required for their formation, but the underlying mechanisms remain unknown. Here, we report that the spine apparatus and synaptopodin are conserved from flies to mammals and that a highly conserved region of this protein is necessary, but not sufficient, for its association with ER. We reveal a dual role of synaptopodin in generating actin bundles and in linking them to the ER. Expression of a synaptopodin construct constitutively anchored to the ER in non-neuronal cells is sufficient to generate stacked ER cisterns resembling the spine apparatus. Cisterns within these stacks are molecularly distinct from the surrounding ER and are connected to each other by an actin-based matrix that contains proteins also found at the spine apparatus of neuronal spines. Our findings shed light on mechanisms governing the biogenesis of this peculiar structure and represent a step toward understanding the elusive properties of this organelle.
内质网（ER）是一个连续的细胞内膜网络，具有局部特化结构。这类特化结构最显著的例子包括神经元树突的棘器和轴突起始段的池状细胞器。这两种细胞器都呈现出具有狭窄内腔的平滑内质网片层堆叠结构，由致密的蛋白质基质相互连接。肌动蛋白结合蛋白突触足蛋白是它们形成所必需的，但潜在机制仍不清楚。在这里，我们报告棘器和突触足蛋白从果蝇到哺乳动物都是保守的，并且该蛋白的一个高度保守区域对于其与内质网的结合是必要的，但并不充分。我们揭示了突触足蛋白在生成肌动蛋白束以及将它们连接到内质网方面的双重作用。在非神经元细胞中组成性锚定在内质网上的突触足蛋白构建体的表达足以产生类似于棘器的堆叠内质网池。这些堆叠中的池在分子上与周围的内质网不同，并且通过基于肌动蛋白的基质相互连接，该基质包含在神经元棘突的棘器中也发现的蛋白质。我们的发现揭示了控制这种特殊结构生物发生的机制，并朝着理解这个细胞器难以捉摸的特性迈出了一步。
