Endocytosis in the axon initial segment maintains neuronal polarity.
Endocytosis in the axon initial segment maintains neuronal polarity.
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轴突初始段中的内吞作用保持神经元极性。
DOI：
10.1038/s41586-022-05074-5
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发表时间：
2022-09
期刊：
影响因子：
64.8
通讯作者：
Shen, Kang
中科院分区：
文献类型：
--
作者：
Eichel, Kelsie;Uenaka, Takeshi;Belapurkar, Vivek;Lu, Rui;Cheng, Shouqiang;Pak, Joseph S.;Taylor, Caitlin A.;Sudhof, Thomas C.;Malenka, Robert;Wernig, Marius;Ozkan, Engin;Perrais, David;Shen, Kang
神经元是高度极化的细胞，它们面临着划分大量多样的蛋白质库以使其正常运作的基本挑战。轴突初始段 (AIS) 是一个专门的域，它将神经元的形态、生物化学和功能上不同的轴突和树突区分开来。 AIS 如何保持这些隔间之间的极性尚不完全清楚。在这里，我们发现，在秀丽隐杆线虫、小鼠、大鼠和人类神经元中，树突状和轴突极化的跨膜蛋白被 AIS 中的内吞机制识别，被强力内吞并靶向晚期内体进行降解。迫使受体与 AIS 主组织者锚蛋白 G 相互作用，拮抗 AIS 中的受体内吞作用，导致 AIS 中受体积累，并导致极性缺陷以及随后的形态和行为缺陷。因此，内吞去除扩散到 AIS 中的极化受体可作为一种膜清除机制，可能与已知的 AIS 扩散屏障机制结合使用，以维持质膜上的神经元极性。我们的结果揭示了 AIS 中保守的内吞清除机制，通过增强轴突和树突室膜边界来维持神经元极性。轴突起始段质膜蛋白的内吞作用和降解，以及扩散屏障机制，维持了秀丽隐杆线虫、小鼠、大鼠和人类神经元中质膜蛋白的极化分布。
Neurons are highly polarized cells that face the fundamental challenge of compartmentalizing a vast and diverse repertoire of proteins in order to function properly. The axon initial segment (AIS) is a specialized domain that separates a neuron’s morphologically, biochemically and functionally distinct axon and dendrite compartments. How the AIS maintains polarity between these compartments is not fully understood. Here we find that in Caenorhabditis elegans, mouse, rat and human neurons, dendritically and axonally polarized transmembrane proteins are recognized by endocytic machinery in the AIS, robustly endocytosed and targeted to late endosomes for degradation. Forcing receptor interaction with the AIS master organizer, ankyrinG, antagonizes receptor endocytosis in the AIS, causes receptor accumulation in the AIS, and leads to polarity deficits with subsequent morphological and behavioural defects. Therefore, endocytic removal of polarized receptors that diffuse into the AIS serves as a membrane-clearance mechanism that is likely to work in conjunction with the known AIS diffusion-barrier mechanism to maintain neuronal polarity on the plasma membrane. Our results reveal a conserved endocytic clearance mechanism in the AIS to maintain neuronal polarity by reinforcing axonal and dendritic compartment membrane boundaries. Endocytosis and degradation of plasma membrane proteins in the axon initial segment, together with the diffusion-barrier mechanism, maintain a polarized distribution of plasma membrane proteins in Caenorhabditis elegans, mouse, rat and human neurons.
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