选择性内质网（ER）吞噬机制重塑神经发生过程中的ER，这一成果由美国哈佛大学医学院J. Wade Harper研究组经过不懈努力而取得。该项研究成果发表在2024年3月1日出版的《自然-细胞生物学》上。

通过将监测体外分化过程中ER重塑的基因可控诱导神经元（iNeuron）系统与蛋白质组学和计算工具相结合，研究人员揭示了选择性自噬调控ER蛋白质组重塑的定量图谱。通过分析单一和组合的ER-吞噬受体突变体，研究确定了每种受体对ER蛋白清除的程度和选择性贡献。

利用空间传感器和通量报告器，研究证明了轴突中ER受体存在特异性自噬捕获；通过冷冻电子断层扫描，研究人员直接观察到了神经元突起中自噬体内的管状ER膜。这种ER蛋白质组重塑的分子机制和多功能基因工具包，为了解细胞状态转换过程中各个ER-吞噬受体对ER重塑的贡献提供了定量工具。

据悉，ER利用多种多样的蛋白质组合来调控不同细胞功能，例如调控蛋白质和脂质的合成、钙离子转运和细胞器间通讯。神经发生是一个典型的ER重塑过程，在这一过程中，管状ER网络通过ER重塑蛋白组装到新形成的神经元突起中，从而形成高度极化的树突和轴突。先前的研究表明，自噬在ER重塑中扮演重要角色；体内自噬缺陷的神经元在轴突突触突起过程中存在ER积聚，而膜嵌入ER-吞噬受体FAM134B与人类感觉神经和自主神经病变有关。然而，对ER选择性清除的机制以及单个ER吞噬受体的功能了解有限。

附：英文原文

Title: Combinatorial selective ER-phagy remodels the ER during neurogenesis

Author: Hoyer, Melissa J., Capitanio, Cristina, Smith, Ian R., Paoli, Julia C., Bieber, Anna, Jiang, Yizhi, Paulo, Joao A., Gonzalez-Lozano, Miguel A., Baumeister, Wolfgang, Wilfling, Florian, Schulman, Brenda A., Harper, J. Wade

Issue&Volume: 2024-03-01

Abstract: The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis to calcium ion flux and inter-organelle communication. A case in point concerns the process of neurogenesis, where a refined tubular ER network is assembled via ER shaping proteins into the newly formed neuronal projections to create highly polarized dendrites and axons. Previous studies have suggested a role for autophagy in ER remodelling, as autophagy-deficient neurons in vivo display axonal ER accumulation within synaptic boutons, and the membrane-embedded ER-phagy receptor FAM134B has been genetically linked with human sensory and autonomic neuropathy. However, our understanding of the mechanisms underlying selective removal of the ER and the role of individual ER-phagy receptors is limited. Here we combine a genetically tractable induced neuron (iNeuron) system for monitoring ER remodelling during in vitro differentiation with proteomic and computational tools to create a quantitative landscape of ER proteome remodelling via selective autophagy. Through analysis of single and combinatorial ER-phagy receptor mutants, we delineate the extent to which each receptor contributes to both the magnitude and selectivity of ER protein clearance. We define specific subsets of ER membrane or lumenal proteins as preferred clients for distinct receptors. Using spatial sensors and flux reporters, we demonstrate receptor-specific autophagic capture of ER in axons, and directly visualize tubular ER membranes within autophagosomes in neuronal projections by cryo-electron tomography. This molecular inventory of ER proteome remodelling and versatile genetic toolkit provide a quantitative framework for understanding the contributions of individual ER-phagy receptors for reshaping ER during cell state transitions.

DOI: 10.1038/s41556-024-01356-4

Source: https://www.nature.com/articles/s41556-024-01356-4