Membrane-shaping proteins characterized by reticulon homology domains play an important part in the dynamic remodelling of the endoplasmic reticulum (ER). An example of such a protein is FAM134B, which can bind LC3 proteins and mediate the degradation of ER sheets through selective autophagy (ER-phagy)¹. Mutations in FAM134B result in a neurodegenerative disorder in humans that mainly affects sensory and autonomic neurons². Here we report that ARL6IP1, another ER-shaping protein that contains a reticulon homology domain and is associated with sensory loss³, interacts with FAM134B and participates in the formation of heteromeric multi-protein clusters required for ER-phagy. Moreover, ubiquitination of ARL6IP1 promotes this process. Accordingly, disruption of Arl6ip1 in mice causes an expansion of ER sheets in sensory neurons that degenerate over time. Primary cells obtained from Arl6ip1-deficient mice or from patients display incomplete budding of ER membranes and severe impairment of ER-phagy flux. Therefore, we propose that the clustering of ubiquitinated ER-shaping proteins facilitates the dynamic remodelling of the ER during ER-phagy and is important for neuronal maintenance.

以网状同源结构域为特征的膜成形蛋白在内质网 (ER) 的动态重塑中起着重要作用。^{这种蛋白质的一个例子是 FAM134B，它可以结合 LC3 蛋白并通过选择性自噬（ER-phagy） 1}介导 ER 片层的降解。FAM134B突变会导致人类神经退行性疾病，主要影响感觉神经元和自主神经元²。在这里，我们报告了 ARL6IP1，这是另一种内质网成形蛋白，它包含网状同源结构域并与感觉丧失相关³, 与 FAM134B 相互作用并参与 ER 吞噬所需的异聚多蛋白簇的形成。此外，ARL6IP1 的泛素化促进了这一过程。因此，小鼠Arl6ip1的破坏会导致感觉神经元中的 ER 片层扩张，随着时间的推移而退化。从Arl6ip1缺陷小鼠或患者获得的原代细胞显示 ER 膜出芽不完全和 ER 吞噬通量严重受损。因此，我们提出泛素化 ER 形成蛋白的聚集促进了 ER 吞噬过程中 ER 的动态重塑，并且对神经元维持很重要。