Degradation of endoplasmic reticulum (ER) by selective autophagy (ER-phagy) is crucial for ER homeostasis. However, it remains unclear how ER scission is regulated for subsequent autophagosomal sequestration and lysosomal degradation. Here, we show that oligomerization of ER-phagy receptor FAM134B (also referred to as reticulophagy regulator 1 or RETREG1) through its reticulon-homology domain is required for membrane fragmentation in vitro and ER-phagy in vivo. Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy. Unexpectedly, FAM134B G216R, a variant derived from a type II hereditary sensory and autonomic neuropathy (HSAN) patient, exhibits gain-of-function defects, such as hyperactive self-association and membrane scission, which results in excessive ER-phagy and sensory neuron death. Therefore, this study reveals a mechanism of ER membrane fragmentation in ER-phagy, along with a signaling pathway in regulating ER turnover, and suggests a potential implication of excessive selective autophagy in human diseases.

中文翻译：

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FAM134B寡聚驱动内质网膜切开，用于ER吞噬。

选择性自噬（ER-phagy）降解内质网（ER）对于ER稳态至关重要。但是，目前尚不清楚如何调节ER分裂以用于随后的自噬体隔离和溶酶体降解。在这里，我们显示通过其网状同源结构域，ER吞噬受体FAM134B（也称为网状调节因子1或RETREG1）的寡聚化是体外膜碎裂和体内ER吞噬所必需的。在内质网应激条件下，活化的CAMK2B使FAM134B的网状同源结构域磷酸化，从而增强FAM134B的寡聚化和膜断裂活性，以适应对内质网吞噬的高需求。出乎意料的是，FAM134B G216R（源自II型遗传性感觉神经和自主神经病（HSAN）患者的变体）显示出功能获得性缺陷，如过度活跃的自我联想和膜分裂，导致过度的ER吞噬和感觉神经元死亡。因此，这项研究揭示了在ER吞噬中ER膜断裂的机制，以及调节ER周转的信号传导途径，并暗示了过度选择性自噬在人类疾病中的潜在影响。