Department of Biochemistry, Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Neurology of Second Affiliated Hospital, Institute of Neuroscience, Mental Health Center, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
EMBO J. 2020 Mar 2;39(5):e102608. doi: 10.15252/embj.2019102608. Epub 2020 Jan 13.
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.
内质网（ER）的选择性自噬（ER 噬）降解对于 ER 稳态至关重要。然而，对于随后的自噬体隔离和溶酶体降解，ER 分裂是如何被调节的仍然不清楚。在这里，我们表明 ER 噬受体 FAM134B（也称为网质体自噬调节因子 1 或 RETREG1）通过其网质体同源结构域的寡聚化对于体外膜分裂和体内 ER 噬是必需的。在 ER 应激条件下，激活的 CAMK2B 磷酸化 FAM134B 的网质体同源结构域，这增强了 FAM134B 寡聚化和在膜分裂中的活性，以适应 ER 噬的高需求。出乎意料的是，源自 II 型遗传性感觉和自主神经病（HSAN）患者的变体 FAM134B G216R 表现出功能获得性缺陷，例如过度的自缔合和膜分裂，这导致过度的 ER 噬和感觉神经元死亡。因此，这项研究揭示了 ER 噬中的 ER 膜分裂的机制，以及调节 ER 周转的信号通路，并提示过度选择性自噬可能与人类疾病有关。
