FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy
FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy
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FAM134B 寡聚化驱动内质网膜分裂以实现 ER 吞噬
DOI：
10.15252/embj.2019102608
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发表时间：
2020-01-13
期刊：
影响因子：
11.4
通讯作者：
Sun, Qiming
中科院分区：
文献类型：
--
作者：
Jiang, Xiao;Wang, Xinyi;Sun, Qiming
选择性自噬（ER-phagy）降解内质网（ER）对内质网稳态至关重要。然而，目前尚不清楚内质网分裂是如何调节随后的自噬体隔离和溶酶体降解的。在这里，我们发现er吞噬受体FAM134B（也被称为网状吞噬调节因子1或RETREG1）通过其网状同源结构域的寡聚化是体外膜断裂和体内er吞噬所必需的。在er胁迫条件下，活化的CAMK2B磷酸化FAM134B的网状同源结构域，从而增强FAM134B的寡聚化和膜断裂活性，以适应er吞噬的高需求。出乎意料的是，来自II型遗传性感觉和自主神经病变（HSAN）患者的变体FAM134B G216R表现出功能获得性缺陷，如过度活跃的自我关联和膜断裂，从而导致er过度吞噬和感觉神经元死亡。因此，本研究揭示了ER吞噬中ER膜断裂的机制，以及调节ER转换的信号通路，并提示过度选择性自噬在人类疾病中的潜在意义。
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.