Regulation of endoplasmic reticulum turnover by selective autophagy
Regulation of endoplasmic reticulum turnover by selective autophagy
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DOI：
10.1038/nature14498
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发表时间：
2015-06-18
期刊：
影响因子：
64.8
通讯作者：
Dikic, Ivan
中科院分区：
文献类型：
--
作者：
Khaminets, Aliaksandr;Heinrich, Theresa;Dikic, Ivan
内质网（ER）是最大的细胞内内膜系统，使蛋白质和脂质合成，离子稳态，新合成的蛋白质和细胞器通信的质量控制（1）。需要恒定的ER周转和调节以满足不同的细胞需求，并且自噬在该过程中具有重要作用（2-8）。然而，其潜在的监管机制仍然无法解释。在这里，我们表明，FAM 134 reticulon蛋白家族的成员是ER驻留受体，结合自噬修饰剂LC 3和GABARAP，并促进ER降解自噬（'ER-吞噬'）。人细胞中FAM 134 B蛋白的下调导致ER的扩增，而FAM 134 B过表达导致ER片段化和溶酶体降解。导致人类感觉神经病变的突变FAM 134 B蛋白（9）不能作为ER-吞噬受体。因此，Fam 134 b在小鼠中的破坏引起ER的扩增，抑制ER周转，使细胞对应激诱导的凋亡性细胞死亡敏感，并导致感觉神经元的变性。因此，通过FAM 134蛋白的选择性ER-吞噬对于哺乳动物细胞稳态是必不可少的，并且控制小鼠和人中的ER形态和周转。
The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication(1). Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process(2-8). However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans(9) are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans.