Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany.
Nature. 2015 Jun 18;522(7556):354-8. doi: 10.1038/nature14498. Epub 2015 Jun 3.
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. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process. 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 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.
内质网（ER）是最大的细胞内内膜系统，能够进行蛋白质和脂质合成、离子稳态、新合成蛋白质的质量控制和细胞器间的通讯。为了满足不同细胞的需求，需要不断地对内质网进行周转和调节，自噬在这个过程中起着重要的作用。然而，其潜在的调节机制仍不清楚。在这里，我们表明 FAM134 网蛋白家族的成员是内质网驻留受体，它们与自噬修饰物 LC3 和 GABARAP 结合，并促进自噬介导的内质网降解（“内质网自噬”）。在人类细胞中下调 FAM134B 蛋白会导致内质网扩张，而过表达 FAM134B 则会导致内质网碎片化和溶酶体降解。导致人类感觉神经病的突变 FAM134B 蛋白无法作为内质网自噬受体发挥作用。同样，在小鼠中破坏 Fam134b 会导致内质网扩张、抑制内质网周转、使细胞对应激诱导的细胞凋亡敏感，并导致感觉神经元退化。因此，通过 FAM134 蛋白进行选择性内质网自噬对于哺乳动物细胞的内稳态是必不可少的，并且控制了内质网在人和小鼠中的形态和周转。
