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Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy
Nature ( IF 50.5 ) Pub Date : 2023-05-24 , DOI: 10.1038/s41586-023-06090-9
Hector Foronda 1 , Yangxue Fu 2 , Adriana Covarrubias-Pinto 2 , Hartmut T Bocker 1, 3 , Alexis González 2 , Eric Seemann 4 , Patricia Franzka 1 , Andrea Bock 1 , Ramachandra M Bhaskara 2, 5, 6 , Lutz Liebmann 1 , Marina E Hoffmann 2 , Istvan Katona 7 , Nicole Koch 4 , Joachim Weis 7 , Ingo Kurth 1, 8 , Joseph G Gleeson 9 , Fulvio Reggiori 10, 11, 12 , Gerhard Hummer 6, 13 , Michael M Kessels 4 , Britta Qualmann 4 , Muriel Mari 10, 11 , Ivan Dikić 2, 5 , Christian A Hübner 1, 14
Affiliation  

Membrane-shaping proteins characterized by reticulon homology domains play an important part in the dynamic remodelling of the endoplasmic reticulum (ER). An example of such a protein is FAM134B, which can bind LC3 proteins and mediate the degradation of ER sheets through selective autophagy (ER-phagy)1. Mutations in FAM134B result in a neurodegenerative disorder in humans that mainly affects sensory and autonomic neurons2. Here we report that ARL6IP1, another ER-shaping protein that contains a reticulon homology domain and is associated with sensory loss3, interacts with FAM134B and participates in the formation of heteromeric multi-protein clusters required for ER-phagy. Moreover, ubiquitination of ARL6IP1 promotes this process. Accordingly, disruption of Arl6ip1 in mice causes an expansion of ER sheets in sensory neurons that degenerate over time. Primary cells obtained from Arl6ip1-deficient mice or from patients display incomplete budding of ER membranes and severe impairment of ER-phagy flux. Therefore, we propose that the clustering of ubiquitinated ER-shaping proteins facilitates the dynamic remodelling of the ER during ER-phagy and is important for neuronal maintenance.



中文翻译:

泛素化 ER 形成蛋白的异聚簇驱动 ER 吞噬

以网状同源结构域为特征的膜成形蛋白在内质网 (ER) 的动态重塑中起着重要作用。这种蛋白质的一个例子是 FAM134B,它可以结合 LC3 蛋白并通过选择性自噬(ER-phagy) 1介导 ER 片层的降解。FAM134B突变会导致人类神经退行性疾病,主要影响感觉神经元和自主神经元2。在这里,我们报告了 ARL6IP1,这是另一种内质网成形蛋白,它包含网状同源结构域并与感觉丧失相关3, 与 FAM134B 相互作用并参与 ER 吞噬所需的异聚多蛋白簇的形成。此外,ARL6IP1 的泛素化促进了这一过程。因此,小鼠Arl6ip1的破坏会导致感觉神经元中的 ER 片层扩张,随着时间的推移而退化。从Arl6ip1缺陷小鼠或患者获得的原代细胞显示 ER 膜出芽不完全和 ER 吞噬通量严重受损。因此,我们提出泛素化 ER 形成蛋白的聚集促进了 ER 吞噬过程中 ER 的动态重塑,并且对神经元维持很重要。

更新日期:2023-05-25
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