德国自由席勒大学Christian A. Hübner等研究人员合作发现，泛素化ER塑形蛋白的异源聚集驱动ER自噬。该研究于2023年5月24日在线发表于国际一流学术期刊《自然》。

研究人员表示，以网状同源结构域为特征的膜塑造蛋白在内质网（ER）的动态重塑中发挥着重要作用。这种蛋白的一个例子是FAM134B，它能与LC3蛋白结合并通过选择性自噬（ER自噬）介导ER的降解。FAM134B的突变导致了人类的一种神经退行性疾病，主要影响感觉和自主神经元。

研究人员报告了ARL6IP1，另一个含有网状同源结构域的ER塑造蛋白，与感觉丧失有关，并与FAM134B相互作用，参与形成ER自噬所需的异源多蛋白聚集。此外，ARL6IP1的泛素化能促进这一过程。因此，中断小鼠的Arl6ip1会导致感觉神经元中ER的扩大，并随着时间的推移而退化。从Arl6ip1缺陷的小鼠或患者身上获得的原代细胞显示出ER膜的不完全出芽和ER自噬通量的严重损害。因此，研究人员提出，泛素化ER塑形蛋白的聚集促进了ER自噬过程中ER的动态重塑，对神经元的维持很重要。

附：英文原文

Title: Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy

Author: Foronda, Hector, Fu, Yangxue, Covarrubias-Pinto, Adriana, Bocker, Hartmut T., Gonzlez, Alexis, Seemann, Eric, Franzka, Patricia, Bock, Andrea, Bhaskara, Ramachandra M., Liebmann, Lutz, Hoffmann, Marina E., Katona, Istvan, Koch, Nicole, Weis, Joachim, Kurth, Ingo, Gleeson, Joseph G., Reggiori, Fulvio, Hummer, Gerhard, Kessels, Michael M., Qualmann, Britta, Mari, Muriel, Diki, Ivan, Hbner, Christian A.

Issue&Volume: 2023-05-24

Abstract: 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.

DOI: 10.1038/s41586-023-06090-9

Source: https://www.nature.com/articles/s41586-023-06090-9