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泛素化调控ER自噬和内质网重塑
2023-05-29 14:38

德国法兰克福大学Ivan Diki?团队发现,泛素化调控内质网(ER)自噬和内质网重塑。2023年5月24日,《自然》杂志在线发表了这项研究成果。

研究人员报告说,ER自噬受体FAM134B在其网状同源结构域(RHD)内的泛素化促进了受体的聚集和与脂质化LLC3B的结合,从而刺激了ER自噬。分子动力学(MD)模拟显示泛素化如何扰乱模型双层中的RHD结构并增强膜曲率诱导。RHD上的泛素分子介导相邻RHD之间的相互作用,形成密集的受体聚集,进而促进脂质双层的大规模重塑。脂质体和泛素化的FAM134B在体外重组了膜重塑。

利用超分辨率显微镜,研究人员发现了细胞中的FAM134B纳米团块和微团块。定量图像分析显示,泛素介导的FAM134B寡聚化和聚集大小的增加。研究人员发现,在多聚体ER自噬受体聚集内的E3连接酶AMFR催化FAM134B泛素化并调节ER自噬的动态通量。这些结果表明,泛素化通过受体聚集增强了RHD的功能,促进了ER自噬,并控制了ER重塑以应对细胞需求。

据介绍,ER通过一种选择性的自噬途径,即ER自噬,不断进行重塑。ER自噬受体在这一过程中起着核心作用,但其调节机制在很大程度上仍是未知的。

附:英文原文

Title: Ubiquitination regulates ER-phagy and remodelling of endoplasmic reticulum

Author: Gonzlez, Alexis, Covarrubias-Pinto, Adriana, Bhaskara, Ramachandra M., Glogger, Marius, Kuncha, Santosh K., Xavier, Audrey, Seemann, Eric, Misra, Mohit, Hoffmann, Marina E., Bruning, Bastian, Balakrishnan, Ashwin, Qualmann, Britta, Dtsch, Volker, Schulman, Brenda A., Kessels, Michael M., Hbner, Christian A., Heilemann, Mike, Hummer, Gerhard, Diki, Ivan

Issue&Volume: 2023-05-24

Abstract: The endoplasmic reticulum (ER) undergoes continuous remodelling via a selective autophagy pathway, known as ER-phagy1. ER-phagy receptors have a central role in this process2, but the regulatory mechanism remains largely unknown. Here we report that ubiquitination of the ER-phagy receptor FAM134B within its reticulon homology domain (RHD) promotes receptor clustering and binding to lipidated LC3B, thereby stimulating ER-phagy. Molecular dynamics (MD) simulations showed how ubiquitination perturbs the RHD structure in model bilayers and enhances membrane curvature induction. Ubiquitin molecules on RHDs mediate interactions between neighbouring RHDs to form dense receptor clusters that facilitate the large-scale remodelling of lipid bilayers. Membrane remodelling was reconstituted in vitro with liposomes and ubiquitinated FAM134B. Using super-resolution microscopy, we discovered FAM134B nanoclusters and microclusters in cells. Quantitative image analysis revealed a ubiquitin-mediated increase in FAM134B oligomerization and cluster size. We found that the E3 ligase AMFR, within multimeric ER-phagy receptor clusters, catalyses FAM134B ubiquitination and regulates the dynamic flux of ER-phagy. Our results show that ubiquitination enhances RHD functions via receptor clustering, facilitates ER-phagy and controls ER remodelling in response to cellular demands.

DOI: 10.1038/s41586-023-06089-2

Source: https://www.nature.com/articles/s41586-023-06089-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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