RNF 213直接泛素化介导的糖原质量控制
RNF213直接泛素化介导的糖原质量控制
作者： 小柯机器人 发布时间：2026/9/21 8:29:02
本期文章：《自然》：Online/在线发表
英国剑桥大学阿登布鲁克医院医学系Felix Randow及其研究小组开发出RNF213直接泛素化糖原的质量控制。这一研究成果于2026年9月15日发表在国际顶尖学术期刊《自然》上。
生物分子的质量控制对机体健康至关重要。虽然DNA修复和蛋白质质量控制已得到充分理解，但细胞如何监测糖原等其他重要生物分子仍不明确。异常、分支不良的糖原积累为不溶性聚葡萄糖苷体，会导致严重疾病。在此，研究人员发现了泛素化异常糖原的自噬，这是一种此前未被认识的质量控制机制，可保护大脑免受聚葡萄糖苷积累的影响。该机制依赖于E3泛素连接酶RNF213。缺乏RNF213连接酶活性的小鼠在小脑、脑桥和海马中积累聚葡萄糖苷。利用被工程化改造以产生聚葡萄糖苷的细胞，研究人员表明RNF213选择性泛素化异常糖原。对结合糖原衍生麦芽七糖的RNF213进行冷冻电镜分析，揭示其CBM20结构域结合线性寡糖。破坏碳水化合物结合会导致针对生理性糖原的E3连接酶活性增强，表明CBM20结构域限制了RNF213对生理性糖原的活性。上位性分析将RNF213置于LUBAC上游，提示存在一个由多种E3连接酶组成的分级网络来监测糖原质量。泛素化的聚葡萄糖苷招募自噬受体SQSTM1、TAX1BP1和optineurin，从而触发其被摄入自噬体。这些发现将RNF213鉴定为一种质量控制因子，通过直接泛素化聚葡萄糖苷来防止星形胶质细胞中聚葡萄糖苷的积累，揭示了非蛋白质泛素化在糖原质量控制中的关键作用。
附：英文原文
Title: Quality control of glycogen through direct ubiquitylation by RNF213
Author: Yip, Matthew C. J., Naydenova, Katerina, Otten, Elsje G., Heatley, Alexander, Moe, Agnes, Anton, Leonie, de los Reyes-Ramrez, Luca, Jolin, Helen E., Langevin, Frederic, Wiacek, Michal, Franco, Catarina, Bertolotti, Anne, Kukulski, Wanda, McKenzie, Andrew N. J., Randow, Felix
Issue&Volume: 2026-09-15
Abstract: Quality control of biomolecules is vital for organismal health. While DNA repair and protein quality control are well understood, how cells monitor other important biomolecules such as glycogen remains ill-defined. The accumulation of aberrant, poorly branched glycogen into insoluble polyglucosan bodies causes severe disease1,2. Here, we discover autophagy of ubiquitylated aberrant glycogen as a previously unrecognized quality control mechanism safeguarding the brain from polyglucosan buildup. This mechanism depends on the E3 ubiquitin ligase RNF213. Mice lacking ligase activity in RNF213 accumulate polyglucosan in cerebellum, pons, and hippocampus. Using cells engineered to produce polyglucosan, we show that RNF213 selectively ubiquitylates abnormal glycogen. Cryo-EM analysis of RNF213 bound to glycogen-derived maltoheptaose revealed its CBM20 domain binds linear oligosaccharides. Disrupting carbohydrate binding results in gain of E3 ligase activity towards physiological glycogen, indicating the CBM20 domain limits RNF213 activity towards physiological glycogen. Epistasis analysis places RNF213 upstream of LUBAC, suggesting a hierarchical network of multiple E3 ligases surveying glycogen quality. Ubiquitylated polyglucosan recruits the autophagy receptors SQSTM1, TAX1BP1, and optineurin, thereby triggering uptake into autophagosomes. These findings identify RNF213 as a quality control factor preventing polyglucosan accumulation in astrocytes through direct ubiquitylation of polyglucosan, revealing an essential role for non-protein ubiquitylation in glycogen quality control.
DOI: 10.1038/s41586-026-11139-6
Source: https://www.nature.com/articles/s41586-026-11139-6