PDF(Pubmed)
Abstract：
The accumulation of protein aggregates is a hallmark of many diseases, including Alzheimer\'s disease. As a major pillar of the proteostasis network, autophagy mediates the degradation of protein aggregates. The autophagy cargo receptor p62 recognizes ubiquitin on proteins and cooperates with TAX1BP1 to recruit the autophagy machinery. Paradoxically, protein aggregates are not degraded in various diseases despite p62 association. Here, we reconstituted the recognition by the autophagy receptors of physiological and pathological Tau forms. Monomeric Tau recruits p62 and TAX1BP1 via the sequential actions of the chaperone and ubiquitylation machineries. In contrast, Tau fibrils from Alzheimer\'s disease brains are recognized by p62 but fail to recruit TAX1BP1. This failure is due to the masking of fibrils ubiquitin moieties by p62. Tau fibrils are resistant to deubiquitylation, and, thus, this nonproductive interaction of p62 with the fibrils is irreversible. Our results shed light on the mechanism underlying autophagy evasion by protein aggregates and their consequent accumulation in disease.
摘要：
蛋白质聚集体的积累是许多疾病的标志，包括老年痴呆症.作为蛋白质稳定网络的主要支柱，自噬介导蛋白质聚集体的降解。自噬货物受体p62识别蛋白质上的泛素，并与TAX1BP1合作募集自噬机制。矛盾的是,尽管p62相关，但蛋白质聚集体在各种疾病中并未降解。这里,我们重建了生理和病理Tau形式的自噬受体的识别。单体Tau通过伴侣和泛素化机制的顺序作用招募p62和TAX1BP1。相比之下,来自阿尔茨海默病大脑的tau原纤维被p62识别，但不能募集TAX1BP1。这种失败是由于p62掩盖了原纤维泛素部分。Tau原纤维对去泛素化有抗性，and,因此，p62与原纤维的这种非生产性相互作用是不可逆的。我们的结果揭示了蛋白质聚集体及其在疾病中积累的自噬逃避机制。
