美国约翰霍普金斯大学医学院Wenchi Zhang和Paul F. Worley共同合作，近期取得重要工作进展。他们研究提出，自噬适配体TRIAD3A通过嵌入相分离促进tau纤维化。相关研究成果2024年7月15日在线发表于《自然—细胞生物学》杂志上。

据介绍，多种神经退行性疾病的特征是tau蛋白的异常积聚。

研究人员报告了一种RING-in-between-RING型E3连接酶，TRIAD3A，它作为tau的自噬接头发挥作用。TRIAD3A（RNF216）是一种重要的基因，其突变会导致年龄进行性神经退行性变。研究结果表明，TRIAD3A E3连接酶催化混合的K11/K63多泛素链并自组装成液-液相分离（LLPS）液滴。Tau被泛素化并在TRIAD3A LLPS液滴内积累，并通过LC3相互作用区域靶向Tau进行自噬降解。出乎意料的是，被隔离在TRIAD3A液滴内的tau迅速转化为纤维状聚集体，而没有tau的过渡液相。

体内研究表明，TRIAD3A在tau蛋白病小鼠模型中减少了磷酸化tau蛋白的积累，TRIAD2A的疾病相关突变增加了磷酸化tau蛋白的积聚，加剧了胶质增生，并增加了病理性tau蛋白扩散。在人类阿尔茨海默病大脑中，TRIAD3A与tau淀粉样蛋白以多种组织学形式共定位，表明其在tau蛋白抑制中起作用。

总之，这一研究表明，TRIAD3A是一种自噬接头，利用E3连接酶和LLPS作为捕获货物的机制，似乎与神经退行性疾病特别相关。

附：英文原文

Title: The autophagy adaptor TRIAD3A promotes tau fibrillation by nested phase separation

Author: Zhou, Jiechao, Chuang, Yang an, Redding-Ochoa, Javier, Zhang, Rongzhen, Platero, Alexander J., Barrett, Alexander H., Troncoso, Juan C., Worley, Paul F., Zhang, Wenchi

Issue&Volume: 2024-07-15

Abstract: Multiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. Here, we report a RING-in-between-RING-type E3 ligase, TRIAD3A, that functions as an autophagy adaptor for tau. TRIAD3A(RNF216) is an essential gene with mutations causing age-progressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyses mixed K11/K63 polyubiquitin chains and self-assembles into liquid–liquid phase separated (LLPS) droplets. Tau is ubiquitinated and accumulates within TRIAD3A LLPS droplets and, via LC3 interacting regions, targets tau for autophagic degradation. Unexpectedly, tau sequestered within TRIAD3A droplets rapidly converts to fibrillar aggregates without the transitional liquid phase of tau. In vivo studies show that TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and a disease-associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis and increases pathological tau spreading. In human Alzheimer disease brain, TRIAD3A co-localizes with tau amyloid in multiple histological forms, suggesting a role in tau proteostasis. TRIAD3A is an autophagic adaptor that utilizes E3 ligase and LLPS as a mechanism to capture cargo and appears especially relevant to neurodegenerative diseases.

DOI: 10.1038/s41556-024-01461-4

Source: https://www.nature.com/articles/s41556-024-01461-4