Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Psychiatry and Neuroscience and Brain Disease Center, China Medical University Hospital, Taichung, Taiwan, Republic of China.
Nat Cell Biol. 2024 Aug;26(8):1274-1286. doi: 10.1038/s41556-024-01461-4. Epub 2024 Jul 15.
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.
多种神经退行性疾病的特征是异常的 Tau 蛋白聚集。在这里，我们报告了一种 RING-in-between-RING 型 E3 连接酶 TRIAD3A，它作为 Tau 的自噬衔接蛋白发挥作用。TRIAD3A（RNF216）是一种必需基因，其突变会导致年龄进展性神经退行性变。我们的研究表明，TRIAD3A E3 连接酶催化混合 K11/K63 多泛素链，并自我组装成液-液相分离（LLPS）液滴。Tau 被泛素化并在 TRIAD3A LLPS 液滴中积累，并通过 LC3 相互作用区域，将 Tau 靶向自噬降解。出乎意料的是，tau 被隔离在 TRIAD3A 液滴中后，迅速转化为纤维状聚集体，而无需 tau 的过渡液相。体内研究表明，TRIAD3A 可减少 Tau 病小鼠模型中磷酸化 Tau 的积累，而 TRIAD3A 的疾病相关突变会增加磷酸化 Tau 的积累，加剧神经胶质增生并增加病理性 Tau 的扩散。在人类阿尔茨海默病大脑中，TRIAD3A 与 Tau 淀粉样蛋白在多种组织学形式中共定位，表明其在 Tau 蛋白稳态中具有作用。TRIAD3A 是一种自噬衔接蛋白，它利用 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。
