An autophagy adaptor TRIAD3A promotes tau fibrillation by phase separation

Abstract Multiple neurodegenerative diseases are characterized by aberrant proteinaceous accumulations of tau. Here, we report an RBR-type E3 ligase TRIAD3A functions as a novel autophagy adaptor for tau. TRIAD3A (RNF216) is an essential gene with mutations causing ageprogressive neurodegeneration. Our studies reveal that TRIAD3A E3 ligase catalyzes a novel mixed K11/K63 polyubiquitin chain 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 amyloid aggregates without the transitional liquid phase of tau. In vivo studies reveal TRIAD3A decreases the accumulation of phosphorylated tau in a tauopathy mouse model, and disease-associated mutation of TRIAD3A increases accumulation of phosphorylated tau, exacerbates gliosis, and increases pathological tau spreading. In human Alzheimer’s disease brain, TRIAD3A colocalizes with tau amyloid in multiple histological forms suggesting a role in tau homeostasis. TRIAD3A is the first autophagic adaptor that utilizes E3-ligase and LLPS as a mechanism to capture cargo and appears especially relevant to neurodegenerative diseases.