ArticleNature cell biology2024
The autophagy adaptor TRIAD3A promotes tau fibrillation by nested phase separation.
Article in Nature cell biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis.bioRxiv : the preprint server for biology · 2026Article
- The role of E3 ubiquitin ligases in selective types of macroautophagy.EMBO reports · 2026Review
- Alzheimer's Disease as a Multi-Layer Network Disorder: A Systems Biology Framework Integrating Multi-Omics Mechanisms.Biomedicines · 2026Review
- A New Anatomy of Autophagic Clearance: On the Roles of Intrinsic Disorder in the Membrane-Less on Membrane-Encapsulated Mechanism.Membranes · 2026Review
- Distinct factors drive the progression of tau pathology in Alzheimer's disease.Fundamental research · 2026Review
- E3 ubiquitin ligases in neurodegenerative diseases.Military Medical Research · 2026Review
- From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer's disease.Frontiers in neuroscience · 2026Review
- Targeting ubiquitination in disease and therapy.Signal transduction and targeted therapy · 2025Review
- Targeting Liquid-Liquid Phase Separation and Autophagy in Alzheimer's Disease: Insights into Molecular Mechanisms and Therapeutic Potential.Neurochemical research · 2025Review
- Tau Liquid-Liquid Phase Separation in Alzheimer's Disease: Mechanisms, Pathogenesis, and Therapeutic Implications.Molecular neurobiology · 2025Review
- Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- Inborn errors of canonical autophagy in neurodegenerative diseases.Human molecular genetics · 2025Review
- Mitophagy in Hypertensive Cardiac Hypertrophy: Mechanisms and Therapeutic Implications.Journal of clinical hypertension (Greenwich, Conn.) · 2025Review
- Rational Modulation of Liquid-Liquid Phase Separation Offers Novel Ways to Combat Tauopathies.International journal of molecular sciences · 2025Review
- Liquid‒liquid phase separation: a potentially fundamental mechanism of sepsis.Cell death discovery · 2025Review
- Targeting a key disulfide linkage to regulate RIG-I condensation and cytosolic RNA-sensing.Nature cell biology · 2025Article
- Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
- Targeting macroautophagy to combat neurodegenerative disease: strategies and considerations.Autophagy reports · 2025Review
- Autophagy in alzheimer disease pathogenesis and its therapeutic values.Autophagy reports · 2025Review
Corrections and comments
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Authors and funding
9 authors.
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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.
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