Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation
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Significance: The mammalian cell cytoplasm contains numerous proteins with direct antimicrobial activity. Although these have been extensively studied in the context of viral and bacterial infection, it is unknown whether pathogenic self-propagating proteins, proposed to underlie common neurodegenerative diseases, can be targeted in a similar manner. We studied the ability of tripartite motif protein 21 (TRIM21), a newly identified intracellular antibody receptor, to intercept assemblies of misfolded tau, a cytoplasmic protein that aggregates in patients with Alzheimer’s disease. We developed tau “seeding” assays in human cells and found that TRIM21 could intercept and potently neutralize antibody-labeled tau assemblies. These findings demonstrate that the intracellular immune system can act against self-propagating misfolded proteins, with implications for ongoing attempts to develop antibody-based therapies for neurodegenerative disorders.
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Binding of a tau-antibody complex to a cytosolic Fc receptor, E3 ubiquitin-protein ligase TRIM21, promotes proteosomal degradation of the complex, thereby inhibiting intracellular seeded tau aggregation.
“Of note, binding of a tau–antibody complex to a cytosolic Fc receptor, E3 ubiquitin-protein ligase TRIM21, promotes proteosomal degradation of the complex, thereby inhibiting intracellular seeded tau aggregation233.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [233]
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Self-citation
- Authors
- McEwan, W. A., Falcon, B., Vaysburd, M., Clift, D., Oblak, A. L., Ghetti, B., Goedert, M., & James, L. C.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Karolinska Institutet (SE)
- Corresponding author
- McEwan, William A.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-01-03
- Volume
- 114
- Issue
- 3
- Pages
- 574-579
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5255578
- OpenAlex
- W2563169901
- Cited by
- 201
- References
- 44
- Citations by year
- 2026: 18 · 2025: 24 · 2024: 22 · 2023: 21 · 2022: 19 · 2021: 22 · 2020: 30 · 2019: 18 · 2018: 14 · 2017: 13
- FWCI
- 15.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- PMC
- Funders
- Medical Research Council (MC_U105184291, U105181010)
- Medical Research Council/AstraZeneca Collaborative Research Fund (n/a)
- HHS | National Institutes of Health (PHS P30 AG010133)
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine (n/a)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- TRIM21, tau aggregation, tau seeding, Alzheimer's disease, Fc receptors, anti-tau antibodies, proteasome, VCP/p97, AAA+ ATPase, neurodegeneration
- MeSH terms
- SS-A Antigen, Animals, Cells, Cultured, Cytosol, Humans, Mice, Inbred C57BL, Nerve Degeneration, Neurons, Receptors, Fc, Ribonucleoproteins, tau Proteins, Mice, Knockout, Proteasome Endopeptidase Complex, Mice, Antibodies, Neutralizing, Proteostasis Deficiencies, Protein Aggregation, Pathological, In Vitro Techniques, Protein Aggregates
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