Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding
Open accessAbstract
Tau is the major microtubule-associated protein in neurons involved in microtubule stabilization in the axonal compartment. Changes in tau gene expression, alternative splicing and posttranslational modification regulate tau function and in tauopathies can result in tau mislocalization and dysfunction, causing tau aggregation and cell death. To uncover proteins involved in the development of tauopathies, a yeast two-hybrid system was used to screen for tau-interacting proteins. We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We defined the tau binding domain to amino acids 552-682 of axotrophin comprising the RING-variant domain. Co-immunoprecipitation and co-localization confirmed the specificity of the interaction. Intracellular localization of axotrophin is determined by an N-terminal nuclear targeting signal and a C-terminal nuclear export signal. In AD brain nuclear localization is lost and axotrophin is rather associated with neurofibrillary tangles. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. In vitro ubiquitination of four-repeat tau results in incorporation of up to four ubiquitin molecules compared to two molecules in three-repeat tau. In summary, we present a novel tau modification occurring preferentially on 4-repeat tau protein which modifies microtubule-binding and may impact on the pathogenesis of tauopathies.
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Axotrophin can ubiquitinate tau in vitro and impair tau microtubule-binding activity.
“Axotrophin can ubiquitinate tau in vitro and impair tau microtubule-binding activity [169].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [169]
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- Authors
- Flach, K., Ramminger, E., Hilbrich, I., Arsalan-Werner, A., Albrecht, F., Herrmann, L., Goedert, M., Arendt, T., & Holzer, M.
- Affiliations
- Leipzig University (DE)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Holzer, Max
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 1842
- Issue
- 9
- Pages
- 1527-1538
- ISSN
- 0925-4439 (ISSN-L)
- PMC
- PMC4311138
- OpenAlex
- W2074690689
- Cited by
- 58
- References
- 59
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 8 · 2023: 3 · 2022: 4 · 2021: 8 · 2020: 5 · 2019: 5 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 1
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- European Regional Development Fund
- European Commission
- Deutsche Forschungsgemeinschaft (HO2368/4-1)
- Sächsische Aufbaubank (100111005)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, E3 ubiquitin ligase, monoubiquitination, microtubule binding, tauopathy, neurofibrillary tangles, Alzheimer's disease, nuclear localization signal, nuclear export signal
- MeSH terms
- Aged, Alzheimer Disease, Animals, Brain, Cells, Cultured, Humans, Immunoenzyme Techniques, Microtubules, Protein Binding, Recombinant Proteins, Blotting, Western, Case-Control Studies, tau Proteins, Mice, Knockout, Two-Hybrid System Techniques, Ubiquitin, Ubiquitin-Protein Ligases, Immunoprecipitation, Cell Proliferation, Mice, Ubiquitination
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