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Tau protein binds to the P53 E3 ubiquitin ligase MDM2

Tau gene mutations cause a progressive dementia and neurotoxic Tau forms deposited in neurofibrillary tangles are hallmarks of neurodegenerative tauopathies. Loss of non-canonical Tau functions may contribute to disease. In fact, Tau depletion affects the cellular response to DNA damage and tauopath...

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Autores principales: Sola, Martina, Rendon-Angel, Azucena, Rojo Martinez, Viviana, Sgrignani, Jacopo, Magrin, Claudia, Piovesana, Ester, Cavalli, Andrea, Paganetti, Paolo, Papin, Stéphanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10290082/
https://www.ncbi.nlm.nih.gov/pubmed/37353565
http://dx.doi.org/10.1038/s41598-023-37046-8
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author Sola, Martina
Rendon-Angel, Azucena
Rojo Martinez, Viviana
Sgrignani, Jacopo
Magrin, Claudia
Piovesana, Ester
Cavalli, Andrea
Paganetti, Paolo
Papin, Stéphanie
author_facet Sola, Martina
Rendon-Angel, Azucena
Rojo Martinez, Viviana
Sgrignani, Jacopo
Magrin, Claudia
Piovesana, Ester
Cavalli, Andrea
Paganetti, Paolo
Papin, Stéphanie
author_sort Sola, Martina
collection PubMed
description Tau gene mutations cause a progressive dementia and neurotoxic Tau forms deposited in neurofibrillary tangles are hallmarks of neurodegenerative tauopathies. Loss of non-canonical Tau functions may contribute to disease. In fact, Tau depletion affects the cellular response to DNA damage and tauopathies exhibit the accumulation of DNA lesions. Moreover, Tau modulates P53 activity and cell fate. Considering that MDM2 is the main antagonist of P53, we investigated, using orthogonal assays, if Tau interacts with MDM2. We report the existence in cells and brain of a Tau-MDM2 complex that, in vitro, exhibits reduced P53 ubiquitination activity in a manner sensitive to a Tau mutation. The Tau-MDM2 interaction involves the microtubule-binding domain of Tau and the acidic domain of MDM2, reminiscent of the binding of Tau to negatively charged microtubules. Notably, MDM2 accumulates aberrantly in neurofibrillary tangles. Aging-associated insults may expose a novel loss-of-function of Tau in neurodegeneration and cancer.
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spelling pubmed-102900822023-06-25 Tau protein binds to the P53 E3 ubiquitin ligase MDM2 Sola, Martina Rendon-Angel, Azucena Rojo Martinez, Viviana Sgrignani, Jacopo Magrin, Claudia Piovesana, Ester Cavalli, Andrea Paganetti, Paolo Papin, Stéphanie Sci Rep Article Tau gene mutations cause a progressive dementia and neurotoxic Tau forms deposited in neurofibrillary tangles are hallmarks of neurodegenerative tauopathies. Loss of non-canonical Tau functions may contribute to disease. In fact, Tau depletion affects the cellular response to DNA damage and tauopathies exhibit the accumulation of DNA lesions. Moreover, Tau modulates P53 activity and cell fate. Considering that MDM2 is the main antagonist of P53, we investigated, using orthogonal assays, if Tau interacts with MDM2. We report the existence in cells and brain of a Tau-MDM2 complex that, in vitro, exhibits reduced P53 ubiquitination activity in a manner sensitive to a Tau mutation. The Tau-MDM2 interaction involves the microtubule-binding domain of Tau and the acidic domain of MDM2, reminiscent of the binding of Tau to negatively charged microtubules. Notably, MDM2 accumulates aberrantly in neurofibrillary tangles. Aging-associated insults may expose a novel loss-of-function of Tau in neurodegeneration and cancer. Nature Publishing Group UK 2023-06-23 /pmc/articles/PMC10290082/ /pubmed/37353565 http://dx.doi.org/10.1038/s41598-023-37046-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sola, Martina
Rendon-Angel, Azucena
Rojo Martinez, Viviana
Sgrignani, Jacopo
Magrin, Claudia
Piovesana, Ester
Cavalli, Andrea
Paganetti, Paolo
Papin, Stéphanie
Tau protein binds to the P53 E3 ubiquitin ligase MDM2
title Tau protein binds to the P53 E3 ubiquitin ligase MDM2
title_full Tau protein binds to the P53 E3 ubiquitin ligase MDM2
title_fullStr Tau protein binds to the P53 E3 ubiquitin ligase MDM2
title_full_unstemmed Tau protein binds to the P53 E3 ubiquitin ligase MDM2
title_short Tau protein binds to the P53 E3 ubiquitin ligase MDM2
title_sort tau protein binds to the p53 e3 ubiquitin ligase mdm2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10290082/
https://www.ncbi.nlm.nih.gov/pubmed/37353565
http://dx.doi.org/10.1038/s41598-023-37046-8
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