Tau protein binds to the P53 E3 ubiquitin ligase MDM2

Sola, Martina; Rendon-Angel, Azucena; Martinez, Viviana Rojo; Sgrignani, Jacopo; Magrin, Claudia; Piovesana, Ester; Cavalli, Andrea; Paganetti, Paolo; Papin, Stéphanie

doi:10.1038/s41598-023-37046-8

Cited by 6 publications

(4 citation statements)

References 63 publications

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“…Since a loss of correlation with mutated P53 could indicate a role for Tau upstream of P53, and considering that MDM2 is the main E3 protein ubiquitin ligase and inhibitor of P53, the Tau-MDM2 link suggested a possible mechanism for the modulatory role of Tau on P53. Notably, we found that Tau binds and modulates MDM2 43 . Alternatively, considering that P53 activation of MDM2 transcription 44 is lost when P53 is mutated, this may explain the reduced MAPT - MDM2 correlation when P53 is mutated in LGG and GBM.…”

Section: Resultsmentioning

confidence: 78%

Cancer-specific association between Tau (MAPT) and cellular pathways, clinical outcome, and drug response

Callari,

Sola,

Magrin

et al. 2023

Sci Data

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Tau (MAPT) is a microtubule-associated protein causing common neurodegenerative diseases or rare inherited frontotemporal lobar degenerations. Emerging evidence for non-canonical functions of Tau in DNA repair and P53 regulation suggests its involvement in cancer. To bring new evidence for a relevant role of Tau in cancer, we carried out an in-silico pan-cancer analysis of MAPT transcriptomic profile in over 10000 clinical samples from 32 cancer types and over 1300 pre-clinical samples from 28 cancer types provided by the TCGA and the DEPMAP datasets respectively. MAPT expression associated with key cancer hallmarks including inflammation, proliferation, and epithelial to mesenchymal transition, showing cancer-specific patterns. In some cancer types, MAPT functional networks were affected by P53 mutational status. We identified new associations of MAPT with clinical outcomes and drug response in a context-specific manner. Overall, our findings indicate that the MAPT gene is a potential major player in multiple types of cancer. Importantly, the impact of Tau on cancer seems to be heavily influenced by the specific cellular environment.

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Section: Resultsmentioning

confidence: 78%

Cancer-specific association between Tau (MAPT) and cellular pathways, clinical outcome, and drug response

Callari,

Sola,

Magrin

et al. 2023

Sci Data

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“…It has been shown that the P53 ubiquitin ligase MDM2 binds and regulates PRC2 stability ( Wienken et al, 2016 ) and that MDM2 modulates gene expression similar to PRC2 ( Wienken et al, 2017 ). Based on our recent work reporting the modulatory interaction between Tau and MDM2 ( Sola et al, 2023 ), we propose that Tau modulates PRC2 stability through a MDM2-dependent mechanism.…”

Section: Discussionmentioning

confidence: 96%

Tau protein modulates an epigenetic mechanism of cellular senescence in human SH-SY5Y neuroblastoma cells

Magrin,

Bellafante,

Sola

et al. 2023

Front. Cell Dev. Biol.

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Introduction: Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimer’s disease. Since Tau is a microtubule-associated protein, a prevalent concept to explain the pathogenesis of tauopathies is that abnormal Tau modification contributes to dissociation from microtubules, assembly into multimeric β-sheets, proteotoxicity, neuronal dysfunction and cell loss. Tau also localizes in the cell nucleus and evidence supports an emerging function of Tau in DNA stability and epigenetic modulation.Methods: To better characterize the possible role of Tau in regulation of chromatin compaction and subsequent gene expression, we performed a bioinformatics analysis of transcriptome data obtained from Tau-depleted human neuroblastoma cells.Results: Among the transcripts deregulated in a Tau-dependent manner, we found an enrichment of target genes for the polycomb repressive complex 2. We further describe decreased cellular amounts of the core components of the polycomb repressive complex 2 and lower histone 3 trimethylation in Tau deficient cells. Among the de-repressed polycomb repressive complex 2 target gene products, IGFBP3 protein was found to be linked to increased senescence induction in Tau-deficient cells.Discussion: Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging.

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“…This may be explained by the intrinsically disordered nature of Praja1, lacking a specific tertiary structure. E3 ligases containing disordered regions adopt suitable conformations in a partner-dependent manner [29,30]. In addition to the characteristics of Praja1, the biochemical properties of interacting proteins may also facilitate the recognition by Praja1.…”

Section: Discussionmentioning

confidence: 99%

E3 ligase Praja1 mediates ubiquitination and degradation of microtubule-associated protein Tau

Aoki,

Kawasaki,

Imadegawa

et al. 2024

Preprint

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RING-H2 type E3 ligase Praja family is composed of Praja1 and Praja2, which promote the degradation of substrates through the ubiquitin-proteasome system. Both paralogs contribute to neuronal maturation and differentiation, indicating a significant role in the nervous system. Aggregation-prone proteins associated with neurodegenerative diseases, including TDP-43 and α-synuclein, are degraded and/or suppressed by Praja1. Furthermore, the expression level of theMAPTgene, which is frequently mutated in Alzheimer’s, is regulated by Praja2. While the Praja family has been shown to recognize various aggregation-prone proteins as substrates, it has not been determined whether Tau, a key protein that aggregates in tauopathies, is also recognized by Praja proteins. In this study, we show that Praja1, but not Praja2, recognizes Tau as a candidate substrate. We observed that Tau expression in human neuroblastoma SH-SY5Y cells decreased depending on the E3 ligase activity of Praja1. Furthermore, Praja1 polyubiquitinated and interacted with Tau, indicating that it is a target substrate. Next, by combining ancestral sequence reconstruction and mutational analysis, we revealed that the Praja1-Tau interaction began via deletion of the N- and C-terminal regions of Praja1, occurring just after the duplication of the Praja family in the common ancestor of placentals. Lastly, to test whether this interaction is disrupted under pathological conditions, P301L Tau was introduced, resulting in a degradation similar to that of wild-type Tau. These results reveal an unidentified mechanism of Tau proteostasis by Praja1 and may provide insight into the pathogenesis of neurodegenerative diseases, including tauopathy.

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Tau protein binds to the P53 E3 ubiquitin ligase MDM2

Cited by 6 publications

References 63 publications

Cancer-specific association between Tau (MAPT) and cellular pathways, clinical outcome, and drug response

Cancer-specific association between Tau (MAPT) and cellular pathways, clinical outcome, and drug response

Tau protein modulates an epigenetic mechanism of cellular senescence in human SH-SY5Y neuroblastoma cells

E3 ligase Praja1 mediates ubiquitination and degradation of microtubule-associated protein Tau

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