E3 ligase Praja1 mediates ubiquitination and degradation of microtubule‐associated protein tau

作者：Shiho Aoki, Wataru Onodera, Akihiko Takashima, Kotaro Kawasaki, Kazuki Imadegawa, Hikaru Kurahashi, Mizuho Oishi, Toru Asahi, Yoshiyuki Soeda · 发表于：FEBS Journal · 年份：2025 · DOI：10.1111/febs.70303 · 被引用次数：4 · 研究领域：Alzheimer's disease research and treatments、Protein Degradation and Inhibitors、14-3-3 protein interactions

The RING-H2 type E3 ligase Praja family is composed of E3 ubiquitin-protein ligases 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 TAR DNA-binding protein 43 (TDP-43) and α-synuclein, are degraded and/or suppressed by Praja1. Furthermore, the expression level of the microtubule-associated protein tau (MAPT) gene, which is frequently mutated in Alzheimer's disease, is regulated by Praja2. Although 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 the tau protein level in human neuroblastoma SH-SY5Y cells decreased depending on the E3 ligase activity of Praja1. Furthermore, the in vivo/in vitro ubiquitination assay showed that Praja1 ubiquitinates 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 just after the duplication of the Praja family in the common ancestor of placentals. Lastly, to test whether this interaction is dis...