SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis

• Published in: Cell reports (Cambridge) Vol. 35; no. 4; p. 109035
• Main Authors: Portillo, Miguel, Eremenko, Ekaterina, Kaluski, Shai, Garcia-Venzor, Alfredo, Onn, Lior, Stein, Daniel, Slobodnik, Zeev, Zaretsky, Adam, Ueberham, Uwe, Einav, Monica, Brückner, Martina K., Arendt, Thomas, Toiber, Debra
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.04.2021
• Subjects: acetylation; Alzheimer Disease - genetics; Alzheimer’s disease; CBP; DNA damage; Humans; nuclear translocation; nucleoli; Protein Biosynthesis - genetics; protein translation; SIRT6; Sirtuins - genetics; Sirtuins - metabolism; Tau; tau Proteins - metabolism; acetylation; CBP; protein translation; Alzheimer’s disease; nuclear translocation; DNA damage; Tau; SIRT6; nucleoli
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109035

Several neurodegenerative diseases present Tau accumulation as the main pathological marker. Tau post-translational modifications such as phosphorylation and acetylation are increased in neurodegeneration. Here, we show that Tau hyper-acetylation at residue 174 increases its own nuclear presence and is the result of DNA damage signaling or the lack of SIRT6, both causative of neurodegeneration. Tau-K174ac is deacetylated in the nucleus by SIRT6. However, lack of SIRT6 or chronic DNA damage results in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression, affecting protein translation, synthesis, and energy production. Concomitantly, Alzheimer’s disease (AD) case subjects show increased nucleolin and a decrease in SIRT6 levels. AD case subjects present increased levels of nuclear Tau, particularly Tau-K174ac. Our results suggest that increased Tau-K174ac in AD case subjects is the result of DNA damage signaling and SIRT6 depletion. We propose that Tau-K174ac toxicity is due to its increased stability, nuclear accumulation, and nucleolar dysfunction. [Display omitted] •DNA damage or SIRT6 absence leads to acetylation of Tau-K174 via CBP•Tau174ac shuttles to the nucleus, where it induces nucleolar activation•SIRT6 regulates Tau-174ac nuclear functions through its deacetylation•Tau174Q increases nucleolar activity and protein synthesis, leading to ATP depletion Portillo et al. show that acetylation of Tau-174 by CBP leads to its nuclear translocation, increasing nucleolar activity and protein synthesis capacity and resulting in ATP depletion. SIRT6 deacetylates nuclear Tau-174ac, preventing its accumulation. SIRT6 depletion, as in Alzheimer’s disease, increases Tau-174ac through the DNA damage response and impaired deacetylation.