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

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.