Tau acetylates and stabilizes β-catenin thereby promoting cell survival.

Overexpressing Tau counteracts apoptosis and increases dephosphorylated beta-catenin levels, but the underlying mechanisms are elusive. Here, we show that Tau can directly and robustly acetylate beta-catenin at K49 in a concentration-, time-, and pH-dependent manner. beta-catenin K49 acetylation inhibits its phosphorylation and its ubiquitination-associated proteolysis, thus increasing beta-catenin protein levels. K49 acetylation further promotes nuclear translocation and the transcriptional activity of beta-catenin, and increases the expression of survival-promoting genes (bcl2 and survivin), counteracting apoptosis. Mutation of Tau's acetyltransferase domain or co-expressing non-acetylatable beta-catenin-K49R prevents increased beta-catenin signaling and abolishes the anti-apoptotic function of Tau. Our data reveal that Tau preserves beta-catenin by acetylating K49, and upregulated beta-catenin/survival signaling in turn mediates the anti-apoptotic effect of Tau.