TAK1 activation of alpha-TAT1 and microtubule hyperacetylation control AKT signaling and cell growth

Acetylation of microtubules (MT) confers mechanical stability necessary for numerous functions including cell cycle and intracellular transport. Although alpha TAT1 is a major MT acetyltransferase, how this enzyme is regulated remains much less clear. Here we report TGF-beta-activated kinase 1 (TAK1) as a key activator of alpha TAT1. TAK1 directly interacts with and phosphorylates alpha TAT1 at Ser237 to critically enhance its catalytic activity, as mutating this site to alanine abrogates, whereas a phosphomimetic induces MT hyperacetylation across cell types. Using a custom phospho-alpha TAT1-Ser237 antibody, we screen various mouse tissues to discover that brain contains some of the highest TAK1-dependent alpha TAT1 activity, which, accordingly, is diminished rapidly upon intra-cerebral injection of a TAK1 inhibitor. Lastly, we show that TAK1 selectively inhibits AKT to suppress mitogenic and metabolism-related pathways through MT-based mechanisms in culture and in vivo. Collectively, our findings support a fundamental new role for TGF-beta signaling in MT-related functions and disease.