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

Nirav Shah, Sanjay Kumar, Naveed Zaman, Christopher C. Pan, Jeffrey C. Bloodworth, Wei Lei, John M. Streicher, Nadine Hempel, Karthikeyan Mythreye and Nam Y. Lee ()
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Nirav Shah: The Ohio State University
Sanjay Kumar: University of Arizona
Naveed Zaman: The Ohio State University
Christopher C. Pan: Duke University
Jeffrey C. Bloodworth: Loyola University Chicago
Wei Lei: University of Arizona
John M. Streicher: University of Arizona
Nadine Hempel: Penn State University
Karthikeyan Mythreye: University of South Carolina
Nam Y. Lee: University of Arizona

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Acetylation of microtubules (MT) confers mechanical stability necessary for numerous functions including cell cycle and intracellular transport. Although αTAT1 is a major MT acetyltransferase, how this enzyme is regulated remains much less clear. Here we report TGF-β-activated kinase 1 (TAK1) as a key activator of αTAT1. TAK1 directly interacts with and phosphorylates αTAT1 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-αTAT1-Ser237 antibody, we screen various mouse tissues to discover that brain contains some of the highest TAK1-dependent αTAT1 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-β signaling in MT-related functions and disease.

Date: 2018
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DOI: 10.1038/s41467-018-04121-y

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