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

• Published in: Nature communications Vol. 9; no. 1; pp. 1696 - 12
• Main Authors: Shah, Nirav, Kumar, Sanjay, Zaman, Naveed, Pan, Christopher C., Bloodworth, Jeffrey C., Lei, Wei, Streicher, John M., Hempel, Nadine, Mythreye, Karthikeyan, Lee, Nam Y.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.04.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/95; 14; 14/19; 38; 631/337/458; 631/80/128/1653; 631/80/86/2368; 96; Acetylation; Acetylation - drug effects; Acetyltransferase; Acetyltransferases - metabolism; AKT protein; Alanine; Animals; Benzamides - pharmacology; Brain; Catalysis; Catalytic activity; Cell culture; Cell cycle; Cell Cycle - drug effects; Cell Cycle - physiology; Cell Line; Cell Proliferation - drug effects; Cell Proliferation - physiology; Cercopithecus aethiops; COS Cells; Dioxoles - pharmacology; Gene Knockdown Techniques; HeLa Cells; Humanities and Social Sciences; Humans; Male; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Metabolic Networks and Pathways - drug effects; Metabolic Networks and Pathways - physiology; Metabolism; Mice; Mice, Inbred ICR; Microtubule Proteins - metabolism; Microtubules; Microtubules - drug effects; Microtubules - metabolism; multidisciplinary; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Signal Transduction - drug effects; Signal Transduction - physiology; Signaling; TAK1 protein; Zearalenone - analogs & derivatives; Zearalenone - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04121-y

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. Acetylation of microtubules (MT) confers mechanical stability necessary for numerous cellular functions but its regulation is unclear. Here the authors show that the MT acetyltransferase αTAT1 is regulated by TGF-β-activated kinase 1 implicating TGF-β signaling in MT-related functions and disease.