A phospho-regulated ensemble signal motif of α-TAT1 drives dynamic microtubule acetylation

Abstract

Spatiotemporally dynamic microtubule acetylation underlies diverse physiological events ranging from cell migration to intracellular trafficking, autophagy and viral infections. Despite its ubiquity, the molecular mechanisms that regulate the sole microtubule acetylating agent, -tubulin N-acetyltransferase 1 (-TAT1) remain obscure. Here we report that dynamic intracellular localization of -TAT1 unexpectedly determines the efficiency of microtubule acetylation. Specifically, we newly identified a conserved signal motif in the intrinsically disordered C-terminus of -TAT1, consisting of three competing regulatory elements - nuclear export, nuclear import and cytosolic retention. Their balance is tuned via phosphorylation by serine-threonine kinases including CDK1 and CK2. While the un-phosphorylated form resides both in the cytosol and nucleus, the phosphorylated form binds to specific 14-3-3 adapters and accumulates in the cytosol for maximal substrate access. Cytosolic localization of -TAT1 predominantly mediates microtubule acetylation, cell proliferation and DNA damage response. In contrast to other molecules with a similar phospho-regulated signal motif including transcription factors, -TAT1 uniquely uses the nucleus as a hideout. As amino acid mutations to the motif have been reported in cancer patients, the present mechanism of subcellular -TAT1 localization may help uncover a spatiotemporal code of microtubule acetylation in normal and aberrant cell functions.