Functional Adaptation of Microtubules by Acetylation

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DESCRIPTION (provided by applicant): Microtubules are ubiquitous eukaryotic structures, built of dimers of 1- and 2-tubulin. Microtubules play key roles in cell motility, intracellular trafficking and cell polarization. It is not well understood how diverse microtubules function in multiple contexts inside the cell. Commonly, motor proteins move specific cellular cargoes along subsets of microtubules, and this selective transport is critical for cell polarization. One striking example is the neuron, where specific cargoes are moved from the cell body either into the dendrite or axon projections. The principles and mechanisms that govern the selective transport on the surface of microtubules are not well understood. We explore a hypothesis that microtubules are functionally adapted for selective transport and other localized functions, by spatially restricted post-translational modifications (PTMs) of tubulin subunits. Acetylation of K40 on 1- tubulin is a highly conserved PTM, that marks microtubules which turnover relatively slowly. In neurons, K40 acetylation of 1-tubulin is highly enriched on microtubules of the axon as compared to microtubules in dendrites. Recent studies indicate that K40 acetylation of axonal microtubules stimulates binding and motility of specific motor proteins, including kinesin-1 inside the axon. We report here an identification of a conserved protein that is required for K40 1-tubulin acetylation in the model protist Tetrahymena and zebrafish. This protein is an ortholog of MEC-17, a previously studied protein which is required for the function of touch receptor neurons in C. elegans. We show that MEC-17 mediates acetylation of K40 on 1- tubulin in vitro. We will test the hypothesis that MEC17 is the long-sought 1-tubulin K40 acetyltransferase, and that MEC-17, by acetylating K40 on 1-tubulin, contributes to neuronal differentiation and function. We will use model organisms, the worm Caenorhabditis elegans and zebrafish Danio rerio, to evaluate the function of MEC-17 and K40 acetylation on 1- tubulin, specifically in two types of neurons: in touch receptor neurons (C. elegans) and in primary motor neurons (zebrafish). As acetylation of 1-tubulin is highly enriched in the nervous system, this proposal is relevant to a broad range of diseases and in particular to the neurodegenerative disorders.