Microtubule Acetylation Promotes Kinesin-1 Binding and Transport

Abstract

Long-distance intracellular delivery is driven by kinesin and dynein motor proteins that ferry cargoes along microtubule tracks . Current models postulate that directional trafficking is governed by known biophysical properties of these motors-kinesins generally move to the plus ends of microtubules in the cell periphery, whereas cytoplasmic dynein moves to the minus ends in the cell center. However, these models are insufficient to explain how polarized protein trafficking to subcellular domains is accomplished. We show that the kinesin-1 cargo protein JNK-interacting protein 1 (JIP1) is localized to only a subset of neurites in cultured neuronal cells. The mechanism of polarized trafficking appears to involve the preferential recognition of microtubules containing specific posttranslational modifications (PTMs) by the kinesin-1 motor domain. Using a genetic approach to eliminate specific PTMs, we show that the loss of a single modification, alpha-tubulin acetylation at Lys-40, influences the binding and motility of kinesin-1 in vitro. In addition, pharmacological treatments that increase microtubule acetylation cause a redirection of kinesin-1 transport of JIP1 to nearly all neurite tips in vivo. These results suggest that microtubule PTMs are important markers of distinct microtubule populations and that they act to control motor-protein trafficking.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…The turnover of mutant Htt is thus regulated through the balance between CBP and HDAC1, and the loss of CBP in HD might explain the accumulation of mutant Htt [91]. Moreover, the acetylation of tubulin (likely through cytoplasmic acetyltransferases) regulates anterograde and retrograde axonal transport through signaling the anchoring of molecular motors, such as Kinesin-1 to microtubules [93]. As a decrease of acetylated-tubulin has been observed in postmortem brain samples [94], one could predict that a disruption of intracellular trafficking could occur in HD patients, as observed in HD mice neuronal culture and leading to the alteration to the alteration of vesicular BDNF transport [95].…”

Cell biology of embryonic migration

“…Of those, a special place belongs to post-translational modification of cytoskeletal proteins by amino acids. It has been long known that tubulin undergoes acetylation that correlates with microtubule stability and microtubule-based organelle transport (Bulinski, 2007;Reed et al, 2006), which is important for the delivery of membranous components for cell polarization and protrusion to the cell leading edge. Tubulin is also modified by post-translational phosphorylation and detyrosynation, as well as addition of tyrosine (Raybin and Flavin, 1977a;b), mono-and poly-glutamine (Audebert et al, 1993;Edde et al, 1990), and glycine (Plessmann and Weber, 1997) (see also (Luduena, 1998) for an overview of tubulin modifications).…”

SIRT2, tubulin deacetylation, and oligodendroglia differentiation

“…In the differentiated catecholaminergic neuronal line CAD and hippocampal neurons, microtubule acetylation appears to be important for the recruitment of molecular motors for polarized transport, such as kinesin, a plus-end directed motor, and dynein, a minus-end directed motor. a-tubulin acetylation at Lys-40 influences the binding and motility of kinesin-1 [Reed et al, 2006]. In striatal neurons, Lys-40 acetylation of a-tubulin by HDAC6 increases the flux of brain-derived neurotrophic factor (BDNF)-containing vesicles.…”