Fat traffic control: S-acylation in axonal transport

Abstract

Neuronal axons serve as a conduit for the coordinated transport of essential molecular cargo between structurally and functionally distinct subcellular compartments via axonal molecular machinery. Long-distance, efficient axonal transport of membrane-bound organelles enables signal transduction and neuronal homeostasis. Efficient axonal transport is conducted by dynein and kinesin ATPase motors that use a local ATP supply from metabolic enzymes tethered to transport vesicles. Molecular motor adaptor proteins promote the processive motility and cargo selectivity of fast axonal transport. Axonal transport impairments are directly causative or associated with many neurodegenerative diseases and neuropathologies. Cargo specificity, cargo-adaptor proteins, and posttranslational modifications of cargo, adaptor proteins, microtubules, or the motor protein subunits all contribute to the precise regulation of vesicular transit. One posttranslational lipid modification that is particularly important in neurons in regulating protein trafficking, protein-protein interactions, and protein association with lipid membranes is S-acylation. Interestingly, many fast axonal transport cargos, cytoskeletal-associated proteins, motor protein subunits, and adaptors are S-acylated to modulate axonal transport. Here, we review the established regulatory role of S-acylation in fast axonal transport and provide evidence for a broader role of S-acylation in regulating the motor-cargo complex machinery, adaptor proteins, and metabolic enzymes from low-throughput studies and S-acyl-proteomic data sets. We propose that S-acylation regulates fast axonal transport and vesicular motility through localization of the proteins required for the motile cargo-complex machinery and relate how perturbed S-acylation contributes to transport impairments in neurological disorders. SIGNIFICANCE STATEMENT: This review investigates the regulatory role of S-acylation in fast axonal transport and its connection to neurological diseases, with a focus on the emerging connections between S-acylation and the molecular motors, adaptor proteins, and metabolic enzymes that make up the trafficking machinery.

Keywords: S-acylation; fast axonal transport; glycolysis; molecular motor proteins; neurological disorders; palmitoylation.

Fig. 1

Protein S-acylation. Cysteine (-SH) residues of proteins are modified by LCFAs (red; here the 16-carbon saturated palmitate) by protein S-acyltransferases and deacylated by various deacylases, including acyl protein thioesterases, palmitoyl protein thioesterases, and α/β hydrolase domain-containing serine hydrolases. S-acylation regulates membrane affinity and protein localization and/or function.

Fig. 2

Comparison of a list of trafficking machinery to S-acyl proteomic studies reveals an enrichment of S-acylation. (A) Heat maps showing the number of S-acyl proteomic studies in which the trafficking machinery were identified. The list includes dynactin, dynein, and kinesin protein subunits, motor protein adaptors, and metabolic enzymes that fuel transport while bound to fast axonal trafficking vesicles. The gene set was compared to data from 48 human, mouse, and rat S-acyl proteomic studies using the Swisspalm database (https://swisspalm.org). Red indicates values above 20 and a red star indicates proteins were verified as S-acylated in at least one low throughput study. (B) Venn diagram depicting the percentage of S-acylated and non-S-acylated proteins for the trafficking machinery dataset. Proteins identified in at least one S-acyl-proteomic study or targeted study were counted as S-acylated.

Fig. 3

S-acylation-dependent regulation of axonal trafficking. Axons are long neuronal output projections in which microtubules are oriented with plus ends toward axon tips. Kinesin motors facilitate transport in the anterograde direction toward axon tips and dynein motors drive transport toward the soma in the retrograde direction (arrows indicate direction of transport). Glycolytic enzymes as well as LDHA and NMNAT2 are metabolic enzymes bound to transport vesicles to produce ATP locally to fuel transport. These metabolic enzymes are likely S-acylated and S-acylation may serve to tether them to membranous fast axonal transport vesicles to fuel transport (indicated by red bar). Many of the motor protein subunits and their adaptors are also likely S-acylated but how and when S-acylation regulates their function in axonal trafficking is unknown (unknown role indicated by “S-acylation?” and arrows or inhibition lines in red). S-acylation of the motor protein subunits and adaptors may negatively regulate trafficking or could be required for retention in cellular compartments or for protein-protein interactions potentially prior to or during axonal transport.