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Review
. 2021 Oct 6;5(4):NS20210005.
doi: 10.1042/NS20210005. eCollection 2021 Dec.

A sticky situation: regulation and function of protein palmitoylation with a spotlight on the axon and axon initial segment

Andrey A Petropavlovskiy #  1 , Jordan A Kogut #  1 , Arshia Leekha #  1 , Charlotte A Townsend #  1 , Shaun S Sanders  1
Affiliations
Review

A sticky situation: regulation and function of protein palmitoylation with a spotlight on the axon and axon initial segment

Andrey A Petropavlovskiy et al. Neuronal Signal. .

Abstract

In neurons, the axon and axon initial segment (AIS) are critical structures for action potential initiation and propagation. Their formation and function rely on tight compartmentalisation, a process where specific proteins are trafficked to and retained at distinct subcellular locations. One mechanism which regulates protein trafficking and association with lipid membranes is the modification of protein cysteine residues with the 16-carbon palmitic acid, known as S-acylation or palmitoylation. Palmitoylation, akin to phosphorylation, is reversible, with palmitate cycling being mediated by substrate-specific enzymes. Palmitoylation is well-known to be highly prevalent among neuronal proteins and is well studied in the context of the synapse. Comparatively, how palmitoylation regulates trafficking and clustering of axonal and AIS proteins remains less understood. This review provides an overview of the current understanding of the biochemical regulation of palmitoylation, its involvement in various neurological diseases, and the most up-to-date perspective on axonal palmitoylation. Through a palmitoylation analysis of the AIS proteome, we also report that an overwhelming proportion of AIS proteins are likely palmitoylated. Overall, our review and analysis confirm a central role for palmitoylation in the formation and function of the axon and AIS and provide a resource for further exploration of palmitoylation-dependent protein targeting to and function at the AIS.

Keywords: S-acylation; acyl protein thioesterase; axon; axon initial segment; palmitoyl acyltransferase; palmitoylation.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1
Figure 1. Dynamic protein palmitoylation
Long-chain fatty acids (red; commonly the 16-carbon saturated palmitic acid) are added to cytosolic cysteine residues (–SH) of proteins by palmitoyl acyltransferases via a thioester bond. This increases the binding affinity of palmitoylated proteins for membranes (grey phospholipid bilayer) and/or membrane subdomains and can regulate protein–protein interactions, protein stability, other post-translational modifications, and protein function. The reverse reaction is catalyzed by depalmitoylases including acyl protein thioesterases, palmitoyl protein thioesterases, and α/β hydrolase domain-containing serine hydrolases. Figure created with BioRender.com.
Figure 2
Figure 2. Palmitoylation-dependent regulation of axon survival and degeneration
(A) In healthy peripheral projecting sensory or retinal ganglion axons DLK and JNK3 are trafficked on axon transport vesicles into distal axons in a palmitoylation-dependent manner along with MKK4/7 and the scaffold JIP3. (B) Following axonal injury DLK is activated on vesicles proximal to the injury site where it phosphorylates its direct targets MKK4/7, which then phosphorylates JNK3. This pro-degenerative signaling transport vesicle traffics retrogradely back to the soma in a palmitoylation-dependent manner to induce neurodegeneration. (C) Also in healthy axons, the labile, pro-survival factors NMNAT2 and SCG10 are continually supplied on axon transport vesicles into distal axons in a palmitoylation-dependent manner. (D) Following axonal injury, the constant supply of SCG10 and NMNAT2 from the soma into distal axons is blocked, and SCG10 and NMNAT2 are quickly degraded, inducing Wallerian degeneration. Figure created with BioRender.com. Abbreviation: NMNAT2, nicotinamide mononucleotide adenylyltransferase 2; SCG10, superior cervical ganglion 10.
Figure 3
Figure 3. Palmitoylation-dependent regulation of protein targeting to the AIS
The AIS is in the proximal part of the axon (pink) and is the site of action potential generation. Action potential firing is dependent on the high density of voltage-gated sodium (Nav; green) and potassium channels (Kv7 [light blue] and Kv1 [light purple]) at this site. These ion channels are clustered at the AIS via interactions with their scaffolds AnkG (light red) and PSD93 (dark blue) that also interact with the cell adhesion molecules NrCAM (dark purple), Neurofascin (brown), and Capsr2 (teal) and with the underlying actin, α2/β4-spectrin, and microtubule cytoskeleton. All these AIS components are either targeted to the AIS in a palmitoylation-dependent manner (solid red bar, AnkG, PSD93, and Kv1 channels) or are palmitoylated, but the role of palmitoylation in AIS targeting is currently unknown (red bar with a question mark). Figure created with BioRender.com. Abbreviation: NrCAM, neuronal cell adhesion molecule.
Figure 4
Figure 4. Palmitoyl-proteome comparison analysis reveals the prevalence of palmitoylation among AIS proteins
(A) Donut charts showing the percentage of palmitoylated proteins in AIS or synaptic proteomes. The totals indicate the number of proteins in each dataset. The AIS proteome gene list was assembled from the highest confidence AIS proteins identified by Hamdan et al. ([214]) and several known AIS proteins missed in the Hamdan study. Synaptic proteome genes were extracted from the SynGO database (SynGO release 1.1-all genes [216]). Both gene sets were subjected to palmitoyl-proteome comparison analysis in SwissPalm using all 54 available mouse, human, and rat proteomes. All proteins found in at least two palmitoyl proteomes or one targeted study were designated as palmitoylated. (B–D) Heat maps showing all genes in membrane-proximal (NF186, B), microtubule-associated (Trim46, C), and shallow cytoplasm (Ndel1, D) and AIS proteomes and the number of palmitoyl proteome and targeted studies for each gene. Red colour designates values above 20. The data on the number of studies were extracted from the palmitoyl-proteome comparison analysis described above.
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