Protein Palmitoylation Dynamics and Mechanisms

Protein palmitoylation refers to the reversible attachment of a 16-carbon fatty acid, palmitate, to specific cysteine residues via a thioester bond. This modification modulates protein hydrophobicity, subcellular localisation, trafficking and stability, thereby influencing diverse cellular processes such as signal transduction, membrane trafficking and synaptic function. The dynamic nature of palmitoylation is governed by a balance between palmitoyl acyltransferases, which catalyse the forward reaction, and depalmitoylases, which hydrolyse the thioester linkage. The best characterised palmitoyl acyltransferases are the zinc finger DHHC (Asp-His-His-Cys) family, which display varying substrate specificities and subcellular localisations. Depalmitoylation is mediated by acyl-protein thioesterases and specialised hydrolases, enabling rapid cycles of attachment and removal that fine-tune protein ensembles at membranes. Recent advances in chemical probes and proteomic workflows have expanded the known palmitoyl-proteome to hundreds of substrates, revealing its pervasive role in immunity, metabolism and neuronal plasticity. Aberrant palmitoylation dynamics are implicated in cancer, neurodegeneration and autoimmunity, making the enzymes that govern this lipid modification attractive therapeutic targets. Emerging studies are now elucidating the kinetics and specificity determinants of acyl-transfer and hydrolase reactions, as well as the interplay between palmitoylation and other post-translational modifications, to build a mechanistic understanding of how lipid cycles orchestrate cellular physiology.

Research from Nature Portfolio

Recent studies have introduced a chemical–genetic platform that selectively labels substrates of individual DHHC enzymes in intact cells, enabling the generation of comprehensive S-acylation maps for five ZDHHC isoforms and the identification of over 300 novel modification sites across diverse protein classes. Parallel work has uncovered a palmitoylation–depalmitoylation cycle controlling Toll-like receptor 9 (TLR9) signalling in immune cells: palmitoylation by DHHC3 in the Golgi promotes endosomal trafficking of TLR9, whereas removal by palmitoyl-protein thioesterase 1 in lysosomes releases TLR9 from its chaperone, thus modulating interferon release and inflammatory responses in systemic autoimmunity. Complementing these insights, dynamic palmitoylation of the fatty-acid receptor CD36 has been shown to regulate caveolae-mediated endocytosis: ligand-induced phosphorylation of DHHC5 followed by depalmitoylation by APT1 controls CD36 internalisation, fatty-acid uptake and lipid droplet formation, highlighting a rapid lipidation switch that underpins metabolic adaptation.

Protein Palmitoylation Dynamics and Mechanisms publication trend

The graph below shows the total number of articles in protein palmitoylation dynamics and mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

S-palmitoylation: Reversible thioester linkage of palmitate to cysteine residues that modulates protein–membrane affinity and function.

DHHC family: Zinc finger acyltransferases characterised by an Asp-His-His-Cys motif that catalyse palmitate transfer to proteins.

Depalmitoylase: Enzyme that hydrolyses palmitoyl thioester bonds, releasing the fatty acid and reversing membrane association.

Thioester linkage: Covalent bond between a fatty-acid carboxyl group and a protein thiol, conferring reversible lipid modification.

Chemical–genetic mapping: Technique combining engineered enzyme mutants and tagged probes to profile enzyme–substrate relationships in cells.

References

1. Thematic review series: Lipid Posttranslational Modifications. Protein palmitoylation by a family of DHHC protein S-acyltransferases. Journal of Lipid Research (2006).
2. Proteome Scale Characterization of Human S-Acylated Proteins in Lipid Raft-enriched and Non-raft Membranes*. Molecular & Cellular Proteomics (2009).
3. A palmitoyl transferase chemical–genetic system to map ZDHHC-specific S-acylation. Nature Biotechnology (2024).
4. Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice. Nature Communications (2024).
5. CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis. Nature Communications (2020).
6. Protein lipidation in health and disease: molecular basis, physiological function and pathological implication. Signal Transduction and Targeted Therapy (2024).
7. ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization. eLife (2015).
8. SwissPalm: Protein Palmitoylation database. F1000Research (2015).