Abstract
S-palmitoylation is a reversible posttranslational lipid modification of proteins. It controls protein activity, stability, trafficking and protein-protein interactions. Recent global profiling of immune cells and targeted analysis have identified many S-palmitoylated immunity-associated proteins. Here, we review S-palmitoylated immune receptors and effectors, and their dynamic regulation at cellular membranes to generate specific and balanced immune responses. We also highlight how this understanding can drive therapeutic advances to pharmacologically modulate immune responses.
Highlights
S-palmitoylation is a posttranslational modification of proteins with lipids
The first step in T cell receptor (TCR) signal transduction involves the binding of TCR to peptide–major histocompatibility complexes (MHCs) on antigen-presenting cells (APCs)
Known stimulator of interferon genes (STING) mutants associated with STING associated vasculopathy with onset in infancy (SAVI) lost their ability to spontaneously activate the interferon regulator factor 3 (IRF3)- and nuclear factor-κB (NF-κB)-dependent gene promoters when combined with S-palmitoylation-impairing mutations at Cys88 and 91 or when palmitoylation was inhibited by 2-BP treatment of cells [62]. These results suggested that palmitoylation of STING could potentially be targeted therapeutically in SAVI
Summary
S-palmitoylation is a posttranslational modification of proteins with lipids. It typically involves the addition of a 16-carbon palmitic acid to cysteines of a protein via a thioester bond (figure 1), but other fatty acids like myristic acid and oleic acid can be added [1]. S-palmitoylation is unique among lipid modifications because the high energy thioester bond between the fatty acyl group and cysteine residue allows it to be a reversible modification and can impart spatio-temporal control of protein function [3] This dynamic fatty acid modification of H- and N-ras enables the protein cycling between the plasma membrane and Golgi apparatus, maintaining subcellular compartmentalization for diversification of signal transduction (figure 1) [4]. Free cysteines of palmitoylated proteins are capped and thioester linkages are subsequently cleaved to generate new thiols These thiols are selectively labelled by biotin for ABE or thiol-reactive resin for acyl-Rac, allowing further enrichment and detection of palmitoylated peptides or proteins. There are excellent reviews that describe the role of protein S-palmitoylation in other physiological processes [79]
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