Abstract
Palmitoylation is a post-translational modification (PTM) based on thioester-linkage between palmitic acid and the cysteine residue of a protein. This covalent attachment of palmitate is reversibly and dynamically regulated by two opposing sets of enzymes: palmitoyl acyltransferases containing a zinc finger aspartate-histidine-histidine-cysteine motif (PAT-DHHCs) and thioesterases. The reversible nature of palmitoylation enables fine-tuned regulation of protein conformation, stability, and ability to interact with other proteins. More importantly, the proper function of many surface receptors and signaling proteins requires palmitoylation-meditated partitioning into lipid rafts. A growing number of leukocyte proteins have been reported to undergo palmitoylation, including cytokine/chemokine receptors, adhesion molecules, pattern recognition receptors, scavenger receptors, T cell co-receptors, transmembrane adaptor proteins, and signaling effectors including the Src family of protein kinases. This review provides the latest findings of palmitoylated proteins in leukocytes and focuses on the functional impact of palmitoylation in leukocyte function related to adhesion, transmigration, chemotaxis, phagocytosis, pathogen recognition, signaling activation, cytotoxicity, and cytokine production.
Highlights
Leukocytes are critical components of innate and adaptive immunity by eradicating microbes and potentially harmful cells or substances
These palmitoyl proteomic approaches have identified an array of palmitoylated proteins, including but not limited to cytokine/chemokine receptors chemokine receptor type 5 (CCR5), TNFR, and INFAR; adhesion molecules PECAM-1 and junctional adhesion molecule c (JAM-C); pattern recognition Toll-like receptors (TLRs)/MYD88 complex; scavenger receptor CD36; T cell coreceptors CD4 and CD8; Src family kinases Lck and Fyn; transmembrane adaptor proteins linker of activated T cells (LAT) and phosphoprotein associated with GEMs (PAG); signaling effectors Gα, Ras, and phospholipase C; and Ca2+ regulator IP3 receptor (IP3R)
We show that the palmitoylation inhibitor 2-BP greatly attenuates the ICAM-1 surface expression of endothelial cells (ECs) in response to IL-1β and blocks leukocyte-EC adhesion in vitro
Summary
Leukocytes are critical components of innate and adaptive immunity by eradicating microbes and potentially harmful cells or substances. Methodological advances have made it possible to perform sensitive and reliable large-scale palmitoyl proteome profiling in different subtypes of leukocytes, including monocyte/macrophages, dendritic cells, T cells and B cells, as well as in cells directly interacting with leukocytes, such as endothelial cells (ECs; Martin and Cravatt, 2009; Merrick et al, 2011; Ivaldi et al, 2012; Marin et al, 2012; Chesarino et al, 2014) These palmitoyl proteomic approaches have identified an array of palmitoylated proteins, including but not limited to cytokine/chemokine receptors CCR5, TNFR, and INFAR; adhesion molecules PECAM-1 and JAM-C; pattern recognition TLR/MYD88 complex; scavenger receptor CD36; T cell coreceptors CD4 and CD8; Src family kinases Lck and Fyn; transmembrane adaptor proteins linker of activated T cells (LAT) and PAG; signaling effectors Gα, Ras, and phospholipase C; and Ca2+ regulator IP3R. Palmitoylation-dependent segregation of proteins in lipid rafts is essential for the amplification of signal propagation in activated cells while preventing the signal activation in resting cells Another unique function of palmitoylation in regulating signal transduction is mediating receptor desensitization and internalization (Resh, 2006a). There has been limited research to characterize the functional impacts and regulatory mechanisms of ABHD17s
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