Current Knowledge on the Biology of Lysophosphatidylserine as an Emerging Bioactive Lipid

Abstract

Lysophosphatidylserine (LysoPS) is an emerging lysophospholipid (LPL) mediator, which acts through G protein-coupled receptors, like lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). LysoPS is detected in various tissues and cells and thought to be produced mainly by the deacylation of phosphatidylserine. LysoPS has been known to stimulate degranulation of mast cells. Recently, four LysoPS-specific G protein-coupled receptors (GPCRs) were identified. These GPCRs belong to the P2Y family which covers receptors for nucleotides and LPLs and are predominantly expressed in immune cells such as lymphocytes and macrophages. Studies on knockout mice of these GPCRs have revealed that LysoPS has immune-modulatory functions. Up-regulation of a LysoPS-producing enzyme, PS-specific phospholipase A1, was frequently observed in situations where the immune system is activated including autoimmune diseases and organ transplantations. Therefore, modulation of LysoPS signaling appears to be a promising method for providing therapies for the treatment of immune diseases. In this review, we summarize the biology of LysoPS-producing enzymes and receptors, recent developments in LysoPS signal modulators, and prospects for future therapeutic applications.

Lysophosphatidylserine Induces MUC5AC Production via the Feedforward Regulation of the TACE-EGFR-ERK Pathway in Airway Epithelial Cells in a Receptor-Independent Manner

“…LysoPS activates these receptors at a few micromolar concentrations that are not cytotoxic [ 38 , 48 , 49 ]. Moreover, the functional effects of LysoPS are often blocked by inhibitors of specific G proteins coupled with each GPCR [ 50 ]. In our hands, NCI-H292 cells do not express any of the four GPCRs, as determined by FACS and western blot analysis.…”

“…Currently, there is little information about the level and pathological role of LysoPS in inflamed lungs. Several enzymes that specifically synthesize and degrade LysoPS have recently been identified [ 50 , 51 , 57 ]. PS-PLA1 is a crucial enzyme that synthesizes LysoPS extracellularly [ 58 ].…”

Small Endogenous Ligands Modulation of Nerve Growth Factor Bioactivity: A Structural Biology Overview

“…Lysophosphatidylserine (Lyso-PS) has earned an increasing interest in the literature in recent years [ 14 ]. It has become clear that Lyso-PS is present in the CNS and in the immune system and its receptors have been characterized [ 15 ]. Further studies have shown that Lyso-PS is showing immunomodulatory functions, and several studies have proven an important link between Lyso-PS and neurodegenerative as well as autoimmune diseases [ 15 ].…”

“…Given the important role of NGF and the other neurotrophins in both the CNS and the immune system, it is plausible to hypothesize that a direct interaction between Lyso-PS and NGF might be of important functional significance. It has been shown that Lyso-PS is involved in histamine degranulation in mast cells [ 15 ]. Different sets of experiments have proven that there is a powerful synergism between Lyso-PS and NGF in mast cells, activating histamine secretion at low Lyso-PS concentrations [ 16 , 17 ] and in the presence of extracellular Ca 2+ [ 18 ] and phospholipase D [ 19 ].…”

“…2D 1 H- 15 N HSQC spectra following a titration with increasing amounts of ATP allowed characterizing the rhNGF residues engaged in the interactions with ATP. The analysis of the combined 1 H/ 15 N Chemical Shift Perturbation (CSP) showed residues that are likely involved directly in ATP binding, i.e., Trp21, Ile31, Asn45, Phe49, Thr56, Leu90, Ala97 and Ile 104.…”