Secreted Phospholipases A₂ - not just Enzymes: Revisited

Abstract

Secreted phospholipases A2 (sPLA2s) participate in a very broad spectrum of biological processes through their enzymatic activity and as ligands for membrane and soluble receptors. The physiological roles of sPLA2s as enzymes have been very well described, while their functions as ligands are still poorly known. Since the last overview of sPLA2-binding proteins (sPLA2-BPs) 10 years ago, several important discoveries have occurred in this area. New and more sensitive analytical tools have enabled the discovery of additional sPLA2-BPs, which are presented and critically discussed here. The structural diversity of sPLA2-BPs reveals sPLA2s as very promiscuous proteins, and we offer some structural explanations for this nature that makes these proteins evolutionarily highly advantageous. Three areas of physiological engagement of sPLA2-BPs have appeared most clearly: cellular transport and signalling, and regulation of the enzymatic activity of sPLA2s. Due to the multifunctionality of sPLA2s, they appear to be exceptional pharmacological targets. We reveal the potential to exploit interactions of sPLA2s with other proteins in medical terms, for the development of original diagnostic and therapeutic procedures. We conclude this survey by suggesting the priority questions that need to be answered.

The Phospholipase Activity of Ammodytoxin, a Prototype Snake Venom β-Neurotoxin, Is Not Obligatory for Cell Internalisation and Translocation to Mitochondria

“…At least two cell-internalisation pathways for β-NTXs have been proposed: via synaptic vesicles during their recycling from the PM after exocytosis, and by receptor-mediated endocytosis using the retrograde protein transport mechanism [4]. Several specific binding proteins for β-NTXs on the PM of nerve and other cells have been characterised (for reviews, see [10,13]); however, none of these have been firmly associated with the process of β-neurotoxicity to date. As the intracellular actions of β-NTXs appear to be essentially responsible for β-neurotoxicity, we addressed here the important issue of the significance of the enzymatic activity of β-NTXs for their trafficking into and within cells.…”

“…Internalisation of Atx and other β-NTXs into cells has also been shown using neuronal cell lines in culture [6][7][8][9]. In addition, Atx was shown to bind several intracellular proteins with high affinity, such as calmodulin, 14-3-3 proteins, protein disulphide isomerase, and cytochrome c oxidase subunit II (CCOX-II) [10]. Nevertheless, the molecular mechanisms of its internalisation into cells and its intracellular trafficking are far from clear.…”

Multimodal regulation of the osteoclastogenesis process by secreted group IIA phospholipase A2

“…The sPLA 2 -IIA cellular functions account for the enzymatic hydrolysis of glycerophospholipids, but can also occur in a catalysis-independent manner ( Murakami et al, 2017 ; Doré and Boilard, 2019 ; Scott et al, 2021 ; Ivanusec et al, 2022 ). Several cellular and soluble receptors for sPLA 2 -IIA have been characterized until now, starting from the cell surface M-type receptor for secreted phospholipases ( Cupillard et al, 1999 ; Lambeau and Lazdunski, 1999 ), and these may be involved in the activation of downstream cellular signaling pathways with hydrolytic activity-independent mechanisms ( Saegusa et al, 2008 ; Ivanusec et al, 2022 ).…”

“…The sPLA 2 -IIA cellular functions account for the enzymatic hydrolysis of glycerophospholipids, but can also occur in a catalysis-independent manner ( Murakami et al, 2017 ; Doré and Boilard, 2019 ; Scott et al, 2021 ; Ivanusec et al, 2022 ). Several cellular and soluble receptors for sPLA 2 -IIA have been characterized until now, starting from the cell surface M-type receptor for secreted phospholipases ( Cupillard et al, 1999 ; Lambeau and Lazdunski, 1999 ), and these may be involved in the activation of downstream cellular signaling pathways with hydrolytic activity-independent mechanisms ( Saegusa et al, 2008 ; Ivanusec et al, 2022 ). On the other hand, the sPLA 2 -IIA protein is highly basic and can easily associate to the cell surface via heparin sulfated proteoglycans ( Koduri et al, 1998 ; Murakami et al, 1999 ; Boilard et al, 2003 ; Boilard et al, 2006 ), and its interaction with the cellular membranes has been proposed to be sufficient to alter the lipid bilayer structure with consequent pathophysiological functions ( Cirino et al, 1994 ; Lomonte et al, 1995 ).…”

Treatment of Mouse Sperm with a Non-Catalytic Mutant of PLA2G10 Reveals That PLA2G10 Improves In Vitro Fertilization through Both Its Enzymatic Activity and as Ligand of PLA2R1

“…Alternatively, PLA2G10 could induce some biological responses through its ability to bind to specific membrane receptors. There are indeed more and more reports showing that sPLA 2 s are ligands for different protein families located at the plasma membrane including PLA2R1 [ 16 ], integrins [ 17 ], heparan sulfate proteoglycans [ 18 , 19 ], and vascular endothelial growth factor receptors (VEGFRs) [ 20 ]; an updated list of sPLA 2 ligands was recently reviewed by [ 21 ]. In particular, the biological response of PLA2G10 may thus be related to its binding property to PLA2R1, to which mouse PLA2G10 binds with a nanomolar affinity [ 16 , 22 ].…”