Lipid metabolism modulation by the P2X7 receptor in the immune system and during the course of infection: new insights into the old view

Abstract

For decades, scientists have described numerous protein pathways and functions. Much of a protein's function depends on its interactions with different partners, and those partners can change depending on the cell type or system. The P2X7 receptor (P2X7R) is one such multifunctional protein that is related to multiple partners and signaling pathways. The relationship between P2X7R and different enzymes involved in lipid metabolism represents a relatively new field in P2X7R research. This field of research began in epithelial cells and currently includes immune and nervous cells. The P2X7R-lipid metabolism pathway is related to many biological functions of P2X7R, such as cell death and pathogen clearance, and this signaling pathway may be involved in many functions that are dependent on bioactive lipids. In the present review, we will attempt to summarize data related to the P2X7R-lipid metabolism pathway, focusing on signaling pathways and their biological relevance to the immune system and infection.

Fig. 1

Lipid metabolism enzymes and P2X7R modulation. a Backbone of a glycerol phospholipid, indicating the biochemical site of cleavage by each phospholipase enzyme and the resulting products. b Backbone of sphingomyelin, indicating the biochemical site of cleavage of neutral sphingomyelinase to generate the product ceramide. The site phosphorylated by ceramide kinase is also indicated. c Representation of P2X7R activation by endogenous ATP or specific purinergic agonists, triggering different lipid enzyme pathways in several cell types. The response specificity of each lipid pathway depends on cell type, and the details of these pathway steps are unclear

Fig. 2

Hypothetical P2X7R activation and the resulting modulation of phospholipid enzyme pathways. a Phosphatidylinositol (PI) is phosphorylated by phosphatidylinositol 4-kinase at inositol carbon 4 to produce phosphatidylinositol 4-phosphate (PIP). PIP is phosphorylated by phosphatidylinositol 5-kinase at inositol carbon 5 to produce phosphatidylinositol 4,5-phosphate (PIP₂). b PIP₂ is a substrate of phosphatidylinositol-specific phospholipase C to produce diacylglycerol (DAG) and inositol triphosphate (IP3). c Activated P2X7R can interact with diverse proteins and molecules. In the presence of PIP₂, a specific motif in the C terminus of P2X7R interacts with PIP₂ and facilitates the interaction between P2X7R and PLA2. At the same time, PLC is negatively modulated by the sequestration of PIP₂ by P2X7R

Fig. 3

Possible intracellular pathways triggered by ATP activation of P2X7R. After ATP coupling, P2X7R could induce (1) de novo ceramide synthesis by the endoplasmic reticulum (ER) with the ceramide then being directed to the plasma membrane to assemble existing lipid rafts or to generate ceramide-rich domains. Likewise, (2) P2X7R can migrate to lipid raft domains. (3) Otherwise, during intracellular infections, PLD could be activated and could promote lysosome-parasitophorous vacuole fusion, leading to pathogen processing