The Isoform Selective Roles of PI3Ks in Dendritic Cell Biology and Function

Abstract

Phosphoinositide-3 kinases (PI3Ks) generate 3-phosphorylated phosphoinositide lipids that are implicated in many biological processes in homeostatic states and pathologies such as cancer, inflammation and autoimmunity. Eight isoforms of PI3K exist in mammals and among them the class I PI3K, p110γ, and PI3Kδ, and class III Vps34 being the most expressed and well characterized in immune cells. Following engagement of pathogen recognition receptors (PRRs), PI3Ks coordinate vital cellular processes of signaling and vesicular trafficking in innate phagocytes such as macrophages and professional antigen presenting dendritic cells (DCs). Although previous studies demonstrated the involvement of PI3K isoforms in innate and adaptive immune cell types, the role of PI3Ks with respect to DC biology has been enigmatic. Thus, this review, based on studies involving PI3K isoforms, highlight how the different PI3Ks isoforms could regulate DC functions such as antigen processing and presentation including PRR responses.

Keywords: PI3K; antigen presentation; dendritic cell; phospholipids; toll like receptors.

Figure 1

Different classes of PI3Ks. All PI3Ks isoforms (p110 α, β, δ, γ, C2α, C2β, C2γ, Vps34) have 3 to 5 domains: an N terminal domain which can bind the regulatory p85 proteins, a Ras binding domain, a C2 domain which binds membranes, an helical domain of unknown function and a catalytic subunit with kinase activity. They associate with a regulatory subunit, p85 isoforms (for p110 α, β, δ), p101, and p87 for p110γ and Vps15 for Vps34. P85 regulatory subunits are encoded by different genes: PI3KR1 (depending on the promoter will give p85α, p55α, p50β), PI3KR2 (p85β), and PI3KR3 (p55γ). PI3Ks use phospatidylinositol lipids as their substrates.

Figure 2

PI3Ks generate membrane phospholipids important for vesicular trafficking events in DCs. (a) Bacteria, cell debris, and large particles are taken up in Rab5⁺ dynamin⁺ early phagosomes that undergo maturation to generate Rab7⁺ LAMP1⁺ late phagosome. Pathogens such as bacteria and yeast can be internalized into LC3 associated phagosome (LAP) where Rac2 and NOX2 are recruited and are required to generate reactive oxygen species (ROS). (b) During endocytosis, ligands bound to G protein coupled- and tyrosine kinase-receptors are taken up from the plasma membrane into Rab5⁺ early endosomes and then either traffic to Rab7⁺ LAMP1⁺ late endosomes or are recycled back to the plasma membrane. (c) During autophagy, a double membrane organelle is generated from an omegasome (specific ER structure) where Vps34, Vps15, and Beclin1 are recruited. This double membrane organelle will form later the autophagosome by ingesting cytoplasmic material. Ultimately, all transport vesicles (late phagosome, late endosome, autophagosome) will fuse with the lysosomes for cargo degradation. PI(4,5)P₂ is enriched proximal to the plasma membrane and in lysosomal location. Class I PI3Ks produce PI(3,4,5)P₃ from PI(4,5)P₂, while class II and III PI3Ks produce PI(3)P following phagosome enclosure, and PI(3,4,5)P₃ is converted into PI(3,4,)P₂ by SHIP1 and SHIP2 (3) phosphatases. PI(3)P and PI(3.5)P₂ are present in late endosomes.