Phosphatidylinositol 4,5-bisphosphate in the Control of Membrane Trafficking

Abstract

Phosphoinositides are membrane lipids generated by phosphorylation on the inositol head group of phosphatidylinositol. By specifically distributed to distinct subcellular membrane locations, different phosphoinositide species play diverse roles in modulating membrane trafficking. Among the seven known phosphoinositide species, phosphatidylinositol 4,5-bisphosphate (PI4,5P₂) is the one species most abundant at the plasma membrane. Thus, the PI4,5P₂ function in membrane trafficking is first identified in controlling plasma membrane dynamic-related events including endocytosis and exocytosis. However, recent studies indicate that PI4,5P₂ is also critical in many other membrane trafficking events such as endosomal trafficking, hydrolases sorting to lysosomes, autophagy initiation, and autophagic lysosome reformation. These findings suggest that the role of PI4,5P₂ in membrane trafficking is far beyond just plasma membrane. This review will provide a concise synopsis of how PI4,5P₂ functions in multiple membrane trafficking events. PI4,5P₂, the enzymes responsible for PI4,5P₂ production at specific subcellular locations, and distinct PI4,5P₂ effector proteins compose a regulation network to control the specific membrane trafficking events.

Keywords: 5P2; PI4; PIPK; autophagy; endosome; lysosome; membrane trafficking.

Figure 1

Schematic representation of the phosphoinositides. (A) Phosphatidylinositol (PI) contains an inositol head group connected to a Diacylglycerol (DAG) via a phosphodiester linkage. (B) Phosphate groups can be attached to any permutation of 3-, 4- and 5-hydroxyl groups of the inositol head of PI to produce different phosphoinositides. The interconversion of PI4,5P₂ with PI4P, PI5P, or PI3,4,5P₃ by phosphorylation and dephosphorylation are indicated.

Figure 2

Model of PI4,5P₂, PIPKs, and PI4,5P₂-effectors in the regulation of multiple membrane trafficking events. PIPKs can be recruited by different targeting factors to distinct subcellular locations such as plasma membrane, endosomes, and lysosomes. Then the local production of PI4,5P₂ by PIPKs recruits specific PI4,5P₂-effectors to modulate different membrane trafficking events.

Figure 3

PI4,5P₂ in the regulation of Clathrin-mediated endocytosis. PI4,5P₂ recruits many clathrin adaptors such as AP2, Epsin, AP180, β-arrestin, Numb, Dab2, and Dynamin to plasma membrane and modulates their functions, which is required for clathrin recruitment to membrane to initiate the formation of clathrin-coated pits. Then by modulating N-WASP, Arp2/3, and Dynamin, PI4,5P₂ is required for induce membrane curvature, invagination, and maturation of clathrin-coated vesicles. After final scission step, clathrin need to be released from the internalized vesicles. The down-regulation of PI4,5P₂ by phosphoinositide phosphatases synaptojanin 1, OCRL, and SHIP2 at the clathrin-coated vesicles is required for the clathrin releasing.

Figure 4

Model of PIPKIγi5 and PI4,5P₂ in the modulation of EGFR endosomal trafficking. PIPKIγi5, an enzyme producing PI4,5P₂, controls the endosomal sorting of EGFR by modulating Hrs-EGFR interaction, Mig6 degradation, and Rab7 recruitment to early endosomes. Hrs can recognize ubiquitinated EGFR at the limiting membrane of early endosomes, and then recruit other component of ESCRT complex to initiate the membrane invagination and EGFR sorting into the intraluminal vesicles (ILVs). Hrs can be ubiquitinated by E3 ligase NEDD4, which decreases it ability to bind EGFR. PIPKIγi5 and PI4,5P₂ facilities SNX5 interaction with Hrs. This blocks Hrs ubiquitination by NEDD4 and is required for Hrs interaction with EGFR. Mig6 is another protein that binds to EGFR and is required for the sorting of internalized EGFR to late endosomes and the subsequently sorting to lysosomes for degradation. By interacting with NEDD4, PIPKIγi5 blocks NEDD4-mediated Mig6 ubiquitination to protect Mig6 from being degraded by proteasomes. Rab7 recruitment to early endosomes is a key step for early to late endosome maturation. PIPKIγi5 interacts with Rab7 and is required for Rab7 recruitment to early endosomes. In this way, PIPKIγi5 controls endosome maturation.

Figure 5

PI4,5P₂ in the modulation of autophagy. PI4,5P₂ together with its effectors and PI4,5P₂ producing enzymes controls multiple steps of autophagy including autophagy initiation, membrane delivery from plasma membrane or recycling endosomes to autophagosome, hydrolases sorting to lysosome, and the fusion of autophagosome and lysosome to form autolysosome.

Figure 6

PI4,5P₂ in the modulation of exocytosis. PI4,5P₂ is required for exocyst-mediated secretory vesicles sorting to plasma membrane. By interacting and modulating Munc13 and CAPS, PI4,5P₂ modulates vesicle priming. By modulating SNARE complex, PI4,5P₂ controls vesicles fusion with plasma membrane.