Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

Abstract

Abstract:Phosphoinositides are lipids involved in the vesicular transport of proteins and lipids between the different compartments of eukaryotic cells. They act by recruiting and/or activating effector proteins and thus are involved in regulating various cellular functions, such as vesicular budding, membrane fusion and cytoskeleton dynamics. Although detected in small concentrations in membranes, their role is essential to cell function, since imbalance in their concentrations is a hallmark of many cancers. Their synthesis involves phosphorylating/dephosphorylating positions D3, D4 and/or D5 of their inositol ring by specific lipid kinases and phosphatases. This process is tightly regulated and specific to the different intracellular membranes. Most enzymes involved in phosphoinositide synthesis are conserved between yeast and human, and their loss of function leads to severe diseases (cancer, myopathy, neuropathy and ciliopathy).Keywords: lipids; membrane trafficking; vesicles; phosphoinositides; phosphatase; kinase Phosphoinositides in Cellular Membranes Lipids, Major Membrane ComponentsThe dynamic modulation of the physicochemical properties of membranes is required for eukaryotic cells function. Indeed, cells live in an environment characterized by temperature, relative humidity, pH, sun exposure, osmotic pressure and nutrient variations. Living organisms have to adapt to variations of these different factors in order to keep their intracellular balance. Eukaryotic cells have achieved this by adopting a compartmentalized organization, which minimizes the intracellular variations resulting from extracellular fluctuations. The plasma membrane is the first barrier separating the cytoplasm from the extracellular medium. Its composition ensures a mechanical protection, but also allows exchanges with the medium through transporters and receptors, as a form of very selective permeability.Membranes are composed of two phospholipid leaflets organized as a bilayer in which sterols, glycolipids and proteins are inserted. The phospholipids of this bilayer are amphiphilic with a hydrophilic group (head) linked to a hydrophobic group (tail) ( Figure 1A). In the bilayer, the hydrophobic groups face each other, thus creating a hydrophobic space in between them, which ensures its role as a barrier. This property is very important for the anchoring of hydrophobic molecules, such as sterols or ceramides, transmembrane domains or the lipid anchor of proteins. The lipid composition of membranes varies according to the organism (eukaryotes or prokaryotes), the cell type (among the different tissues of a multicellular organism), the membrane type (plasma Int.

Leishmaniaparasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine inLeishmaniainfections

“…The PH‐Akt (GFP) probe is reactive to both PI (3,4)P2 and PI (3,4,5)P3 lipids (Manning & Cantley, ). These lipids have distinct biosynthetic and metabolic schemes (De Craene, Bertazzi, Bär, & Friant, ). To gain more insight into which of these phosphoinositides is displayed on LPVMs, we sought to determine whether the precursor lipids for PI (3,4)P2 and PI (3,4,5)P3 are also displayed on LPVs.…”

A Network of Phosphatidylinositol 4,5-bisphosphate Binding Sites Regulate Gating of the Ca2+-activated Cl− Channel ANO1 (TMEM16A)

“…For example, X-ray crystallography, coarse-grained MD, and reconstitution in artificial membranes have demonstrated that the Arf GTPase and its GEF Brag2 form a complex that binds to the membrane via multiple PI(4,5)P2 interaction sites (36). There is also mutational and biochemical evidence that profilin-1 and gelsolin have two PI(4,5)P2 binding sites, as do TRPV1 channels (45,62), EAG1 channels (17), and Kir2.1 (14,40).…”

PIKfyve deficiency in myeloid cells impairs lysosomal homeostasis in macrophages and promotes systemic inflammation in mice

“…Intracellular trafficking events are modulated by several signaling molecules, which include members of the phosphoinositide family (3–5). In particular, the phosphatidylinositol (3,5)-bisphosphate [PI(3,5)P2] is critical for the trafficking along the endolysosomal system (6–8) and has been implicated in lysosome biogenesis and autophagy (9–12).…”