Phosphoinositides, Major Actors in Membrane Trafficking and Lipid Signaling Pathways

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: kinase; lipids; membrane trafficking; phosphatase; phosphoinositides; vesicles.

Figure 1

Phosphoinositides synthesized in yeast Saccharomyces cerevisiae (S. cerevisiae) and in human cells with the enzymes involved. (A) The chemical structure of phosphatidylinositol (PI); (B) Phosphorylation reactions are represented with black arrows and dephosphorylation reactions by grey arrows. The name of the yeast enzyme (when relevant) is written on top of its human homologue.

Figure 2

Intracellular localization of the different phosphoinositides and the membrane trafficking pathways. The different phosphoinositides (PPIn) are represented by symbols: circles for PPIn involved in intracellular trafficking with the corresponding steps they regulate; squares for PPIn involved in cell signaling, the latter being absent from yeast. The human proteins interacting with the different PPIn are represented by a rectangle. The MVB stands for multivesicular body and the VPS for vacuolar protein sorting.