Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

Abstract

Phosphoinositides (PIs) make up only a small fraction of cellular phospholipids, yet they control almost all aspects of a cell's life and death. These lipids gained tremendous research interest as plasma membrane signaling molecules when discovered in the 1970s and 1980s. Research in the last 15 years has added a wide range of biological processes regulated by PIs, turning these lipids into one of the most universal signaling entities in eukaryotic cells. PIs control organelle biology by regulating vesicular trafficking, but they also modulate lipid distribution and metabolism via their close relationship with lipid transfer proteins. PIs regulate ion channels, pumps, and transporters and control both endocytic and exocytic processes. The nuclear phosphoinositides have grown from being an epiphenomenon to a research area of its own. As expected from such pleiotropic regulators, derangements of phosphoinositide metabolism are responsible for a number of human diseases ranging from rare genetic disorders to the most common ones such as cancer, obesity, and diabetes. Moreover, it is increasingly evident that a number of infectious agents hijack the PI regulatory systems of host cells for their intracellular movements, replication, and assembly. As a result, PI converting enzymes began to be noticed by pharmaceutical companies as potential therapeutic targets. This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

A phosphoinositide conversion mechanism for exit from endosomes

“…In the latter case, substrate specificity could be defined by compartment-specific regulatory proteins and lipid-substrate availability (De Matteis and Godi 2004;. The local balance, distribution and regulation of PI species is determined by the organelle specific subset of PI metabolizing enzymes (Balla 2013) (For a comprehensive overview see Table 1). Their membrane recruitment and sub-compartmental targeting is mostly regulated by PI-binding domains, membrane-anchors, such as reversible palmitoylation, or peripheral membrane proteins, including small Rab GTPases and transport coat components.…”

Spatial control of phospholipid flux restricts endoplasmic reticulum sheet formation to allow nuclear envelope breakdown

“…In metazoans, lipin is at a branching point in the phospholipid synthesis pathway; the major building blocks of membrane bilayers (phosphatidylcholine [PC] and phosphatidylethanolamine [PE]) are synthesized from the lipin product DAG, whereas phosphatidylinositol (PI) is synthesized from the lipin substrate PA Lagace and Ridgway 2013;Siniossoglou 2013). PI is converted to phosphoinositides (PIPs) when transported to other organelles that house specific PIP kinases and phosphatases (Balla 2013). Within the ER, PC and PE make up >70% of total phospholipid, whereas PI makes up <10% (van Meer et al 2008).…”

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P 2 and maintenance of KCNQ2/3 ion channel current

“…phosphoinositides | wortmannin | pleckstrin homology domain T his paper concerns the dynamics of cellular pools of phosphoinositides, a family of phospholipids located on the cytoplasmic leaflet of cellular membranes, that maintain cell structure, cell motility, membrane identity, and membrane trafficking; they also play key roles in signal transduction (1). Phosphatidylinositol (PI) can be phosphorylated at three positions to generate seven additional species.…”