The multiple roles of PtdIns(4)P – not just the precursor of PtdIns(4,5)P2

Abstract

The phosphoinositides (PIs) are membrane phospholipids that actively operate at membrane-cytosol interfaces through the recruitment of a number of effector proteins. In this context, each of the seven different PI species represents a topological determinant that can establish the nature and the function of the membrane where it is located. Phosphatidylinositol 4-phosphate (PtdIns(4)P) is the most abundant of the monophosphorylated inositol phospholipids in mammalian cells, and it is produced by D-4 phosphorylation of the inositol ring of PtdIns. PtdIns(4)P can be further phosphorylated to PtdIns(4,5)P 2 by PtdIns(4)P 5-kinases and, indeed, PtdIns(4)P has for many years been considered to be just the precursor of PtdIns(4,5)P 2 . Over the last decade, however, a large body of evidence has accumulated that shows that PtdIns(4)P is, in its own right, a direct regulator of important cell functions. The subcellular localisation of the PtdIns(4)P effectors initially led to the assumption that the bulk of this lipid is present in the membranes of the Golgi complex. However, the existence and physiological relevance of 'non-Golgi pools' of PtdIns(4)P have now begun to be addressed. The aim of this Commentary is to describe our present knowledge of PtdIns(4)P metabolism and the molecular machineries that are directly regulated by PtdIns(4)P within and outside of the Golgi complex.Key words: Phosphoinositides, PtdIns(4)P, PtdIns(4)P-binding proteins, PI 4-kinase, Golgi complex, Lipid-transfer protein SummaryThe multiple roles of PtdIns (4) Journal of Cell Science 1956The cellular role and regulation of yeast and mammalian PI4Ks YeastThe use of Saccharomyces cerevisiae as a model system has been of outstanding importance in the dissection of the regulation and roles of the PI4Ks. The yeast genome contains three genes that encode PI4Ks (Strahl and Thorner, 2007): Pik1 (the PI4KIIIβ orthologue that accounts for the production of 45% and 40% of the total cellular PtdIns(4)P and PtdIns(4,5)P 2 content, respectively); Stt4 (the PI4KIIIα orthologue that accounts for the production of 40% and 60% of the total cellular PtdIns(4)P and PtdIns(4,5)P 2 content, respectively); and Lsb6 (the PI4KII orthologue that accounts for the remaining PtdIns(4)P content) (Strahl and Thorner, 2007).Pik1p localises both on cytoplasmic puncta that are positive for the trans-Golgi complex marker Sec7p and in the nucleus (Strahl et al., 2005). The localisation of Pik1p in the nucleus is determined by specific karyopherins that regulate both the nuclear import and export of Pik1p (Strahl et al., 2005). The association of Pik1p to the Golgi complex is instead dependent on its binding to Frq1p, an essential 22-kDa N-myristoylated protein that apparently has Pik1p as its only downstream effector (Hendricks et al., 1999). Yeast cells need both nuclear and Golgi-localized Pik1p for viability, because Pik1p mutants that have a restricted nuclear and Golgi localisation cannot reverse the non-viable phenotype in Pik1Δ cells (Strahl et al., 2005).Interestingly...

Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication

“…However, PIP 2 levels at the membranes supporting replication were unaltered and even decreased along the course of CVB3 infection [20]. Recently, PI4P lipids were demonstrated to have additional important functions in the early secretory pathway through their ability to serve as docking sites for various proteins [24,26]. Consistent with this ability of PI4P, the RNA-dependent RNA polymerase 3D pol of CVB3 was shown to bind preferentially to PI4P lipids over other cellular lipids in vitro [20].…”

“…The purpose of PI4P lipids in enterovirus replication is currently unknown. Under physiological conditions, PI4P lipids were for a long time merely perceived as precursors for the production of PIP 2 and IP 3 in the classical inositol cycle important for intracellular Ca 2+ signaling [24]. However, PIP 2 levels at the membranes supporting replication were unaltered and even decreased along the course of CVB3 infection [20].…”

“…In mammalian cells, PI4P lipids present in the early secretory pathway can be produced by three of the four different isoforms of PI4K, namely PI4KIIα (localized to the Golgi), PI4KIIIα (ER), and PI4KIIIβ (Golgi). PI4KIIβ does not localize to the early secretory pathway, but is situated on the plasma membrane and on endosomes [24,25]. We first investigated which PI4K isoforms are involved in the Golgi-localization of FAPP1-PH-GFP in our cells.…”

“…PI4KIIIβ, another downstream effector of Arf1, catalyzes the synthesis of phosphatidylinositol-4-phosphate (PI4P) lipids in Golgi membranes. These PI4P lipids are not only precursors for the classical inositol cycle important for Ca 2+ signaling cascades, but have recently also been shown to carry out other functions [24][25][26], such as aiding biogenesis and fusion of transport vesicles in the secretory pathway [27,28]. In enterovirus-infected cells, PI4KIIIβ is actively recruited to the replication sites to create a microenvironment rich in PI4P lipids.…”

ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system

“…Phosphatidylinositol 4-kinases (PI4Ks) are a group of lipid kinases that phosphorylate PI to PIP at 4-OH. Mammalian PI4Ks were classified as types II and III based on their sensitivities to two specified inhibitors [21] . The so-called type I PI4Ks were later identified to be PI3K.…”