Nuclear phosphoinositides and their impact on nuclear functions

Abstract

Polyphosphoinositides (PPIn) are important lipid molecules whose levels are de‐regulated in human diseases such as cancer, neurodegenerative disorders and metabolic syndromes. PPIn are synthesized and degraded by an array of kinases, phosphatases and lipases which are localized to various subcellular compartments and are subject to regulation in response to both extra‐ and intracellular cues. Changes in the activities of enzymes that metabolize PPIn lead to changes in the profiles of PPIn in various subcellular compartments. Understanding how subcellular PPIn are regulated and how they affect downstream signaling is critical to understanding their roles in human diseases. PPIn are present in the nucleus, and their levels are changed in response to various stimuli, suggesting that they may serve to regulate specific nuclear functions. However, the lack of nuclear downstream targets has hindered the definition of which pathways nuclear PPIn affect. Over recent years, targeted and global proteomic studies have identified a plethora of potential PPIn‐interacting proteins involved in many aspects of transcription, chromatin remodelling and mRNA maturation, suggesting that PPIn signalling within the nucleus represents a largely unexplored novel layer of complexity in the regulation of nuclear functions.

The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1

“…T he existence of nuclear, nonmembrane pools of signaling phosphorylated derivatives of phosphatidylinositols or phosphoinositides (PIP n ) was reported over two decades ago (1)(2)(3). Consistent with these early reports, lipid-modifying enzymes responsible for phosphoinositide metabolism were also found in the nucleus (4)(5)(6)(7); however, the function of PIP n in this cellular compartment remains poorly defined. The nuclear receptors (NRs) steroidogenic factor 1 (SF-1, NR5A1) and liver receptor homolog 1 (LRH-1, NR5A2) bind phosphoinositides as well as other phospholipids in their large hydrophobic pockets (8)(9)(10)(11)(12)(13).…”

The yeast Pmp3p has a significant role in plasma membrane organization

“…They are products of 3′, 4′ and 5′ phosphorylation on the inositol in all of the possible combinations of the structural lipid phosphatidylinositol. These molecules are localized along the secretory and endocytic pathways, as well as in the nucleus in eukaryotes (Shah et al, 2013). They regulate various structural and developmental functions in all eukaryotic models, such as membrane biogenesis, lipid homeostasis, vesicular trafficking, and cytoskeleton organization and dynamic (D'Angelo et al, 2008;Ischebeck et al, 2010;Saarikangas et al, 2010).…”

Phosphatidylinositol-4-phosphate 5-Kinase 1α Modulates Ribosomal RNA Gene Silencing through Its Interaction with Histone H3 Lysine 9 Trimethylation and Heterochromatin Protein HP1-α

“…Reports from several laboratories have demonstrated the role of PIP 2 in modulating various nuclear functions (3,31). It might be argued that the nuclear presence of PIP5K is obvious to produce PIP 2 .…”

“…PIP5K is a 61-kDa protein migrating at about 68 kDa in SDS-PAGE (2). Although classical phosphoinositide signaling is concentrated in the plasma membrane, recent studies have suggested the presence of a distinct phosphoinositide signaling in the nucleus (3). PIP 2 in the nucleus has been mapped onto detergent-insoluble fractions co-localizing with small nuclear ribonucleoprotein particles in nuclear speckles (4) and at electron-dense structures (5), suggesting its involvement in pre-mRNA processing.…”