Citation: Bura, A.; ˇ Cabrijan, S.; Ðuri´ c, I.; Bruketa, T.; Jurak Begonja, A. A Plethora of Functions Condensed into Tiny Phospholipids: The Story of PI4P and PI(4,5)P 2 . Cells 2023, 12, 1411. https://doi.org/10.3390/ cells12101411 Academic Editor: Smaragdi Antonopoulou Received: 10 April 2023 Revised: 8 May 2023 Accepted: 9 May 2023 Published: 17 May 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cells Review A Plethora of Functions Condensed into Tiny Phospholipids: The Story of PI4P and PI(4,5)P 2 Ana Bura, Sara ˇ Cabrijan, Iris Ðuri´ c , Tea Bruketa and Antonija Jurak Begonja * Laboratory of Hematopoiesis, Department of Biotechnology, University of Rijeka, R. Matejcic 2, 51000 Rijeka, Croatia * Correspondence: ajbegonja@biotech.uniri.hr; Tel.: +385-51-584-581; Fax: +385-51-584-599 Abstract: Phosphoinositides (PIs) are small, phosphorylated lipids that serve many functions in the cell. They regulate endo- and exocytosis, vesicular trafficking, actin reorganization, and cell mobility, and they act as signaling molecules. The most abundant PIs in the cell are phosphatidylinositol- 4-monophosphate (PI4P) and phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ]. PI4P is mostly localized at the Golgi apparatus where it regulates the anterograde trafficking from the Golgi ap- paratus to the plasma membrane (PM), but it also localizes at the PM. On the other hand, the main localization site of PI(4,5)P 2 is the PM where it regulates the formation of endocytic vesicles. The levels of PIs are regulated by many kinases and phosphatases. Four main kinases phosphorylate the precursor molecule phosphatidylinositol into PI4P, divided into two classes (PI4KIIα, PI4KIIβ, PI4KIIIα, and PI4KIIIβ), and three main kinases phosphorylate PI4P to form PI(4,5)P 2 (PI4P5KIα, PI4P5KIβ, and PI4P5KIγ). In this review, we discuss the localization and function of the kinases that produce PI4P and PI(4,5)P 2 , as well as the localization and function of their product molecules with an overview of tools for the detection of these PIs. Keywords: phosphatidylinositol-4-monophosphate; phosphatidylinositol-4,5-bisphosphate; trafficking; Golgi apparatus; plasma membrane; PI4K; PI4P5KI 1. Introduction Phospholipids are abundant, complex, and highly diverse components of cell architec- ture [1]. In addition to their main function as membrane building blocks, phospholipids have also been shown to be involved in intracellular trafficking and signal transduction, thus having a more dynamic role in cellular physiology [2]. A type of low-abundant phospholipids, called phosphoinositides (PIs), in addition to being a component of the cell membranes, interact with numerous effector proteins and were shown to serve as either signaling molecules themselves or to generate secondary messengers within different cells [3]. To date, PIs have been shown to serve important functions in processes such as cytoskeleton reorganization and membrane curvature generation upon endo-, exo-, or phagocytosis [4,5], polarized cell migration [6,7], cell adhesion [5,8,9], cellular transport uti- lizing either ion channels [5], concentration gradient, or protein and lipid transfer proteins, as well as receptor-mediated signaling [10–12] and gene expression [13]. Despite the range of different PI-dependent cellular processes, the extending spectra of evidence confirming the role of PIs in various physiological and pathophysiological states still manage both to surprise and excite the scientific community. PI metabolism is strictly spatially and temporally controlled by a pool of different kinases, phosphatases, and phospholipases, maintaining their levels and determining multiple aspects of cellular fate [8]. A recent mathematical model predicts that there are 19 kinases and 35 phosphatases involved in the PI pathway alone [14,15]. The distorted homeostasis in PI metabolism was shown to be involved in neurodegeneration [11,16] and neuroinflammation [17], oncogenesis [4,18], infection [19,20], and immune response [21,22]. In this review, we highlight the localization, Cells 2023, 12, 1411. https://doi.org/10.3390/cells12101411 https://www.mdpi.com/journal/cells