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Review
. 2023 Sep 1;15(9):a041406.
doi: 10.1101/cshperspect.a041406.

Phosphoinositides in New Spaces

Elizabeth Michele Davies  1 , Christina Anne Mitchell  2 , Harald Alfred Stenmark  3   4
Affiliations
Review

Phosphoinositides in New Spaces

Elizabeth Michele Davies et al. Cold Spring Harb Perspect Biol. .

Abstract

Phosphoinositides (PIs) are phospholipids derived from phosphatidylinositol. PIs are regulated via reversible phosphorylation, which is directed by the opposing actions of PI kinases and phosphatases. PIs constitute a minor fraction of the total cellular lipid pool but play pleiotropic roles in multiple aspects of cell biology. Genetic mutations of PI regulatory enzymes have been identified in rare congenital developmental syndromes, including ciliopathies, and in numerous human diseases, such as cancer and metabolic and neurological disorders. Accordingly, PI regulatory enzymes have been targeted in the design of potential therapeutic interventions for human diseases. Recent advances place PIs as central regulators of membrane dynamics within functionally distinct subcellular compartments. This brief review focuses on the emerging role PIs play in regulating cell signaling within the primary cilium and in directing transfer of molecules at interorganelle membrane contact sites and identifies new roles for PIs in subcellular spaces.

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Figures

Figure 1.
Figure 1.
Subcellular distribution of phosphoinositide (PI) species. PtdIns is synthesized in the endoplasmic reticulum (ER) membrane. PtdIns(4,5)P2 predominantly localizes to the cytoplasmic leaflet of the plasma membrane where it can be transiently phosphorylated to PtdIns(3,4,5)P3 in response to agonist stimulation. PtdIns(3,4)P2 is generated by hydrolysis of PtdIns(3,4,5)P3 by PI 5-phosphatase family members at the plasma membrane or through phosphorylation of PtdIns4P by the class II PI3K during endocytosis. PtdIns4P localizes to the plasma membrane and the Golgi. PtdIns5P localizes to the plasma membrane. PtdIns3P is recruited to early endosomes (EEs) and is phosphorylated to PtdIns(3,5)P2 as endocytic vesicles mature to become late endosomes (LEs) and multivesicular bodies (MVBs). PtdIns(3,5)P2 is also resident on lysosomal membranes. (Created with BioRender.com.)
Figure 2.
Figure 2.
Examples of phosphoinositides in membrane contact sites. (A) Extended synaptotagmins (E-Syts) form membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and the plasma membrane (PM) by binding PtdIns(4,5)P2 at the PM. (B) ORP5 and ORP8 form ER-PM contacts by binding PtdIns4P at the PM, and their oxysterol-binding protein (OSBP)-related domain (ORD) extracts PtdIns4P from the PM and delivers it to the ER where it is dephosphorylated by SAC1. The ORD then brings back phosphatidylserine (PS) from the ER to the PM. (C) OSBP forms ER-Golgi contacts by binding PtdIns4P at the Golgi, and its ORD extracts PtdIns4P from the Golgi and delivers it to the ER where it is dephosphorylated by SAC1. The ORD then brings back cholesterol from the ER to the Golgi. (D) Protrudin forms MCS with an endolysosome by coincident detection of RAB7 and PtdIns3P in the endolysosome membrane. MCS formation triggers delivery of Kinesin-1 to FYCO1, which, like Protrudin, binds to the endolysosome through coincident detection of RAB7 and PtdIns3P. The endolysosome can now detach from the ER and move along microtubules toward the PM, powered by Kinesin-1. (E) Upon damage of the endolysosome, PtdIns4P is produced by PI4K2A, and this triggers recruitment of ORP1L, which delivers cholesterol from ER to the damaged endolysosome, OSBP, which transports PtdIns4P from the endolysosome to the ER, and ORP9, ORP10, and ORP11, which transfer PS and other phospholipids from the ER to the damaged endolysosome. Red arrows indicate lipid extraction, whereas green arrows indicate lipid delivery.
Figure 3.
Figure 3.
Ciliary localization of phosphoinositides (PIs) and their associated kinases and phosphatases. PI 3-kinase (PI3K)-C2α is localized to the pericentriolar recycling endocytic compartment (PRE), where it generates PtdIns3P. PtdIns4P is predominantly localized along the length of the ciliary membrane, while PtdIns(4,5)P2, PtdIns(3,4,5)P3, and PtdIns(3,4)P2 have been identified at the TZ. The PI 5-phosphatase INPP5E has been detected at the TZ and along the length of the cilium. OCRL has been identified at the cilium base and also within the cilium along with INPP5B. PIP5K1C is resident at the basal body. (Created with BioRender.com.)
Figure 4.
Figure 4.
Regulation of PtdIns(4,5)P2 promotes cilia stability. Redistribution of ciliary PtdIns(4,5)P2 to the distal cilium, following INPP5E depletion or ciliary targeting of PIP5K1C, initiates actin polymerization within the cilium, which facilitates membrane remodeling, cilia decapitation, and ectovesicle release, preceding AURKA/HDAC6-dependent microtubule disassembly. Released ectovesicles contain growth-promoting IFT-B components. (Created with BioRender.com.)
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